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Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2, IDH1/2, ASXL1, and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.

Background: The use of HCT to treat older (≥60 years) patients with hematological malignancies has markedly increased in recent years, however, the long-term effects of HCT on distress, psychosocial functioning, and HQOL in older HCT survivors is largely unknown. Though older HCT survivors have a higher risk of disease recurrence, they may have less access to resources and subsequently experience more pronounced late effects of disease and treatment. Confidence in Survivorship Information (CSI) in this specific age group has not been reported. Methods: We conducted a secondary analysis on a subgroup of patients enrolled in INSPIRE (NCT01602211) and PCORI-SCP (NCT02200133) clinical trials. Eligibility criteria for inclusion include HCT patients who were ≥ 60 years at time of transplant performed in 2003-2014, survived ≥ 1 year post-transplant with no evidence of disease relapse or secondary cancers. Patients were eligible for inclusion irrespective of transplant type (autologous or allogeneic), diagnosis, donor source or conditioning regimen. Primary endpoint was distress level in older HCT survivors; secondary endpoints included CSI and HQOL outcomes. We collected baseline distress level as measured by Cancer and Treatment Distress (CTXD) score, HQOL (measured by SF-12 Mental and Physical Component Summaries (PCS/MCS) and CSI (measured by a 15-item CSI questionnaire). Sociodemographic, disease and transplant factors were extracted from medical databases. Nonparametric (Wilcoxon rank sum/Kruskal-Wallis) test was conducted for comparing 2 or 3 groups. Spearman correlation and univariate linear regression model were used to evaluate associations between CTXD/CSI and PCS/MCS. Bonferroni correlation was used to adjust for multiple pairwise comparisons within age group. Results: A total of 567 patients satisfied the eligibility criteria and were included in this analysis. Median age at time of HCT was 69 years with 57% male; two-thirds were autologous HCT recipients. Table 1 details patient characteristics. The median CTXD score for older HCT survivors was 0.7 (range 0-2.7, SD 0.6) indicating low/insignificant level of distress post-HCT. 20-30% of HCT survivors reported moderate distress when asked about concerns regarding relapse risk, loss of energy and functional decline. Type of transplant (auto vs allo), age group ( 2 years) showed no apparent effect on reported distress level. CSI median score was 1.4 (range 0-2) which remains consistent with the score reported previously by the original trial including all age groups, indicating that older HCT survivors may have similar level of confidence in their survivorship information as their younger counterparts. Of note, close to 20% of the older HCT survivors reported poor CSI when asked about strategies for prevention and treatment of long-term effects of HCT and when asked about their confidence in availability of community resources to deal with long-term HCT complications. No statistically significant correlation was identified between CSI in older survivors and transplant type, time from HCT, or age group. HQOL outcomes indicated a median PCS of 48.2 (range 21.1 - 62.9) and a median MCS of 54.7 (range of 14.9 - 67.2). Interestingly, even though not reflected on the overall median CTXD and CSI scores for this cohort, a significant individual association between CTXD/CSI and PCS/MCS measures of HQOL was found (Figure 1). A subgroup analysis conducted on older alloHCT recipients confirmed the same findings of clinically insignificant distress level (mean CTXD ≤1.1) while having a similar level of CSI when compared to all age groups. Interestingly, time from HCT (≤2 years vs > 2 years) showed no significant effect on distress level reported by older alloHCT survivors, and cGVHD status did not correlate with CTXD or CSI scores nor with PCS/MCS in older alloHCT survivors. Conclusion: This is the largest study to date to investigate patient-reported distress, CSI and HQOL in older HCT survivors. Our data indicate that older HCT survivors have low levels of stress after HCT and had confidence in survivorship information in most aspects of their care. However, targeted interventions should focus on improving strategies for prevention, treatment and availability of community resources to deal with late effects of HCT; aspects reported as points of low CSI by older HCT survivors. Figure 1 Figure 1. Disclosures Farhadfar: Incyte: Consultancy. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Devine: Be the Match: Current Employment; Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy. Wingard: Merck: Consultancy; AlloVir: Consultancy; Celgene: Consultancy; Shire: Consultancy; Janssen: Consultancy; Cidara Therapeutics: Consultancy.

Background: Hematopoietic cell transplantation (HCT) survivors have a complex and multiphase recovery period. Health care delivery and psychosocial interventions for HCT survivors are challenging as many HCT recipients live great distances from the facility where they had their HCT. Therefore, identifying factors associated with a patient's capability to self-manage symptoms is an important focus of survivorship research. A patient's self-efficacy may be important for the successful management of major stressors associated with treatments and recovery. Here, we aimed to evaluate the impact of perceived self-efficacy on distress, quality of life (QoL), depression, and fatigue, and identify the factors associated with lower self-efficacy. Methods: This cross-sectional study analyzed baseline data from a randomized controlled internet based self-management intervention trial (INSPIRE, NCT01602211) in adult (age 18 and older) survivors 2-10 years post HCT. Patients with recurrence or subsequent malignancy requiring cancer treatment during the two years prior to enrollment, inability to read and understand English and lack of access to email and the Internet were excluded. Data included medical records and patient-reported outcomes (PROs) including Cancer and Treatment Distress (CTXD) with 6 subscales, Patient Health Questionnaire depression scale (PHQ-8), Short Form 12 Health Survey (SF-12) physical function (PCS) and mental function (MCS) scores, Brief Fatigue Inventory (BFI) and Health Self-Efficacy. Pearson correlations were used to test bivariate associations for self-efficacy with CTXD, SF-12, BFI, and PHQ8. General linear models were used to test the independent association for CTXD and SF-12 outcomes with self-efficacy, controlling for selected sociodemographic and treatment covariates. Tenability of statistical model assumptions were examined, and no remediation was necessary. Results: Total of 1078 HCT survivors were included in the analysis. Participants were 18 to 76 years (mean age 51), 53% male, and over 90% white and non-Hispanic. Only 16% reported living in a rural area. A majority received an autologous HCT (55%) and were less than 5 years from their first HCT (54%). Among the allogeneic HCT recipients, more than half (60%) had active chronic Graft-versus-Host (cGVHD) and nearly 40% were on active systemic treatment. The mean self-efficacy score was 3.01 (SD 0.49). Female gender (p=0.014), younger age at HCT, younger age at cGVHD presentation, moderate to severe currently active cGVHD (p=0.003) and household income less than $40,000 (p < 0.001) were associated with lower self-efficacy. In bivariate analyses, self-efficacy was negatively correlated with mean total CTXD (r -0.5, p In a regression model investigating the impact of self-efficacy on CTXD controlled for demographics and disease characteristics , lower self-efficacy was independently associated with higher CTXD (beta -0.232; 95% CI (-0.294, -0.169), p< 0.001) (Table 1). Moreover, there was a significant positive relationship between self-efficacy and both mental (beta 4.68; 95% CI (3.82, 5.54); p Conclusion: Our study demonstrates that lower levels of self-efficacy reported by HCT survivors was independently associated with higher levels of symptoms such as fatigue and depression, lower QoL, and more cancer -related distress. Furthermore, self-efficacy is more likely to be impaired in females, younger adults, those with lower incomes, and survivors with active cGVHD. These findings support the value of self-management interventions focused on improving self-efficacy as having the potential to improve multiple symptoms and QoL in HCT survivors. Figure 1 Figure 1. Disclosures Farhadfar: Incyte: Consultancy. Jim: RedHill Biopharma: Consultancy; Janssen Scientific Affairs: Consultancy; Merck: Consultancy; Kite pharma: Research Funding. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy. Wingard: Merck: Consultancy; AlloVir: Consultancy; Celgene: Consultancy; Shire: Consultancy; Janssen: Consultancy; Cidara Therapeutics: Consultancy.

Introduction: The adverse events associated with hematopoietic stem cell donation have been extensively studied. There is an increasing literature linking psychological factors including stress, anxiety and depression to higher levels of inflammatory burden leading to poorer post-procedural outcomes including longer hospital stays and increased pain perception. Here, we aimed to evaluate whether pre-donation health related quality of life (HRQoL) markers predict toxicity profile and stem cell yield following stem cell donation in healthy donors. Methods: The study population included adult granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell (PBSC) related donors (RD) (n= 157) and unrelated donors (URD) (n=179) who were enrolled in Related Donor Safety Study (RDSafe) and Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 clinical trials. Pre-donation HR QoL was assessed using the Short-Form (SF-8) in RDSafe and SF-12 questionnaire in BMT CTN 0201 (higher score is better). Pain and toxicity were collected on study specific forms. The primary outcome was the incidence of skeletal pain on day 5 of G-CSF administration. The secondary outcomes were the incidence of skeletal pain and highest toxicity level across selected body symptoms at 1 month, 6 months and 1-year post-donation. Another secondary outcome included CD34+ per liter of blood processed (x10 6/L) on day 5 of G-CSF as a measure of collection yield. The association between pre-apheresis HRQOL measures and pain and acute toxicities was characterized using means and SDs and compared using the t-test. Association between HRQoL and cell yield was assessed using the Pearson correlation coefficient. RD and URD were analyzed separately. Results: URDs were younger than RDs (median age 35 vs. 63). A higher proportion of RDs were female (50% vs. 40%) and obese (41% vs. 35%). A higher proportion of RD PBSC donations required 2 days or more (44% vs 21%). More RDs were collected with lower volume procedures ( The mean pre-donation physical component summary (PCS) and mental component summary (MCS) score of RDs were 54.5 (SD 7.0) and 55.1 (SD 5.8), respectively . In the univariate analysis (table 1), pre-donation lower PCS score of RDs was associated with significantly more grade 2-4 pain at 1 month (p=0.0038) and 1-year post-donation (p=0.0099) (Table 1). In multivariable analysis (table 2), pre-donation PCS remained significantly associated with grade 2-4 pain 1-month post-donation (p=0.0098). More specifically, RDs with pre-donation PCS scores in the higher quartile were less likely to experience pain compared with donors with PCS scores in the lower quartile (OR 0.1; 95% CI 0.01-0.83; p=0.005). There was also a trend toward increased grade 2-4 pain at 1-year post-donation among RDs with lower PCS score (p=0.0176). Other outcomes such as pain at day 5 of G-CSF, other toxicities at day 5 of G-CSF, 1 month, 6 months and 1-year post-donation were not associated with pre-donation PCS score. Similarly, there was no significant association between RD pre-donation MCS score and collection-related symptoms at any time point. The mean pre-donation PCS and MCS scores of URDs were 56.2 (SD 4.7) and 54.5 (SD 5.5), respectively . In a univariate analysis, there was no association between PCS score or MCS score and donation associated pain and toxicities at any time point post-donation. Due to low event rates, multivariable analysis was not performed in the URD setting. Based on the multivariable regression analysis, there was no correlation between pre-apheresis HRQoL score (PCS or MSC) and PBSC collection yield in either the RD or URD setting. Conclusion: Our study demonstrates that pre-donation QoL markers are significantly associated with the toxicity profile after PBSC donation in the RD setting as adult RD with lower pre-donation physical QOL experience increased levels of pain after a PBSC collection procedure. There were no such associations found in URD in this small sample. Our findings may help clinicians to identify donors at higher risk of pain with donation, and lead to personalized information and interventions (e.g. increased analgesia) for specific donors. Future study with a larger sample is required to validate the results. Figure 1 Figure 1. Disclosures Farhadfar: Incyte: Consultancy. Stefanski: Novartis: Honoraria. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

Background: AlloHCT survivors generally report higher rates of cancer- and treatment-related distress compared to the general population, although data on cancer and treatment Distress (CTXD) and Confidence in Survivorship Information (CSI) in older alloHCT recipients are limited. We have reported that older HCT survivors have generally low levels of distress and intermediate-high level of CSI (Al-Mansour et al, abstract submitted to ASH 2021 meeting). In this study, we describe specific distress and CSI concerns reported by older alloHCT survivors and their association with other patient-reported outcomes and transplant-related factors. Methods: This cross-sectional retrospective secondary analysis used baseline data from two randomized controlled trials of survivorship interventions in alloHCT recipients enrolled in 18 US transplant centers (combined dataset from survivorship care plan trial [NCT00799461] and internet based self-management intervention trial [NCT01602211]). A total of 181 enrolled patients transplanted from 2003-2014 were ≥60 years of age at alloHCT and were alive and disease-free at ≥1-year post-transplant. All donor and graft types were included in this analysis. Distress was measured by CTXD scale, in which higher values indicate higher levels of distress. Survivorship confidence was based on the CSI questionnaire, in which higher values indicate greater confidence. Health-related quality of life (HQOL) was assessed with the SF-12, with high scores indicating better physical function (PCS) and mental function (MCS). Clinical and sociodemographic variables were summarized in descriptive statistics. Non-parametric test (Wilcoxon rank sum test / Kruskal-Wallis test) was conducted for comparing two or three groups for CTXD/CSI. Spearman correlation and univariate linear regression model were used to evaluate associations between CTXD/CSI and PCS/MCS. Bonferroni correlation was used to adjust for multiple pairwise comparisons within age group at transplant. Results: The median age of this older sample at alloHCT was 64 (range 60-81), with the largest proportions non-Hispanic (96%), White (97%), and males (57%). The majority received peripheral blood grafts (88%) from an unrelated donor (65%) for their first (96%) transplant. At the time of the survey, survivors were at a median of 3 years (range 1-9) from alloHCT. Mean CTXD overall score was 0.85 (standard deviation [SD] 0.44). Among CTXD items, highest distress was reported for "low energy" (mean 1.42, SD 0.97) followed by "feeling tired and worn out" (mean 1.32, SD 0.93) and "not being able to do what I used to do" (mean 1.28, SD 0.98), while the lowest distress was reported for "communication with medical people"(mean 0.32, SD 0.66) and "getting information when I need it" (mean 0.39, SD 0.70; Figure 1). Similarly, mean CSI overall score was 1.39 (SD 0.44) in this Among CSI items, information on "disease treated" (mean 1.79, SD 0.41) scored the highest in confidence level followed by "treatment received for transplant" (mean 1.75, SD 0.46); meanwhile, information on "community resources for long-term effects of disease" (mean 1.14, SD 0.72) followed by "strategies for treating long-term physical effects of your treatment" (mean 1.15, SD 0.71) scored the lowest in confidence level (Figure 2). There were negative correlations between CTXD and PCS/MCS (P2 years) showed no apparent effect on CTXD or CSI overall scores. Conclusion: Older alloHCT survivors report low level of cancer- and treatment-related distress and a relatively high level of CSI. Physical and mental function were associated with lower distress and increased CSI. Survivorship intervention needs in older alloHCT recipients include management of fatigue, education on long-term effects, and improving knowledge of and access to resources for long-term recovery and reintegration to society. The CTXD and CSI scales provide opportunities to evaluate and tailor interventions to the needs of older survivors with the potential to improve alloHCT survivorship care for older adults. Figure 1 Figure 1. Disclosures Hong: Adaptive Biotechnology: Other: Current employment of my spouse. Farhadfar: Incyte: Consultancy. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Devine: Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Tmunity: Current Employment, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Kiadis: Consultancy, Research Funding. Wingard: Merck: Consultancy; AlloVir: Consultancy; Celgene: Consultancy; Shire: Consultancy; Janssen: Consultancy; Cidara Therapeutics: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Introduction: Cryopreservation of peripheral blood stem cell (PBSC) or bone marrow (BM) grafts is rarely performed, thus information about the effect of cryopreservation on graft characteristics and HCT outcomes is limited. Given the global pandemic leading to changing practices for donor graft collection and increasing utilization of cryopreservation, we evaluated the outcomes of HCT recipients who received either fresh or cryopreserved allogeneic BM or PBSC grafts. The primary endpoint was engraftment. Secondary endpoints were incidence of acute graft-vs.-host disease (aGVHD), relapse, transplant related mortality (TRM), disease free survival (DFS), and overall survival (OS). Methods: We included 7397 patients transplanted between 2013 and 2018. 1883 cryopreserved graft recipients were divided into three cohorts based on graft source and donor type: matched related (MRD) PBSC (n=1,051), matched unrelated (MUD) PBSC (n=678), and matched related or unrelated bone marrow donors (n=154). All patients received conventional calcineurin-based GVHD prophylaxis strategies. Patients who received cryopreserved grafts were matched with 5514 patients who received fresh adjusting for graft type (BM vs. PB), donor source (MRD vs. 8/8 MUD), Disease Risk Index (DRI, low risk vs. intermediate risk vs. high risk), recipient age (within 5-years) and propensity score (within 1 standard deviation from pooled sample). The propensity score was based on age, Karnofsky score, diagnosis, disease risk index, HCT-comorbidity index, and conditioning intensity. The level of statistical significance for the main analyses was p Results: Baseline characteristics for all cohorts are shown in Table 1. CD34+ doses reflect enumeration at infusion. In univariate analyses, rates of graft failure and neutrophil recovery at day 28 were similar for cryopreserved and fresh grafts for BM or related PBSC recipients but differed in cryopreserved vs. fresh MUD PBSC (5% vs 2%, p Conclusions: The retrospective nature of this analysis, and the fact that cryopreservation is likely to have been performed in recipients with a different (higher) risk profile compared to those receiving fresh products limits our ability to draw firm confusions. Despite these limitations, we conclude that cryopreservation in some patient populations may have a negative impact on engraftment and transplant outcomes. The decision to cryopreserve donor grafts, particularly PBSC grafts, should be carefully considered and highlights the need for further investigation of the effect of cryopreservation of allogeneic grafts where patient factors can be controlled for. Disclosures Farhadfar: CSL Behring: Research Funding; Incyte pharmaceutical: Other: Member of GVHD advisory forum. Frey:Kite Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Devine:Magenta Therapeutics: Consultancy. Shaw:Orca Bio: Consultancy. Wingard:Shire: Other: Personal Fees - serve on data monitoring committee for clinical trial; Ansun: Other: Personal Fees - serve on data monitoring committee for clinical trial; Merck: Other: Personal Fees - serve on data monitoring committee for clinical trial; Cidara: Other: Personal Fees - serve on data monitoring committee for clinical trial; ReViral: Other: Personal Fees - serve on data monitoring committee for clinical trial.

Introduction: Acute GVHD (aGVHD) contributes to poor outcomes and increased healthcare resource utilization (HRU) after allogeneic stem cell transplantation (allo-HCT). However, HRU and the economic burden of aGVHD based on severity of the disease and organ involvement is not well characterized. We examined the HRU, cost and mortality associated with aGVHD severity from initial hospitalization (index admission) up to 100 days post allo-HCT. Methods: Study cohort included 290 adult (≥ age 18) recipients of a first allo-HCT at the University of Florida between 1/2010 and 1/2019. The electronic medical records were reviewed for all patients who developed aGVHD as well as 116 patients without aGVHD who lived at least 1 month after HCT. Clinical measures that characterize the severity of aGVHD and extent of organ involvement were collected from electronic medical records. Medical costs and total hospital days were retrieved from administrative data that allocate costs to services based on departmental input for resource use and were adjusted to 2018 dollars. Wilcoxon rank sum test was used to compare number of inpatient days and total cost. Chi-squared test was used to compare ICU admission rate. Multivariable linear regression was fitted on log transformed cost. Results are shown as cost multipliers that represent ratios on original cost scale. Results: Of the 290 patients, 174 developed aGVHD within 100 days of allo-HCT. A higher proportion of patients with aGVHD had a Karnofsky performance status Development of aGVHD was associated with a significantly higher total (inpatient and outpatient) cost. The mean total cost for patients with and without aGVHD were $226,545 and $165,622, respectively (P Conclusion: HRU, cost, and clinical outcomes were associated with the severity of aGVHD. Development of higher grades of aGVHD and LGI aGVHD were associated with a poor clinical outcome and considerably increased healthcare economic burden. Given these clinical and economic risks it is imperative that new therapeutic strategies are developed for this patient population. Disclosures Farhadfar: Incyte pharmaceutical: Other: Member of GVHD advisory forum; CSL Behring: Research Funding. Leather:CSL Behring: Research Funding. Itzler:CSL Behring: Current Employment, Current equity holder in private company. Wingard:CSL Behring: Research Funding.

In the absence of prospective studies that examine the effect of conditioning regimen intensity after T-cell–replete haploidentical transplant for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS), a retrospective cohort analysis was performed. Of the 1325 eligible patients (AML, n = 818; ALL, n = 286; and MDS, n = 221), 526 patients received a myeloablative regimen and 799 received a reduced-intensity regimen. Graft-versus-host disease prophylaxis was uniform with posttransplant cyclophosphamide, a calcineurin inhibitor, and mycophenolate mofetil. The primary end point was disease-free survival. Cox regression models were built to study the effect of conditioning regimen intensity on transplant outcomes. For patients aged 18 to 54 years, disease-free survival was lower (hazard ratio [HR], 1.34; 42% vs 51%; P = .007) and relapse was higher (HR, 1.51; 44% vs 33%; P = .001) with a reduced-intensity regimen compared with a myeloablative regimen. Nonrelapse mortality did not differ according to regimen intensity. For patients aged 55 to 70 years, disease-free survival (HR, 0.97; 37% vs 43%; P = .83) and relapse (HR, 1.32; 42% vs 31%; P = .11) did not differ according to regimen intensity. Nonrelapse mortality was lower with reduced-intensity regimens (HR, 0.64; 20% vs 31%; P = .02). Myeloablative regimens are preferred for AML, ALL, and MDS; reduced-intensity regimens should be reserved for those unable to tolerate myeloablation.

Allogeneic hematopoietic cell transplant (allo-HCT) can be curative for certain hematologic malignancies, but the risk of graft-versus-host disease (GVHD) is a major limitation for wider application. Ideally, strategies to improve allo-HCT would involve suppression of T lymphocytes that drive GVHD while sparing those that mediate graft-versus-malignancy (GVM). Recently, using a xenograft model, we serendipitously discovered that myxoma virus (MYXV) prevented GVHD while permitting GVM. In this study, we show that MYXV binds to resting, primary human T lymphocytes but will only proceed into active virus infection after the T cells receive activation signals. MYXV-infected T lymphocytes exhibited impaired proliferation after activation with reduced expression of interferon-γ, interleukin-2 (IL-2), and soluble IL-2Rα, but did not affect expression of IL-4 and IL-10. MYXV suppressed T-cell proliferation in 2 patterns (full vs partial) depending on the donor. In terms of GVM, we show that MYXV-infected activated human T lymphocytes effectively deliver live oncolytic virus to human multiple myeloma cells, thus augmenting GVM by transfer of active oncolytic virus to residual cancer cells. Given this dual capacity of reducing GVHD plus increasing the antineoplastic effectiveness of GVM, ex vivo virotherapy with MYXV may be a promising clinical adjunct to allo-HCT regimens.

In this issue of Blood , Haak et al describe an association between the abundance of butyrate-producing intestinal bacteria early after allogeneic hematopoietic cell transplantation (HCT) and the subsequent occurrence of lower respiratory tract viral infections during the first 6 months after transplant. 1

Introduction Long-term hematopoietic stem cell transplant (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population, yet no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guidelines for Americans (DGA), specifically designed to provide guidance for making healthy food choices. The aims of this study were to evaluate the extent to which HCT survivors adhere to the DGA and to determine nutrient intake adequacy. A secondary aim was to assess their willingness to take part in a future nutritional program or dietary intervention. Methods The study population included adults (≥18 y), who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1-year post-transplantation. Dietary intake was assessed using the Block 2014 food frequency questionnaire and diet quality (adherence to the DGA) was estimated using the Healthy Eating Index-2015 (HEI-2015). A HEI score of ≤50 indicates "poor diet quality", 51-80 suggests a "diet that needs improvement", and >81 indicates "good diet quality" out of maximum of 100. HEI-2015 scores by patient and transplant characteristics were analyzed by ANCOVA. Nutrient intake adequacies of the group were estimated by determining the percentage of the group falling below the Estimated Average Requirement (EAR) of the Dietary Reference Intakes. Receptivity to participate in a dietary intervention to stay healthy was measured by the question, "How willing would you be to take part in a healthy nutrition program or diet intervention?" Response categories included, "not at all," "somewhat," and "definitely". Results Between December 2017 and September 2018, 124 survivors were invited to participate, of whom 90 (51 autologous and 39 allogeneic HCT survivors) completed the dietary intake assessment and were included in the analysis. Majority were male (56%), White (72%), married (81%) and completed some college education (57%). Most participants were overweight (34%) or obese (37%). The median time from the HCT was 5.2 years. Mean ±SE HEI-2015 scores were 61.6 ± 1.3 and 60.7 ± 2.2 for the 18-64 y and ≥65 y age groups, respectively, slightly higher than the US general population. Adherence to a good quality diet was reported by only 10% of survivors. The majority of the survivors reported a diet in need of improvement (82%) or a poor-quality diet (8%). Intakes of vitamin A (720 ± 447 mcg/d), vitamin C (82 ± 73 mg/d), vitamin D (4.4 ± 3.4 mcg/d), magnesium (253 ± 133 mg/d), and calcium (781 ± 430 mg/d) suggested inadequacy, as more than 50% of the group fell below the specific EARs. Sodium intake at 2834 ± 1345 mg/d exceeded the DGA recommendation of 2300 mg/d. Fiber intake at 8.9 g per 1000 kcal/d was significantly below the Adequate Intake of 14 g per 1000 kcal/d. "Change in taste" was the only variable associated with lower quality of diet (p=0.02). Interestingly, 29% of HCT survivors reported persistent altered taste sensation. No significant relationships were seen for participant's demographics and diet quality which may be due to a sample population skewed toward older, causations and socioeconomically advantaged individuals. More than two thirds of participants (73%) indicated an interest in participating in dietary intervention. HCT survivors within 2 years of transplant were more likely to be receptive to participation in a diet intervention study compared to survivors beyond 2 years (52% vs 28%, p=0.0013). Conclusion Adult HCT survivors report poor adherence to the 2015 Dietary Guidelines for Americans and have numerous short-fall nutrient intakes. However, the willingness to participate in a nutritional program or dietary intervention in this survivorship population was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care. Disclosures Wingard: Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy; Ansun: Consultancy; Pluristem: Consultancy.

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR>90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.

Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity.

Single-center studies have reported an association between early (before day 100) cytomegalovirus (CMV) reactivation and decreased incidence of relapse for acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation. To substantiate these preliminary findings, the Center for International Blood and Marrow Transplant Research (CIBMTR) Database was interrogated to analyze the impact of CMV reactivation on hematologic disease relapse in the current era. Data from 9469 patients transplanted with bone marrow or peripheral blood between 2003 and 2010 were analyzed according to 4 disease categories: AML (n = 5310); acute lymphoblastic leukemia (ALL, n = 1883); chronic myeloid leukemia (CML, n = 1079); and myelodysplastic syndrome (MDS, n = 1197). Median time to initial CMV reactivation was 41 days (range, 1-362 days). CMV reactivation had no preventive effect on hematologic disease relapse irrespective of diagnosis. Moreover, CMV reactivation was associated with higher nonrelapse mortality [relative risk [RR] among disease categories ranged from 1.61 to 1.95 and P values from .0002 to

Pulmonary nodules and nodular infiltrates occur frequently during treatment of hematologic malignancies and after hematopoietic cell transplantation. In patients not receiving active immunosuppressive therapy, the most likely culprits are primary lung cancer, chronic infectious or inactive granulomata, or even the underlying hematologic disease itself (especially in patients with lymphoma). In patients receiving active therapy or who are otherwise highly immunosuppressed, there is a wider spectrum of etiologies with infection being most likely, especially by bacteria and fungi. Characterization of the pulmonary lesion by high-resolution CT imaging is a crucial first diagnostic step. Other noninvasive tests can often be useful, but invasive testing by bronchoscopic evaluation or acquisition of tissue by one of several biopsy techniques should be performed for those at risk for malignancy or invasive infection unless contraindicated. The choice of the optimal biopsy technique should be individualized, guided by location of the lesion, suspected etiology, skill and experience of the diagnostic team, procedural risk of complications, and patient status. Although presumptive therapy targeting the most likely etiology is justified in patients suspected of serious infection while evaluation proceeds, a structured evaluation to determine the specific etiology is recommended. Interdisciplinary teamwork is highly desirable to optimize diagnosis and therapy.

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Risks of secondary solid cancers among allogeneic hematopoietic cell transplant (HCT) recipients who receive conditioning without total body irradiation are not well known. We evaluated the incidence and risk factors for solid cancers after HCT using high-dose busulfan-cyclophosphamide conditioning in 4318 recipients of first allogeneic HCT for acute myeloid leukemia in first complete remission (N = 1742) and chronic myeloid leukemia in first chronic phase (N = 2576). Our cohort represented 22 041 person-years at risk. Sixty-six solid cancers were reported at a median of 6 years after HCT. The cumulative-incidence of solid cancers at 5 and 10 years after HCT was 0.6% and 1.2% among acute myeloid leukemia and 0.9% and 2.4% among chronic myeloid leukemia patients. In comparison to general population incidence rates, HCT recipients had 1.4× higher than expected rate of invasive solid cancers (95% confidence interval, 1.08-1.79, P = .01). Significantly elevated risks were observed for tumors of the oral cavity, esophagus, lung, soft tissue, and brain. Chronic graft-versus-host disease was an independent risk factor for all solid cancers, and especially cancers of the oral cavity. Recipients of allogeneic HCT using busulfan-cyclophosphamide conditioning are at risk for developing solid cancers. Their incidence continues to increase with time, and lifelong cancer surveillance is warranted in this population.

The significance of conditioning regimen intensity on the outcomes of T-cell replete HLA-haploidentical transplants is not known. This study compared outcomes of commonly used myeloablative (MAC) to reduced intensity (RIC) conditioning regimens in 1325 such transplants (AML; n=818; ALL; n=286 and MDS; n=221) in the US between 2008 and 2016. The median age of the study population was 54 years (18 - 70). Most patients (80%) with AML and ALL were in first or subsequent remission; 83% of those with MDS had refractory anemia with excess blasts at transplantation. Fifty-one percent of patients with AML and ALL had intermediate disease risk index (DRI). In contrast, 50% of patients with MDS had high or very high DRI. Patients received MAC (n=526; 40%) or RIC (n=799; 60%) transplant conditioning regimens and a uniform graft-versus-host disease (GVHD) prophylaxis: post-transplant cyclophosphamide, calcineurin inhibitor and mycophenolate. Approximately 50% of patients reported a HCT-CI score of 0-2 in MAC and RIC groups. Sixty-six percent of MAC and 42% of RIC recipients received peripheral blood grafts. Total body irradiation (TBI) + fludarabine (TBI/Flu; 33%) and busulfan with cyclophosphamide with/without Flu (Bu/Cy ± Flu; 36%) were the predominant MAC regimens. Other MAC regimens included TBI/Cy or other agents (10%), Flu/Bu4 (13%), melphalan (140 mg/m2) + Flu ± thiotepa (Flu/Mel ± TT; 9%). TBI (200cGy)/Cy/Flu (84%) was the predominant RIC regimen. Other RIC regimens included TBI 200cGy + Bu or Mel + Flu (7%), Flu/Bu2 (1%) and Flu/Mel (100mg/m2) ± TT (5mg/kg) (8%). The primary endpoint was disease-free survival (relapse or death). Cox regression models were built to study the effect of conditioning regimens on transplant outcomes after adjusting for other factors significantly associated with outcomes. Differences in transplant-outcomes were observed between ages 18-54 years and 55-70 years. The effect of age was further tested within the 18-54 and 55-70 age groups and there were no differences in outcome. In patients aged 18-54 years (n=689), 55% received MAC and 54% received RIC regimens. In patients aged 55-70 years (n=636), 22% received MAC and 78% received RIC regimens. Table 1 shows the effect (hazard ratio; HR) of conditioning regimen intensity in the two age groups adjusted for HCT-CI, recipient CMV serostatus, disease, DRI and graft type and the 2-year probabilities for the outcomes of interest. In patients aged 18-54 years who were equally likely to receive MAC or RIC regimens, relapse risks were higher after RIC regimens that resulted in lower disease-free survival. There were no differences in non-relapse mortality (NRM) or overall survival by conditioning regimen intensity. In patients aged 55-70 years who were more likely to receive RIC regimen, NRM was lower after RIC but without an advantage for relapse, disease-free or overall survival. Figure 1A and 1B show the 2-year probability of disease-free survival by conditioning regimen intensity in patients aged 18-54 and 55-70 years, respectively. Consistent with the main analysis, a subset analysis limited to AML also confirmed higher relapse (HR 1.43, p=0.03) and lower disease-free survival (HR 1.38, p=0.02) after RIC regimens in patients aged 18-54 years but not in patients aged 55-70 years. Acute GVHD (HR 1.01, p=0.94) and chronic GVHD (HR 0.82, p=0.14) did not differ by conditioning regimen intensity. Table 2 compares the effect of TBI- and non-TBI containing MAC and RIC regimens adjusted for age, HCT-CI, recipient CMV serostatus, disease, DRI and graft type. NRM risks were higher after RIC non-TBI compared to RIC TBI regimens. The predominant RIC non-TBI regimen was Flu/Mel (100mg/m2) ± TT (5mg/kg). In conclusion, a MAC regimen offers higher disease-free survival for those aged 18-54 years and can tolerate MAC regimens. For patients who are unable to tolerate MAC regimens, regardless of their age, TBI200 cGy/Cy/Flu is preferred to Flu/Mel ± TT to minimize NRM risks. Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Exelexis: Equity Ownership; Geron: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Oncosec: Equity Ownership. Brunstein:Gamidacell: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Hamadani:Celgene Corporation: Consultancy; Merck: Research Funding; Janssen: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Cellerant: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding. McGuirk:Gamida Cell: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding. Vasu:Boehringer Ingelheim Inc: Membership on an entity's Board of Directors or advisory committees. Waller:Pharmacyclics: Other: Travel Expenses, EHA, Research Funding; Cambium Medical Technologies: Consultancy, Equity Ownership; Celldex: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kalytera: Consultancy.

Introduction. There is little information on the effect of donor body mass index (BMI) on mobilization response to Filgrastim (G-CSF), especially in the unrelated donor setting. Obesity has been associated with chronic low-grade inflammation due to chronic activation of the innate immune system. Obesity-induced pro-inflammatory cytokines can interfere with bone marrow SDF1/CXCR4 axis and promote mobilization of progenitor cells leading to persistent leukocytosis and an increase in number of circulating progenitor cells. Given a higher number of circulatory progenitor cells in obese individuals compared to non-obese, a reduced G-CSF dose in obese donors may elicit adequate response, thus reducing the adverse events associated with peripheral blood stem cell (PBSC) collection. The aim of this study is to evaluate the impact of donor BMI on G-CSF mobilized peripheral blood progenitor cell yield in healthy donors. This study also examines whether there is a G-CSF dose threshold above which there is a significant increase in skeletal pain and other acute toxicities from mobilization without an appreciable increase in progenitor cell yield. Methods. The primary outcome was examination of CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF administration as a measure of collection yield. The secondary outcomes were the incidence of skeletal pain and highest toxicity level across selected body symptoms (fatigue, nausea, anorexia, insomnia, dizziness) at 24 hours after first G-CSF dose, day 1 to 5 of G-CSF administration, 2 days and 1-week post collection. The population studied was domestic unrelated G-CSF mobilized PBSC donors reported to the NMDP/CIBMTR between 2006 and 2016. G-CSF dosing was based on the NMDP weight-based dosing schema rounded to the nearest vial content. Donors were divided into normal, overweight, obese, and morbidly obese categories based on BMI. Multivariate analysis of collection yields between cohorts were done using linear regression analysis. Stepwise variable selection was used to add variables to the model: BMI group and G-CSF dose was forced into the final model as the variables of interest. Pain and acute toxicities at each time point were described using frequencies and compared between groups using chi-squared test or Fisher's exact test after adjusting for donor and baseline characteristics. Results. Examination of 20, 884 PBSC donors mobilized by G-CSF revealed a significant increase in collection yield in obese and morbidly obese compared to normal and overweight donors. Median CD34+ per liter of blood processed (x106/L) on Day 5 of G-CSF was 29.6, 36.4, 40.8 and 42.9 in normal, overweight, obese and morbidly obese donors, respectively (p Figure 1 shows the time course and degree of toxicities in different BMI categories. Obese and morbidly obese were more likely to experience grade 2-4 pain and toxicities compared with normal or overweight in both the peri-collection and early post-donation recovery period but by one week after donation most toxicities abated and there was no difference. Donors with a higher BMI were more likely to experience grade 2 to 4 skeletal pain 24 hours post first G-CSF dose, 2 days post donation and at day 1 to 5 G-CSF administration. In addition, donors with higher BMI were more likely to have grade 2-4 toxicities (fatigue, anorexia, insomnia) at day 1 to 5 of G-CSF and 2 days after collection. However, within each BMI group, incremental increase in G-CSF dose was not associated with greater pain or other toxicities. Conclusions. Our data indicates a correlation between average daily G-CSF dose and CD34+ cell yield in normal and overweight donors. However, in obese and morbidly obese donors, there was no benefit in CD34+ yield with increasing average daily G-CSF dose above 780 mcg and 900 mcg respectively. Therefore, there appears to be a maximum effective G-CSF dose for mobilization in obese and morbidly obese donors where higher doses of G-CSF add no additional benefit and may result in additional complications. Disclosures Pulsipher: Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Adaptive Biotech: Consultancy, Research Funding; CSL Behring: Consultancy.

NF and RZG contributed equally to this work Background: Preservation of intact gut microbiota (GM) in allogeneic hematopoietic stem cell transplant (alloHCT) recipients has gained intense attention over the last decade. Loss of GM diversity and a shift in GM composition after alloHCT has been associated with adverse consequences, including increased treatment related mortality due to acute graft-versus-host disease (GVHD), infection and organ failure. Despite a growing understanding of relationships among GM, systemic inflammation and acute GVHD in early stage (up to day 100) recovery, little is known about the GM alterations in late phase (beyond 100 days) recovery of alloHCT recipients with chronic GVHD (cGVHD). We compared the GM microbiota composition (diversity, richness and taxa abundance) and prototypical cytokines (IL10, anti-inflammatory and TNFα, pro-inflammatory) between alloHCT recipients with and without cGVHD in late phase HCT recovery. Method: This cross-sectional study included two groups of adults (age > 18 years) who received T cell repleted grafts and had a fecal and blood sample collected in late phase recovery of alloHCT. Group 1 (n=9) included patients with active moderate to severe cGVHD requiring systemic steroids +/- therapeutic dose Tacrolimus. Group 2 (n=11) included patients without cGVHD off Tacrolimus or on Tacrolimus taper (n=7: no cGVHD history and n=4: resolved cGVHD). Independent t-tests were used to examine clinical and transplant characteristics between groups. The V1-V3 region of the 16S rRNA gene in fecal specimens was sequenced using Illumina MiSeq. Sequenced data were processed using Quantitative Insights into Microbial Ecology (QIIME) version 1.9.1. Taxonomic assignment was done using ribosomal database project classifier with confidence cutoff set to 50%. Beta diversity analysis through Principal Coordinate Analysis (PCoA) was generated from UniFrac and Bray-Curtis distances. Difference in GM composition was tested using PERMANOVA. Alpha diversity analysis was done using Chao1 and Shannon diversity indices. Linear discriminant analysis effect size (LEfSe) was used to find markers that differentiate between groups. Cytokines were analyzed in plasma using Bioplex® multi-plex assay. Differences between groups were tested using Mann-Whitney U test. Correlations between cytokines and F. prausnitzii were tested using Spearman's Rho. Significance was set at < 0.05 for all tests. Results: No significant differences noted in characteristics of the two groups except for lower performance status in cGVHD (Table 1). There was a significant difference in GM composition between groups (Figure A, P = 0.002). Alpha diversity (richness) was significantly lower in setting of cGVHD (Figure B, p < 0.05). Based on LEfSe analysis, 13 GM taxa were associated with Group 1 and 48 taxa were associated with Group 2. The GM community in Group 1 was enriched with Bacteroides, Lactobacillus, Clostridium and Veillonella whereas GM of Group 2 was enriched with Ruminococcus, Blautia and Faecalibacterium (p 2). Interestingly, Faecalibacteriumprausnitzii (F. prausnitzii) was significantly enriched in group 2 (Figure C, p= 0.01). F. prausnitzii, a member of the Firmicutes phylum, is a well-known anti-inflammatory commensal bacterium. Previous studies have shown lower levels F. prausnitzii in patients with intestinal inflammatory diseases including active ulcerative colitis. Recently, F. prausnitzii has also been linked to response to anti-PD1 therapy. Differences in levels of IL10 and TNFα between groups were nearing significance (p=0.06 and p= 0.08, respectively). There was a significant correlation between IL10 level and F. prausnitzii (rho=0.55, p= 0.01) but not between TNFα and F. prausnitzii (rho= -0.35, p= 0.12). Conclusion: These data suggest patients with cGVHD have reduced GM diversity and distinct GM composition compared to patients without cGVHD. The finding of decreased abundance of F. prausnitzii, in patients with cGVHD offers insights into the mechanisms of inflammation in cGVHD and suggests a role for commensal bacteria-mediated anti-inflammatory activities in this population. Future studies are needed to better understand the immunomodulatory effects and potential therapeutic role of F.prausnitzii and GM composition in cGVHD to develop targeted interventions to improve outcomes of alloHCT recipients. Disclosures No relevant conflicts of interest to declare.

Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874.

Dendritic cells (DCs) are key antigen-presenting cells with a potential role in tumor vaccines. We investigated the hypothesis that early reconstitution of DCs after allogeneic hematopoietic stem cell transplantation (SCT) improves survival. We also correlated DC reconstitution with complications of relapse and acute graft-versus-host disease (aGVHD). Fifty patients underwent transplantation between February 2000 and March 2003, with a median follow-up of 501 days (range, 136-1263 days). Most (92%) received blood stem cells, and the remainder received bone marrow from HLA-matched sibling donors for predominantly high-risk hematologic malignancies. Around the time of engraftment, peripheral blood underwent flow cytometry analysis for DCs, and the cells were divided as DC1 and DC2. Using Kaplan-Meier analysis, patients with lower DC counts (< 4.97 cells/μL) were found to have significantly worse survival (P = .002), increased incidence of relapse (P = .002), higher incidence of aGVHD onset (P = .0005), and a composite end point of relapse or death (P = .0017). A Cox proportional hazards multivariate model adjusted for important covariates confirmed that low DC count is independently associated with death (hazard ratio [HR], 3.8; P = .02), time to relapse (HR, 11.6; P = .001), and aGVHD (HR, 3.3; P = .04). Sensitivity and specificity rates for low DC count in predicting death or relapse are 73% and 75%, respectively. Low numbers of circulating DCs significantly increase the risk for relapse and acute GVHD and predict death after allogeneic SCT. (Blood. 2004;103:4330-4335)

Pneumonia is a major cause of death in acute leukemia patients. In this issue of Blood , [Leiva-Juarez et al][1] demonstrate a novel way to prevent pneumonia in acute leukemia by inhalation of a synergistic combination of Toll-like receptor 2/6 (TLR 2/6) and TLR9 agonists (Pam2-ODN) to induce

Human hematopoietic progenitor cells (HPCs) from mobilized peripheral blood mononuclear cells (PBMCs), adult bone marrow (ABM), and fetal bone marrow (FBM) were evaluated for their ability to produce multilineage human hematopoietic engraftment in vivo. Sublethally irradiated BNX (beige/nude/xid) mice were injected with either unfractionated cells or CD34+ cells purified from these sources. The presence of human cells in the mouse PB, BM, and spleen was evaluated by flow cytometry at either 6 to 8 weeks or 6 months postinjection. Recipients with > or = 1% human cells in any of these tissues were considered chimeric. Of 26 mice injected with FBM, 4 showed up to 73% human cells in the BM or spleen at 6 months. The phenotypes of these cells included CD13/33+ myelomonocytic cells (38%), CD19+ B cells (67%), and CD34+ progenitor cells (28%). In contrast, ABM gave rise to a mean of 5% human cells in the PB in 2 of 42 (4%) recipients at 6 to 8 weeks. These circulating human cells were predominantly CD3+, whereas CD13/33+ and CD34+ cells were detected in the BM for up to 6 months. A total of 18% of mice injected with PBMCs showed a mean of 36% human cells in the PB. Both the BM and spleens of PBMC-injected mice contained CD3+ cells in a proportion similar to that observed in the PB. These CD3+ cells were phenotypically mature CD4+,CD8-or CD4-,CD8+ T cells and coexpressed a variety of Vbeta T-cell receptor (TCR) genes. The percentage of CD3+ cells in the circulation of chimeric recipients injected with either FBM, ABM, or PBMCs correlated well with the input CD3+ cell dose for each of these HPC sources (r = .99). The high levels of engraftment of CD3+ cells in recipients of PBMCs and the long-term multilineage engraftment of FBM recipients have important implications for developing strategies to study the regulation of these human cells in vivo.

FK506 (Tacrolimus) is an immunosuppressive drug that blocks the activation of antigen-specific T lymphocytes, a major component in the pathogenesis of graft-versus-host disease (GVHD). This study was designed to obtain first estimates of the safety and efficacy of FK506 monotherapy in the prevention of GVHD following HLA-identical sibling marrow transplantation. Additionally, a subset of patients was studied to define the pharmacokinetic profile of FK506. Twenty-seven adult patients with leukemia or myelodysplasia received FK506 starting the day before transplant at a dose of 0.04 mg/kg/d by continuous intravenous infusion. When clinically possible, FK506 was given orally in two divided doses starting at five times the daily intravenous dose. FK506 doses were adjusted to target a steady state or trough blood level between 10 to 30 ng/mL. These patients were followed for 6 months posttransplant. All patients had sustained marrow engraftment. Frequently noted adverse events included reversible renal dysfunction, diarrhea, fever, nausea, vomiting, and headache. Most patients required FK506 dose reductions associated with elevated serum creatinine. Two (7%) patients relapsed, one of whom died of the disease within the 6- month study period. A second patient died due to pulmonary mucor. Whole blood pharmacokinetic parameters indicated a half-life of 18.2 +/- 12.1 hours; volume of distribution of 1.67 +/- 1.02 L/kg; clearance of 71 +/- 34 mL/h/kg; and bioavailability of 32 +/- 24%. Eleven of 27 (41%) patients developed grade II to IV acute GVHD, including 10 grade II and one grade III. Six of 24 (25%) evaluable patients developed chronic GVHD. These data indicate that FK506 monotherapy has activity in preventing GVHD. Further studies of FK506 with lower doses to improve tolerability and in combination with other immunosuppressants to augment efficacy are warranted.

Background: Hypomethylating agents (HMAs) (e.g., azacitidine (aza), decitabine (dec)) and lenalidomide (len) are approved agents and used in the treatment of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Despite their widespread use, HMAs fail in the majority of MDS and AML patients, and len fails in 75% of non-del(5q) MDS. Unfortunately, no method exists to predict disease response, thus the management of MDS and AML patients is challenging. Predicting treatment response would improve treatment effectiveness, restrict treatment-related adverse events to those who would benefit, and reduce health care costs. Ideally, patient prediction would be based on disease biology. Aim: To determine the biological and clinical predictive values of a genomics-informed computational biology method in patients with AML and MDS who are treated with aza, dec or len. Methods: Patients with AML or MDS were recruited in a prospective clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of treatment response to actual clinical response. Genomic profiling was conducted by conventional cytogenetics, whole exome sequencing (SureSelectXT Clinical Research Exome, Agilent), and array CGH (Agilent). These genomic results were inputted into computational biology software (Cellworks Group), which generates disease-specific protein network maps using PubMed and other online resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each patient-specific protein network map was digitally screened for the extent by which aza, dec or len reduced simulated disease growth in a dose-respondent manner. Treatment was physician's choice based on SOC. Before initiating treatment, treating physicians were masked to the results of whole exome sequencing and computational predictions. Clinical outcomes were prospectively recorded. To be eligible for efficacy assessment, patients must have had at least 4 cycles of HMA treatment or 2 cycles of len treatment. For AML, CR+PR was used to define response (IWG 2003). For MDS, CR+PR+HI was used to define response (IWG 2006). To validate the predicted protein network perturbations, Western blot assays were performed on pertinent pathway proteins. Comparisons of computer-predicted versus actual responses were performed using 2x2 tables, from which prediction values were calculated. Fisher's exact test was used to compare prediction values of the genomics-informed computer method versus empiric drug administration. Results: Between June 2015 and June 2016, 80 patients were recruited. 40/80 (50%) had AML and 40/80 had MDS (50%). The median age was 66 (range 24-91). 44/80 (55%) were treatment-naïve and 36/80 (45%) were treatment-refractory. 99% completed all planned molecular tests and computational analyses. Laboratory validation study of computer-predicted, activated protein networks in 19 samples from 13 different patients showed correct prediction of 5 activated networks (Akt2, Akt3, PIK3CA, p38, Erk1/2) in 17 samples, exhibiting 89% accuracy. At the time of this report, 20/80 patients were eligible for efficacy evaluation. 6/20 patients showed clinical response to SOC therapy, while 14/20 did not achieve clinical response. 18 patients' outcome predictions were correctly matched to their actual clinical outcomes, and 2/20 were incorrectly matched, resulting in 90% prediction accuracy, 75% positive predictive value (PPV), 100% negative predictive value (NPV), 100% sensitivity, and 86% specificity. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration (p=1.664e-05). New genomic signature rules were discovered to correlate with clinical response after aza, dec or len. Conclusions: A computational method that models multiple genomic abnormalities simultaneously showed high predictive value of protein network perturbations and clinical outcomes after standard of care treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials. Disclosures Vali: Cellworks Group: Employment. Abbasi:Cellworks: Employment. Kumar:Cellworks group: Employment. Kumar Singh:Cellworks group: Employment. Basu:Cellworks Group: Employment. Kumar:Cellworks Group: Employment. Husain:Cellworks Group: Employment. Wingard:Ansun: Consultancy; Merck: Consultancy; Fate Therapeutics: Consultancy; Astellas: Consultancy; Gilead: Consultancy.

Background: Allogeneic HCT is a potentially curative procedure for many hematologic malignancies, but is associated with several complications. Acute GvHD is a condition that affects 35-50% of allogeneic HCT recipients, typically occurs within 100 days after transplant, and can be life-threatening. Existing treatments are poorly tolerated and frequently ineffective. While the clinical consequences of acute GvHD are understood, the economic burden of the condition has not been well characterized. Methods: Using a large US healthcare claims database (Truven MarketScan® Commercial Claims and Encounters Database), patients aged ≥2 years old were identified who underwent allogeneic HCT between October 2009 and March 2013. Patients without continuous health plan enrollment or evidence of hematologic malignancy in the 6-month period prior to the "Index Admission" (hospital admission during which HCT was performed) were excluded. Patients were followed from the first day of the Index Admission until death, plan disenrollment, or one year; whichever occurred first ("Follow-Up"). Patients were classified into two cohorts: "Acute GvHD" based on ICD-9 CM diagnosis codes within first 100 days of Follow Up, or "No Acute GvHD". Total healthcare costs (inpatient care, outpatient care, outpatient pharmacy) and hospital length of stay (LOS) at discharge from Index Admission, the 100th day of Follow-Up, and the 365th day of Follow-Up were determined. Reimbursed amounts (plan payment plus patient liability) were used as a proxy for healthcare costs. Total healthcare costs and LOS between the two cohorts were compared for each of the three evaluation periods using Student's t-tests (unadjusted analyses), and analyses of covariance (ANCOVA; adjusting for differences in age, sex, plan type, geography, year of Index Admission, type of malignancy, Charlson Comorbidity Index score, and pre-admission healthcare cost). Results: 1,635 patients underwent HCT and met all selection criteria (mean age was 48 years, 56% were men, acute myeloid leukemia was the most common malignancy); 42% met the criteria for inclusion in the Acute GvHD cohort. Univariate mean total healthcare costs for the Acute GvHD cohort (vs No Acute GvHD) were $36,651 greater during Index Admission, $83,322 greater at the 100th day of Follow-Up, and $123,220 greater at the end of the 1-year Follow-Up (all p Conclusions: Over the one-year period following allogeneic HCT, patients who develop Acute GvHD experience over $100,000 more in total healthcare costs-and nearly three additional weeks in hospital-relative to those who do not. While healthcare claims appear to represent a good source with which to assess the impact of complications of HCT, confirmation with prospective clinical studies is recommended. Given that nearly one-half of patients develop Acute GvHD, our findings suggest that therapeutic strategies that prevent this complication may confer substantial savings to the healthcare system. Disclosures Grubb: Fate Therapeutics: Employment, Equity Ownership. Huse:Evidera: Employment; Fate Therapeutics: Consultancy. Alam:Evidera: Employment; Fate Therapeutics: Consultancy. Dychter:Fate Therapeutics: Employment, Equity Ownership. Wingard:Merck: Consultancy; Ansun: Consultancy; Fate Therapeutics: Consultancy; Gilead: Consultancy; Astellas: Consultancy. Berger:Evidera: Employment; Fate Therapeutics: Consultancy.

T cell-replete haploidentical donor transplants (HAPLO-HCT) using post-transplant cyclophosphamide for control of alloreactivity is now being increasingly utilized. HAPLO-HCTs were originally performed using BM grafts. However, recently, a few single center studies have reported good outcomes using G-CSF mobilized PBSC grafts for HAPLO-HCT. No prospective randomized comparisons of BM to PBSC grafts for HAPLO-HCT have been performed. Therefore, we analyzed outcomes for 687 adults (496 BM, 191 PBSC) who received HAPLO-HCT for hematologic malignancies using post-transplant cyclophosphamide + mycophenolate + calcineurin inhibitor for GVHD prophylaxis between 2009 and 2014 in the United States. The primary outcome was overall survival. The characteristics of recipients of BM and PBSC were similar except BM recipients were older, more likely to have a performance score ≥90, HCT-CI index ≤2, be CMV seronegative, have a lymphoid malignancy and receive reduced-intensity conditioning. Most PBSC transplants occurred between 2012 and 2014. The median follow-up was 35 and 20 months for recipients of BM and PBSC grafts, respectively. Cox regression models were built to study the effect of graft type adjusted for other significant factors on overall mortality, non-relapse mortality, relapse and graft-versus-host disease (GVHD) and outcomes censored at 2-years to accommodate differential follow-up between treatment groups (Table 1). After adjusting for age, CMV serostatus, disease risk index (disease type/disease status for myeloid and lymphoid malignancy and cytogenetic risk for acute leukemia and myelodysplastic syndrome) and transplant conditioning regimen there were no significant differences in risks for overall mortality (HR 1.00, p= 0.98; 2-year overall survival: 54% and 57%) or non-relapse mortality (HR 0.92, p=0.74; 2-year non-relapse mortality: 17% and 16%) after transplantation of BM compared to PBSC, respectively. However, relapse risks were higher after transplantation of BM compared to PBSC (HR 1.49, p=0.009; 2-year relapse: 45% and 28%). Subset analyses explored the effect of graft type separately for myeloablative and reduced intensity conditioning regimen adjusting for age, CMV serostatus and disease risk index. Consistent with the main analysis there were no differences in overall or non-relapse mortality risks and relapse risks were higher with BM compared to PBSC with myeloablative regimens (Table 1). Although this may in part be explained by lower chronic GVHD risks with transplantation of BM grafts, chronic GVHD was not significantly predictive of relapse risk when modeled as a time-dependent covariate (HR= 0.73, p=0.49). Grade II-IV acute GVHD risks (HR 0.45, p Table 1. Table 1. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board. Hamadani:Takeda: Research Funding. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees. Wingard:Ansun: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

Introduction: High dose melphalan followed by autologous hematopoietic stem cell transplant (ASCT) is the standard of care in eligible multiple myeloma (MM) patients (pts). It is common practice to collect sufficient stem cells for two transplants, for the first ASCT immediately after induction, and for salvage ASCT following disease progression. We investigated the frequency of salvage second ASCT in the era of novel agents to determine if there has been a change in practice. Methods: We retrospectively reviewed medical records of MM pts who had stem cells collected for two ASCTs from 03/1996 to 12/2014. We then compared pts who received their first ASCT prior to January 2007 to those after this time. We excluded pts who received their second transplant as part of a clinical protocol, who received subsequent allogenic transplants, and pts who received 2 ASCT transplants as part of initial therapy. Fisher's exact test was used to assess significance of categorical independent variables and t-test was used to assess significance of continuous variables. Results: Forty of 506 pts (7.9%) received salvage second ASCT (Fig 1). Among 195 MM pts who received their first ASCT before 2007, 19 pts (9.7%) received salvage ASCT. After 2007, 21 of 311 MM pts (6.7%) received salvage ASCT (P= 0.24). When comparing salvage ASCT in the two time periods, no significant differences were noted, with the exception of a slightly lower KPS status (80% vs 70%, P=0.001), and the use of novel agents before the salvage therapy (0/19 (0%) vs 17/21 (81%), p Conclusions: Outside of clinical trials, the use of salvage second ASCT for relapsed MM is not frequent, and was noted to be decreasing further after 2007. We speculate that this 30% relative reduction in the frequency of salvage ASCT after 2007 is likely explained by the introduction of novel agents such as bortezomib and lenalidomde into the clinical practice, the use of maintenance therapy post-ASCT, and more non-ASCT options for salvage treatment after relapse. Further studies are needed to investigate the optimal timing for salvage ASCT and the patients who will best benefit from such treatment. Figure 1 Figure 1. Disclosures Wingard: Astellas: Consultancy; Gilead: Consultancy; Ansun: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

Controversy exists as to whether hematopoietic progenitor cells are infected by human immunodeficiency virus-1 (HIV-1) in vivo. Most studies have focused on patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex, and little data are available on asymptomatic patients with well preserved CD4+ T-cell counts. To determine if CD34+ hematopoietic progenitor cells are infected early in the course of HIV-1 disease, we evaluated 10 asymptomatic HIV-1 seropositive (HIV-1+) patients. The CD34+ cell fraction was purified by a two-step procedure consisting of both affinity chromatography and fluorescence-activated cell sorting that resulted in a median purity of over 99%. Using conventional and nested polymerase chain reaction (PCR) assays, we evaluated the presence and frequency of HIV-1 proviral DNA. Both bone marrow mononuclear cells and CD34- cells from all 10 patients were strongly positive for the HIV-1 pol and/or gag gene sequences. In contrast, sorted CD34+ cells from only two of 10 patients were positive, and the number of copies of proviral DNA in these samples was estimated to be from 2 to 5 per 250,000 cells. To test the in vitro functional capacity of CD34+ progenitors, these cells were assayed in both methylcellulose and long-term stromal culture. We found no significant reduction in the number of colony-forming unit-erythroid (CFU-E), burst-forming unit-erythroid (BFU-E), or colony-forming unit- granulocyte macrophage (CFU-GM) colonies, or in the frequency of cobblestone area forming cells from limit dilution analysis in HIV-1+ asymptomatic patients. Pooled methylcellulose colonies generated from CD34+ cells were HIV-1- in nine of 10 samples. All progeny from long- term cultures of CD34+ cells were HIV-1-. We conclude that the CD34+ hematopoietic progenitor compartment is not infected in the majority of asymptomatic HIV-1+ patients, and that these cells may represent a suitable target for strategies designed to protect developing CD4+ T cells from infection.

We analyzed the outcome of 450 HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia (CML) in chronic phase performed between 1985 and 1990 and reported to the International Bone Marrow Transplant Registry (IBMTR). All patients received either hydroxyurea (n = 292) or busulfan (n = 158) to treat their CML before transplant. The median interval between diagnosis and transplant was 10 months (range, 1 to 191). Patients treated with hydroxyurea had a higher probability (95% confidence interval) of leukemia-free survival (LFS) at 3 years than those treated with busulfan (61% [51% to 70%] v 45% [36% to 55%], P < .0003). Probability of LFS was also higher in patients transplanted within 1 year of diagnosis (61% [53 to 68%] v 47% [38% to 57%], P < .001). After adjustment for patient and transplant covariables in a multivariate analysis, prior chemotherapy and duration of disease pretransplant were independently associated with LFS. These data support the use of hydroxyurea rather than busulfan and transplant within 1 year of diagnosis for patients with CML and an HLA-identical sibling.

We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Introduction: Persistent AML is a known risk factor for poor outcomes after allo-HCT. The impact of MRD in patients who achieve complete remission (CR) or CR with incomplete count recovery (CRi) has been less well studied. Methods: We retrospectively reviewed the records of AML patients who underwent allo-HCT in morphological remission ( Results: A total of 166 eligible patients were identified. The median follow-up among living patients is 46 months (range, 13-103).Thirty seven (22%) patients had evidence of MRD (13 by flow cytometry only, 17 by cytogenetics/FISH only and 7 by both). MRD was more common in patients with poor risk karyotype at diagnosis and CRi at the time of allo-HCT (Table 1). PFS (P= 0.0016), OS (P=0.002), and CIR (P=0.02) were all significantly worse in MRD+ patients (Figures 1& 2). In univariate analysis, MRD+ patients, assessed by flow cytometry had worse PFS (P=0.0216) and OS (P=0.0314) compared to MRD- patients. Similarly patients with evidence of MRD+ by cytogenetics/FISH had worse PFS (P=0.007) and OS (P=0.0031). In a multivariate cox proportional hazards model 1) any MRD positivity prior to allo-HCT, 2) poor-risk karyotype at diagnosis, and 3) CRi at allo-HCT independently predicted significantly poor PFS and OS. Only poor-risk karyotype was associated with a significant increase in CIR, while MRD positivity showed a trend towards higher CIR. Conclusion: MRD positivity prior to HCT by either flow cytometry or by cytogenetics/FISH independently predicts adverse AML outcomes. Table 1. Comparison of pre-transplant variables Covariate Label MRD + (N=37) MRD - (N=129) P-Value Age(years) < 40 8 (21%) 20 (16%) 0.708 40 - 59 20 (53%) 69 (54%) ≥ 60 10 (26%) 39 (30%) Karyotype risk Favorable/ Intermediate 19 (53%) 95 (74%) 0.011 Poor 18 (47%) 33 (26%) Timing of Allo-HCT 1st remission (CR1) 28 (74%) 97 (76%) 0.792 > CR1 10 (26%) 31 (24%) Allo-HCT after1st relapse(>CR1): duration of CR1 > 12 mo 31 (82%) 113 (88%) 0.285 ≤ 12 mo 7 (18%) 15 (12%) Secondary AML No 23 (60%) 78 (61%) 0.964 Yes 15 (40%) 50 (39%) Complete remission vs CRi CR 28 (74%) 110 (86%) 0.077 CRi 10 (26%) 18 (14%) Conditioning Regimen Ablative 24 (63%) 72 (56%) 0.449 Other 14 (37%) 56 (44%) Donor Type Matched sibling donor 12 (32%) 42 (33%) 0.887 Other 26 (68%) 86 (67%) Female donor: male recipient (FDMR) Other 28 (80%) 91 (78%) 0.844 FDMR 7 (20%) 25 (22%) Disclosures No relevant conflicts of interest to declare.

Background: We have demonstrated that blood vessels can be a sanctuary site for acute myeloid leukemia (AML). Therefore, we evaluated a novel vascular disrupting agent, OXi4503, for the treatment of patients with AML and higher risk myelodysplastic syndromes (MDS). Methods: Patients with AML and MDS were treated with OXi4503 monotherapy in a phase IA 3x3 dose escalation/de-escalation study (ClinicalTrials.gov NCT01085656). Drug was administered via intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle. Dose escalation occurred as tolerated according to protocol. With the goal of defining maximum tolerated dose (MTD), patients were monitored for side effects and dose-limiting toxicities (DLTs). Therapy continued until drug intolerance or disease progression. Results: From May 2011 to May 2015, 18 patients diagnosed with refractory MDS (RAEB-1 or RAEB-2) or refractory AML were treated with OXi4503. Overall, 78% of patients were male, while 22% were female. The median patient age was 63 years (range, 24 to 80). Sixteen of 18 (89%) of patients had refractory AML and 2/18 (11%) had refractory MDS. For patients with AML, 11/16 (69%) were intermediate and 5/16 (31%) unfavorable cytogenetic risk. For patients with MDS, one had intermediate and one had very poor cytogenetic risk. The median number of prior therapies was 4 (range, 1-10). In two small run-up cohorts, two patients received 2.5 mg/m2 IV weekly and two received 3.75 mg/m2. In the main trial, nine patients received 5 mg/m2, three received 6.25 mg/m2, and two received 7.81 mg/m2. Expansion of the 5 mg/m2 cohort occurred after two patients withdrew due to disease progression and one patient withdrew due to grade 4 disseminated intravascular coagulopathy (DIC). The median number of cycles received was 1 (range, 1-10). Transient elevations in D-dimer were observed in 14/18 patients (78%). DIC was observed in 5/18 patients (28%). Four of five patients with DIC only had laboratory evidence and no clinical sequelae. One patient treated with 5 mg/m2 died of DIC; however, he also had evidence of infection. The coagulopathic laboratory changes typically resolved within 4-6 days. Fever occurred in 7/18 patients (39%) and typically resolved within 24 hours after drug administration. Fever was irrespective of coagulopathic laboratory changes. Other drug-related side effects (all grades) included bone pain in 5/18 (28%), flu-like symptoms in 5/18 (28%), hypertension in 5/18 (28%), thrombocytopenia in 5/18 (28%). Grade 3 or 4 hypertension and QT prolongation were not observed. One patient achieved a marrow complete remission after one cycle, but then died of fungal pneumonia. Another patient achieved partial remission and received 10 cycles of OXi4503 treatment. He eventually withdrew from the study due to disease progression. Conclusions: OXi4503 doses of up to 7.81 mg/m2 have been safely and feasibly administered to patients with AML and MDS. The MTD has not been reached and the trial is ongoing. Based on evidence that OXi4503 chemosensitizes AML cells to cell cycle agents, after reaching MTD, the next step is a phase IB/II clinical trial combining OXi4503 with cytarabine in relapsed/refractory AML and MDS. Disclosures Off Label Use: OXi4503. Chaplin:OXiGENE: Employment. Cogle:OXiGENE: Research Funding.

Introduction: Although day D14 BM after initiation of induction chemotherapy is accepted standard of care in AML patients (pts), it has poor predictive value and low accuracy for refractory disease. Currently there are no established clinical and laboratory factors which accurately predict which AML pts with positive D14 BM require immediate reduction chemotherapy for persistent disease and which pts achieve complete remission (CR) Methods: We retrospectively analyzed pretreatment factors and post-induction response in AML pts to determine if clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Results: Among 297 pts with D14 BM biopsies, 183 pts (61%) had positive D14 BM (either ≥ 5% myeloblasts or cellularity ≥ 20%). Of those with a positive D14 BM biopsy, no reinduction chemotherapy was given to 89 pts of which 57 (64%) pts had persistent disease at count recovery and 32 (36%) pts achieved CR. Persistent disease at count recovery after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, history of relapsed disease, and poor-risk disease category than pts with positive D14 BM who achieved CR. Age, D14 BM cellularity, and WBC at first day of induction chemotherapy had no significant influence on remission status in pts with a positive D14 BM (Table 1). We developed, and tested in a validation cohort, new prediction model using both D14 BM status and clinical/laboratory factors such as the percentage of blasts, history of relapsed disease, and poorer disease risk category. Then we compared results of this prediction model to that of D14 BM alone without the usage of clinical/laboratory prognostic factors. Our prediction model significantly improved the positive predictive value (84% vs.64% P=0.001) and the accuracy of prediction of recovery marrow status (0.88% vs. 80%, P=0.002) in AML pts with positive D14 BM (Table 2). Conclusion: In this study we developed and validated a new prediction model for interpreting D14 BM biopsies in AML pts after induction chemotherapy. With the addition of readily available clinical and laboratory information, our multivariable model provides a more accurate prediction of recovery bone marrow status and identification of patients with positive D14 BM who may not benefit from early reduction chemotherapy. | | Persistent AML at count recovery | CR+CRi | P value | | ----------------------------------------------------------------- | -------------------------------- | ----------------------- | ----------- | | Number | 57 | 32 | | | Age, years Median (min, max) | 59 (19, 75) | 55.5 (20, 78) | 0.064* | | WBC Count at Induction, x 109/L Median (min, max) | 5.7 (0, 285) | 3 (0, 95) | 0.25* | | D14 Cellularity, % Median (min, max) | 10 (5, 40) | 10 (3, 60) | 0.079* | | D14 Blasts, % 0-10 10%-30 >30 | 13 20 24 | 15 13 4 | 0.0023* | | Disease Status Before Induction Therapy De novo Relapsed | 19 38 | 26 6

It is not known whether pandemic 2009 influenza A/H1N1 (2009 H1N1) leads to more serious disease than seasonal influenza in hematopoietic cell transplant (HCT) recipients. In a retrospective study in HCT recipients with virologically proven influenza virus infection, a total of 161 HCT recipients (18 2009 H1N1, 103 seasonal influenza A, and 40 seasonal influenza B) were analyzed. In multivariable analyses, more patients with 2009 H1N1 had lower respiratory tract disease (LRD), hypoxemia, and prolonged viral shedding compared with seasonal influenza A. Seasonal influenza A and B outcomes were similar. There was no difference in overall and influenza-associated mortality among influenza virus types. Both early and delayed administration of antiviral therapy was shown to be beneficial in terms of decreased rates of development of LRD, although earlier intervention appeared to be more effective. Profound lymphopenia and lack of early antiviral therapy were associated significantly with LRD, hypoxemia, and death. High-dose corticosteroid treatment (≥ 1 mg/kg) given at the time of influenza diagnosis was associated with a reduced risk for mechanical ventilation. Thus, our data suggest that infection with 2009 influenza A/H1N1 resulted in more severe respiratory disease in HCT recipients compared with seasonal influenza.

Background: Bortezomib, a proteasome inhibitor, is frequently used in treatment of patients with multiple myeloma (MM). Bortezomib is generally well tolerated with gastrointestinal symptoms and peripheral neuropathy being the most common adverse effects. Here we report cases of severe diffuse alveolar hemorrhage (DAH) associated with bortezomib administration. Methods and Results: We identified 3 cases of severe DAH that were associated with bortezomib administration in MM patients treated at our institution between 2010 and 2014 (Table 1). All 3 patients presented with fever and worsening hypoxia shortly after initiation of bortezomib therapy and later developed progressive respiratory failure due to DAH. None of 3 patients had any respiratory symptoms or preexisting pulmonary conditions prior to bortezomib initiation. In one patient respiratory symptoms developed after 4 doses of bortezomib, improved off therapy, however rapidly progressed to a respiratory failure with a subsequent bortezomib treatment. Imaging studies showed diffuse areas of ground-glass opacities, apparent prominence of segmental and subsegmental bronchi and interlobular septal thickening. Infectious workup, which included bronchoscopy with bronchoalveolar lavage and respiratory viral studies, was completely negative in all 3 patients. All patients received supportive care, empiric broad-spectrum antimicrobial therapy and high-dose glucocorticoids, which were started within 4 days of hospital admission. Two patients died from complications of DAH and 1 patient recovered without pulmonary sequelae. Conclusion: Bortezomib-associated DAH is a rare, but serious and potentially fatal adverse event. Pathogenesis remains unclear and is likely related to impaired regulation of the inflammatory response. Early recognition of bortezomib associated DAH is essential for immediate discontinuation of the drug and prompt initiation of high dose steroids. More reports are needed to provide further insights about the pathogenesis and most optimal management of bortezomib induced DAH. | Pt | Age/ Gender/Race | Smoker | Sx | Bor dose | Bor schedule | # of Bor doses | Time of onset after last bor dose (days) | Platelet count at the onset (103/mm3) | Imaging/BAL findings | Time to initiation of high dose steroids | Outcome | | -- | ------------------------ | ------ | ------------- | --------- | ------------ | -------------- | ---------------------------------------- | ------------------------------------- | -------------------------------------- | ---------------------------------------- | -------- | | 1 | 67/M/C | Never | SOB, fever | 1.3 mg/m2 | IV/2Xwk | 8 | 5 | 157 | Bilateral infiltrates and GGO/DAH | 2 | Death | | 2 | 72/M/C | Yes | Fever, cough | 1.3 mg/m2 | IV/2Xwk | 2 | 3 | 108 | Bilateral infiltrates/DAH | 4 | Recovery | | 3 | 55/M/C | Yes | Fever, chills | 1.5 mg/m2 | IV/2Xwk | 1 | 2 | 144 | Bilateral diffuse airspace disease/DAH | 4 | Death | Abstract 5761. Table 1: Patients who developed DAH after bortezomib administration Abbreviations: Pt, patient; M, male; C, Caucasian; Sx, symptoms; Bor, bortezomib; BAL, broncho-alveolar lavage; GGO, ground-glass opacities. Disclosures No relevant conflicts of interest to declare.

Background: The association of clinical trial participation with outcomes in cancer patients is controversial, with some studies reporting better outcomes for trial participants while others do not. It is possible that the difference in outcomes is due to differences in baseline characteristics of participants and non-participants. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 trial was a large randomized, multi-center study comparing peripheral blood (PB) with bone marrow (BM) for hematopoietic cell transplantation (HCT) from HLA-matched or 1 allele mismatched unrelated donors (URD) in patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndromes. The trial reported no significant survival differences between PB and BM; there was decreased risk of graft failure but increased risk of chronic graft-versus-host disease (GVHD) with PB grafts (Anasetti et al NEJM 2012). Methods: We compared characteristics of BMT CTN 0201 study participants (n=494) with HCT recipients who did not participate on the trial (n=1384) but were potentially eligible by virtue of known characteristics. These patients received similar conditioning and GVHD prophylaxis as trial participants at 38 United States trial centers during the study time-period. Centers that had no eligible non-trial participants were excluded. Outcomes between patients on and off trial were compared using Cox proportional hazards regression models. Data were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) that collects patient data on all trial and non-trial allogeneic HCT recipients through its registry function. Results: Approximately 29% [494/1878] of apparently eligible patients were randomized and analyzed as part of the trial. There were no significant differences between study participants and non-participants in age or sex distribution, disease types, HLA or sex matching, comorbidities, or interval from diagnosis to HCT. Higher proportions of non-participants were Hispanic, had a lower performance status and lower disease risk, and received myeloablative conditioning and antithymocyte globulin (ATG) or Campath than the study participants. PB was used more commonly as the graft source in the non-participants as compared to the study participants (65% vs. 50%, p Conclusion: Approximately 29% of patients who appeared eligible and were treated with conditioning and GVHD prophylaxis regimens allowed on the trial were enrolled. Despite some differences in clinical characteristics, most of the outcomes of non-trial participants were comparable to trial participants, suggesting that there is no definitive evidence that the outcomes of patients in a clinical trial are superior to those of the non-participants treated in a similar fashion. The comparable outcomes also indicate that the results of this trial were not seriously affected by selection bias and are therefore representative of the larger population. Figure 1: Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 1:. Adjusted overall survival in BMT CTN 0201 trial participants and non-participants Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Patient reported outcomes (PROs) including symptoms and health related quality of life (HRQOL) predict mortality in multiple cancers, such as myeloma, head and neck, lung and prostate cancer. The relationship of PROs with survival is not clear in hematopoietic cell transplantation (HCT). We tested three hypotheses about the relationship between HRQOL and survival after HCT: (1) Pre-HCT HRQOL (particularly physical HRQOL) reflects functional status and predicts survival after allogeneic (allo) HCT independently of traditional risk factors and indices; (2) Post-HCT change in physical HRQOL reflects the “toll” of the HCT and predicts subsequent outcomes, including survival, among early survivors; (3) Since autologous (auto) HCT is associated with lower risks for treatment-related morbidity and mortality, PROs may not be as predictive for this group. METHODS: We tested these hypotheses using data from the 711 participants in BMT CTN 0902 (sponsored by NHLBI and NCI, NCT 01278927), a randomized study of pre-transplant exercise and stress management training for patients undergoing auto or allo HCT. Because the primary analysis for BMT CTN 0902 did not show a significant effect for exercise or stress management training, intervention groups were combined for these analyses. However, auto and allo recipients were analyzed separately because of the expected substantial differences in the subsequent risks for morbidity and mortality in the two populations. The HRQOL measures used were the physical component score (PCS) and mental component score (MCS) from the SF-36, measured pre-HCT and at day 100. RESULTS: Among 310 alloHCT recipients with a median follow-up of 23 months, while there were no pre-HCT clinical covariates (including age, conditioning intensity, donor type, graft source, disease, disease stage) that predicted survival, pre-HCT physical HRQOL (PCS on the SF-36) was strongly prognostic for survival (HR for death of 0.72 per 10 points increase, 95% CI 0.60-0.85, p CONCLUSION: In summary, among alloHCT recipients who participated in BMT CTN 0902, lower pre-HCT physical HRQOL and early decline in physical HRQOL were strongly predictive for worse overall survival and higher transplant-related mortality. These results suggest that patient-reported data are an important component of risk assessment and could assist in clinical decision-making. High-risk individuals could be targeted for different management strategies or more aggressive supportive care interventions to reduce treatment-related morbidity and mortality in this population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background AML depends on blood vessel networks for disease progression and protection from chemotherapy. In prior preclinical work, we demonstrated that the vascular disrupting combretastatin, OXi4503, had significant activity against human AML by dual targeting of nascent blood vessels and malignant myeloblasts. Therefore, we initiated a phase I clinical study of OXi4503 in patients with relapsed and refractory AML and MDS. Methods The primary objectives of the phase I dose finding study (NCT01085656) were to assess safety and determine maximal tolerated dose (MTD) in patients with refractory AML or MDS (RAEB-1, RAEB-2). OXi4503 was administered by intravenous infusion over 10 minutes on Days 1, 8, 15 and 22 of each 28-day cycle, and escalated according to a defined dose schema. Continued weekly dosing was permitted until disease progression or unacceptable toxicities. Results Between May 2011 and August 2013, 11 patients with refractory AML or advanced MDS were enrolled. The median age was 62 years (range, 24–76). Most patients were male (82%). Cytogenetics were unfavorable in 7 patients and intermediate in 4. The median number of prior therapies was 4 (range, 1–5). Two subjects received 2.5 mg/m2, two received 3.75 mg/m2, and seven received 5 mg/m2. The 5 mg/m2 cohort was expanded because 1 patient developed a grade 4 DIC without hemorrhage and 2 withdrew due to rapid disease progression. Median number of cycles was 1 (range, 0-10). 7/11 subjects (64%) had transient increases in D-dimer that resolved one week after OXi4503 infusion. Other adverse events attributable to OXi4503 infusion included bone pain, fever, anemia, and thrombocytopenia. No patients developed grade 3 or 4 hypertension or QT prolongation. Plasma LDH and Uric Acid increased by at least two-fold within hours after OXi4503 infusions. One patient treated with 2.5 mg/m2 achieved a marrow complete remission (mCR) within the first cycle of therapy and then died of a pneumonia in the second cycle. Another patient treated with 5 mg/m2 achieved a partial remission (PR) and received 10 cycles of therapy. 10/11 (91%) subjects discontinued the study due to disease progression and 1 due to pneumonia. Analysis of bone marrow after OXi4503 infusions revealed vascular sinusoids lined with plump endothelial cells (ECs) and increased VEGF, indicating treatment effects. Conclusions The vascular disrupting combretastatin OXi4503 is well tolerated with preliminary evidence of disease response in heavily pre-treated, refractory AML and advanced MDS. Biological activity associated with OXi4503 included transient increases in D-dimer, changes in bone marrow EC morphology, and an angiogenic cytokine response. The phase I study continues to recruit subjects, as an optimal dose has yet to be defined. It is estimated that an additional 12-15 subjects will be required to reach MTD. Disclosures: Chaplin: OXiGENE: Consultancy. Cogle:OXiGENE: Research Funding; Leukemia & Lymphoma Society: Research Funding.

Following up on single institution studies suggesting that engaging patients in exercise and/or stress reduction techniques during hematopoietic cell transplantation (HCT) improves functional status and quality of life, we conducted a randomized study through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). METHODS: Patients (n=711) at 21 US centers provided symptom and quality of life data at enrollment. They were randomized to 1 of 4 groups using a 2x2 factorial design, stratified by center and transplant type. Prior to HCT, each group received a 15 minute stress management training session or a 15 minute exercise training session, both, or neither, with trained personnel to discuss the importance of managing stress and/or keeping active during HCT. The 3 intervention groups were also given a DVD, pamphlet and diary to track participation in exercise and/or stress management. The trainer reviewed the goals of practicing the intervention, proper technique, identification of barriers and plans to overcome them. Exercise training also included calculation of target heart rate. The exercise goal was walking 3-5 times a week for at least 20-30 minutes at 50-75% of estimated heart rate reserve. The stress management goal was to use paced abdominal breathing, progressive muscle relaxation with guided imagery, and coping self-statements to decrease stress. The interventionists re-contacted patients at 30 and 60 days after HCT to review the training goals, discuss barriers and provide encouragement. The fourth group was a usual care control group. All groups received a DVD of general information about HCT. Participants provided self-reported assessments at 30, 60, 100 and 180 days after transplant. The primary endpoints were the physical (PCS) and mental (MCS) component subscales of the SF36 at day 100. The study was designed to have 85% power to detect a difference of 0.5 STD in the exercise or stress management groups on each of the two endpoints, maintaining an overall type I error rate of 0.05. Primary analysis was on an intention to treat (ITT) basis with values assigned to patients who died or otherwise did not provide information. Enrollment occurred from January 2011-June 2012. Results The groups were well-balanced for baseline characteristics. There were no differences in the primary endpoints of PCS and MCS at day +100 among any of the groups based on the ITT analysis (Table). Results were similar using other conditional and imputed methods. Higher PCS at day +100 was associated with higher PCS at enrollment (p Conclusions No improvements in functional status as measured by PCS and MCS at day +100 were evident between the groups. Functional status was highly associated with pre-transplant functioning and type of transplant but not with conditioning regimen intensity.TableDay 100 SF36 scoresExercise (n=358) Median (25th-75th)No Exercise (n=353) Median (25th-75th)p-valuePCS37.5 (19.7-46.7)39.7 (27.1-47.7)0.14MCS49.4 (27.3-57.7)50.1 (34.2-57.8)0.33Stress Management (n=356) Median (25th-75th)No Stress Management (n=355) Median (25th-75th)PCS37.8 (22.1-46.6)39.7 (25.7-47.9)0.21MCS50.7 (31.0-58.2)49.1 (30.5-56.8)0.30 Disclosures: No relevant conflicts of interest to declare.

Background Early response to induction therapy for AML assessed by bone marrow (BM) evaluation on day 14 (D14) post chemotherapy is considered an important predictor of achieving complete remission (CR). Our aim was to identify clinical and laboratory factors influencing the probability of CR in AML patients (pts) with positive D14 BM without receiving further chemotherapy. Methods Records of pts with AML treated between 1998 and 2011 were retrospectively reviewed to identify subjects with positive D14 BM who did not receive re-induction chemotherapy. The distribution of following variables such as age, white blood cell count (WBC) at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk was compared by the univariate analysis. Recovery BM status (positive vs. negative for disease) as the response variable and age, WBC at the time of induction therapy, BM cellularity, percentage of blasts, disease status, and risk as explanatory variables were assessed by the logistic regression analysis. Poor risk AML was defined as the presence of adverse karyotype, treatment related disease or presence of antecedent hematologic disorder. Positive BM was defined as either cellularity ≥20% or ≥5% myeloblasts by IHC staining. CR was defined according to IWG 2003 criteria. Results 169/378 (44%) had a positive D14 BM after induction therapy and 92/169 (54%) did not receive re-induction chemotherapy. 68/92 (74%) underwent repeated BM evaluation at WBC recovery, which occurred 4-5 weeks after induction chemotherapy. Recovery BM showed refractory AML in 38/68 (56%) of cases. However, in 30/68 (44%) cases CR was achieved despite previously positive D14 BM. As demonstrated in Table 1, clinical and laboratory characteristics of the CR and refractory groups showed significant differences in the absolute percentage of D14 myeloblasts, abnormal vs. normal myeloblast phenotype, de novo vs. relapse disease status, and risk stratification. Higher blast percentage (P=.0016) was associated with significantly higher probability of having refractory AML and each 1% increase blasts on D14 BM increased the odds of refractory AML on recovery BM by 6% (OR=1.06 95% CI 1.022-1.099) (Figure 1) In contrast, no clear association between D14 BM cellularity and the recovery BM status was found. The results from the multivariate analysis were comparable with that from the univariate analysis. Blast percentage, disease status, and AML risk were strongly and jointly associated with the status of BM recovery. By using a logistic model including myeloblast percentage, myeloblast phenotype, disease status, and AML risk category we correctly predicted 31 refractory AML cases out of 38 (sensitivity = 82%) and we correctly predicted 23 CR cases out of 30 (specificity = 77%). For example, based on our formula, which incorporated blast percentage, disease status, and AML risk we estimated that in a patient with de novo, not a poor risk AML with 5% blasts on D14 BM the probability of positive recovery BM status was 6%, whereas in a patient with relapsed poor risk AML and 50% blasts on D14 BM the probability of positive recovery BM status was 98%. Conclusions Significant proportion of pts with positive D14 BM may achieve CR without subsequent chemotherapy administration. Low blast percentage, absence of phenotypically abnormal myeloblasts, de novo diagnosed AML, and absence of poor risk AML are associated with a significantly higher probability of CR. We developed a useful formula for predicting remission status in the setting of positive D14 BM that would be valuable in clinical trial protocols involving decision trees for re-induction chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Background Umbilical cord blood (UCB) is an important alternative source of stem cells for patients who lack matched adult donors, particularly in ethnic minorities. The infused total nucleated cell (TNC) and CD34+ cell dose are important prognostic factors on transplant outcomes. UCB units collected from African Americans (AA) have lower TNC and CD34+ cell counts and more likely to be disqualified for banking compared to other racial and ethnic groups. Furthermore, AA, including pregnant women, have increased prevalence of vitamin D deficiency. Vitamin D has an established role in hematopoiesis; therefore, we investigated the racial differences in UCB vitamin D content and its correlation with UCB cell composition and hematopoietic potential. Methods 119 UCB units that did not meet the TNC count banking criteria were analyzed. 51 UCB units were collected from AA mothers and 68 from Caucasian mothers. We analyzed UCB variables including volume, hematocrit (HCT), TNCs, mononucleated cells (MNC), CD34+ cells, plasma 25-Hydroxy vitamin D [25(OH)D] and in vitro progenitor cell hematopoietic potential measured by Colony-Forming Cell (CFC) assay. Results The median values of 25(OH)D in UCB units were significantly lower in AA compare to Caucasians (p= Univariate analysis of 25(OH)D effect on UCB variables revealed a correlation between 25(OH)D level and TNC (r= 0.193, 95% CI 0.013-0.36; p= .0353) and UCB HCT (r= 0.196, 95% CI 0.016-0.363; p= .0327). A significantly higher MNC count was noted when 25(OH)D concentration was ≥ 20ng/mL (4.5x 108, range (1.7-9.5) vs. 3.9x 108, range (0.8-9); p= .0329). This correlation between 25(OH)D level and TNC and MNC was not detected after adjustment for race (Figure 1). However, 25(OH)D concentration ≥ 20 ng/mL significantly correlated with CBU HCT in AA race (median 31.9% (24-42) vs. 27.8%, range (21.4 - 40); p= .0124). Conclusion 25(OH)D level, TNC and HCT are all significantly lower in UCB units from AA compare to Caucasians. Independent of race, 25(OH)D directly correlated with TNC and MNC. These data suggest vitamin D and other yet to be determined factors play an important role in the mechanism of low UCB cell and progenitor counts. Disclosures: No relevant conflicts of interest to declare.

With the new treatments for multiple myeloma (MM), increasing numbers of patients fail to mobilize sufficient peripheral blood stem cells (PBSC) for autologous stem cell transplant (ASCT). Multiple studies have identified clinical and laboratory factors, such as age, number of lines of chemotherapy, radiation exposure, bone marrow involvement, and low PLT count as risks for poor mobilization. However, there are fewer studies that analyze only the effect of multiple clinical risk factors on mobilization outcomes. We retrospectively analyzed 259 MM patients who underwent first apheresis after GCSF mobilization between December 2000 and December 2012. Clinical risk factors analyzed include age, number of lines of chemotherapy, number of cycles of chemotherapy, number of doses of cyclophosphamide, number of doses of lenalidomide, and prior external beam radiation. The standard dose of GCSF was 10 mcg/kg/day, however the exact dose for a significant number of patients was not known. Patients were assessed as to whether optimal (≥8x106 CD34+ cells/kg) or minimal (≥4x106 CD34+ cells/kg) number of stem cells for two ASCTs were collected. The median age of the entire cohort was 59.7 years (27.9-76.0). Overall 10.8% and 32.6% failed to collect the minimal and optimal number of stem cells after one round of apheresis. Of the twenty patients who underwent a second round of apheresis, 9 (45%) collected minimal and 7 (35%) collected optimal total number of stem cells, with an overall failure rate of 4.6% and 29.8%, respectively. The effect of the number of clinical risk factors on the mobilization failure during first apheresis is summarized in Table 1. For each additional clinical risk factor, the likelihood of collecting the minimal and optimal number of CD34+ cells is reduced by 34% (CI=0.484-0.893, p=0.0072) and 32% (CI=0.538–0.860, p=0.0013) respectively. On univariate analysis, all risk factors were analyzed as continuous variables, except for prior radiation which was analyzed as a categorical variable. Prior lenalidomide exposure (odds ratio=0.502, CI=0.297–0.845, p=0.0096), and prior radiation therapy (odds ratio=0.502, CI=0.293–0.861, p=0.0123) had the greatest negative predictive value. Of the 38 patients who were exposed to lenalomide (median 4 cycles; range 1-24 cycles), 13% and 42% failed to collect minimal and optimal number of stem cells in the first apheresis cycle, respectively. An association was seen between number of days required to collect target number of stem cells and number of risk factors (p≤0.001). Median number of days required to collect target number of stem cells for 0, 1 or 2+ clinical risk factors was 2, 2, and 4 days, respectively. When the effect of clinical risk factors were analyzed according to number of CD34+ cells/kg collected on each day of apheresis, statistically significant differences in collection efficiency were seen on the first 3 days of apheresis (Figure 1). In summary, clinical characteristics of patients with MM can potentially be used to predict mobilization failure. The presence of 2 or greater clinical risk factors adversely affect the ability to successfully collect the target stem cell dose. These risk factors may help in identifying high-risk MM patients who may benefit from alternative mobilization regimens that can be tested in prospective clinical trials.Number of Clinical Risk Factors012+N1128561% Patients not collecting optimal # of cells on 1st apheresis cycle23.231.850.895% CI15.8-32.122.1-42.833.7-63.9p-value0.19710.0003% Patients not collecting minimal # of cells on 1st apheresis cycle5.411.818.095% CI2.0-11.35.8-20.69.4-30.0p-value0.11950.0096Median number of days of collection224Range1-81-91-10p-value0.4233 Disclosures: No relevant conflicts of interest to declare.

Peripheral blood stem cell (PBSC) collection is increasingly used in allogeneic stem cell transplantation. However, a small percentage of healthy donors have a poor mobilization response to G-CSF. Very little information exists on the effect of donor race or ethnicity on PBSC mobilization. We analyzed 10776 unrelated donors from the National Marrow Donor Program (NMDP) who underwent G-CSF mobilized PBSC collection from 2006–2012. We investigated the effect of self-reported donor race/ethnicity on collection efficiency, defined as number of CD34+ cells/L (of donor blood processed), number of mononuclear cells (MNC)/L and CD34+ cells/MNC collected on the first day of apheresis. Categorical variables were analyzed by the Chi-square test and the Kruskal-Wallis test was used for continuous variables. A linear regression model was used to compare the various race/ethnic groups while controlling for potential confounding factors (such as age, BMI, gender, and year of apheresis). The result of our analysis is shown in Table 1. Univariate analysis revealed statistically significant differences in CD34+ cells/L, MNC/L and CD34+/MNC in all races analyzed. In general, African Americans (AA) had the highest collection efficiency while Caucasians had the lowest. Other races/ethnicities had collection efficiencies between the two groups. On multivariate analysis, statistically significant differences in CD34+ cell/L were seen in Hispanics, AA and Asian/Pacific Islanders (API), primarily in the obese (Hispanic, AA, API) and overweight (AA, API) donors. In the API group the differences in collection efficiency were predominately seen in males. No differences were seen between Caucasians and Native Americans. This study reveals significant racial/ethnic differences in the efficiency of collection of CD34+ cells in unrelated donors. Although these differences do not appear to interfere with the ability to collect adequate numbers of PBSC, it is currently unknown why they exist. This is an area for continued research. Disclosures: No relevant conflicts of interest to declare.

Abstract 3074 Background: Disease relapse after allogeneic hematopoietic stem cell transplant (HCT) remains a major obstacle to treatment success and cure for patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Early identification of patients at a high risk for disease relapse has significant practical implications allowing early therapeutic interventions. We evaluated a novel approach for an early identification of a post-transplant relapse in patients with MDS and AML. Methods: CD34+ specific donor chimerism analysis was obtained in 6 HCT recipients with CD34+ AML and MDS. Starting at day +30 post HCT CD34+ cells from peripheral blood were positively selected by immunomagnetic isolation and then underwent fluorescence-activated cell sorting. Purified CD34+ cells were subsequently evaluated for percentage of donor DNA contribution by short tandem repeat (STR) analysis. CD34+ specific donor chimerism analysis was repeated monthly until hematologic relapse or death occurred. Simultaneously, conventional donor chimerism analysis was measured in the subpopulations of peripheral blood cells. Results: CD34+ cells were isolated from peripheral blood with a very high purity >95% and in sufficient quantity for reliable STR analysis in all study patients. Out of 6 evaluated patients, 3 developed hematologic relapse confirmed by bone marrow evaluation. In each relapsed patient CD34+ specific chimerism dropped to 80% (Figure 1). Moreover, obvious and steady decline in CD34+ specific donor chimerism significantly preceded the time of hematologic relapse. In contrast, no decline in CD34+ chimerism was identified in 3 patients without hematologic relapse. (Figure 1). Conclusion: Though this is a preliminary study, the results suggest that CD34+ specific donor chimerism analysis is a useful technique for timely identification of hematologic relapse in MDS and AML patients after HCT and may provide significantly earlier relapse detection than conventional chimerism analysis. Disclosures: No relevant conflicts of interest to declare.

Abstract 4335 Background: AML depends on blood vessel networks for disease progression and protection from conventional chemotherapy. In prior preclinical work, we demonstrated that the vascular disrupting combretastatin, OXi4503, had significant activity against human AML by dual targeting of nascent blood vessels and malignant myeloblasts. In solid tumor studies, the maximal tolerated dose (MTD) of OXi4503 was 11–14 mg/m2 and the dose limiting toxicity (DLT) was hypertension. Therefore, we initiated a phase I clinical study of OXi4503 in patients with relapsed and refractory AML and advanced MDS. Methods: The primary objectives of the phase I dose escalation study (NCT01085656) were to establish safety and determine MTD in patients with hematological malignancies. Eligibility included history of AML or MDS (RAEB-1, RAEB-2), failure to respond to at least one induction therapy, good performance status (ECOG ≤ 2), adequate kidney and liver functions, blood pressure < 140/90 mmHg, no history of major operative surgery within 28 days, and no history of cerebrovascular accident. DLT was defined as grade 3 or greater non-hematological drug-related toxicity or failure of blood count recovery by Day 42 after the start of Cycle 1. Amlodipine was administered as pre-medication if baseline blood pressure was > 120/80 mmHg. OXi4503 was administered by intravenous infusion over 10 minutes on Days 1, 8, 15 and 22 of each 28-day cycle, and escalated according to a defined dose schema. Continued weekly dosing was permitted until disease progression or unacceptable toxicities. Results: Between May 2011 and August 2012, 5 patients with refractory AML were enrolled in an ongoing phase I safety study. The median age was 61 years (range, 46–76). Most patients were male (80%). Cytogenetics were adverse in one patient and intermediate in four. The median number of prior therapies was 4 (range, 1–7). Two subjects were assigned to the 2.5 mg/m2 dosing cohort, two received 3.75 mg/m2 and one received 5 mg/m2. No patients developed DLTs. Adverse events attributable to OXi4503 infusion included bone pain, fever, anemia and thrombocytopenia. The mean change in systolic blood pressure after OXi4503 infusion was +11.5 mmHg in the 2.5 mg/m2 cohort, +5.5 mmHg in the 3.75 mg/m2 cohort, and +0.82 mmHg in the 5 mg/m2 cohort. Plasma LDH and uric acid increased by at least two-fold within hours after OXi4503 infusions, suggesting leukemia cell lysis. Overall response was 2/5 (40%), with one patient achieving a marrow complete remission (mCR) and one patient achieving a partial remission (PR). Median number of cycles was 1 (range, 1–6). Three of five subjects discontinued the study due to AML progression and one due to pneumonia. One patient with AML treated with 5 mg/m2 OXi4503 has received 6 months of treatment and continues to receive weekly infusions. Analysis of bone marrow (BM) after OXi4503 infusions showed alterations in endothelial cell (EC) morphology and acute increases in VEGF expression (1.28–1.75 × pre-dose levels). Conclusions: At low doses the vascular disrupting combretastatin OXi4503 is well tolerated with preliminary evidence of disease response in heavily treated, refractory AML. Biological activity associated with OXi4503 included changes in BM EC morphology and a reactive VEGF response, suggesting that addition of angio-inhibitory agents such as anti-VEGF agents to vascular disruption with OXi4503 may be worthy of study to improve AML regression. Disclosures: Cogle: OXiGENE: Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chaplin:OXiGENE: Consultancy. Balkissoon:OXiGENE: Employment.

2799 Background: Chronic immunosuppression, a known risk factor for many malignancies, has not been identified as a risk factor for chronic myeloid leukemia (CML). Here we report higher than expected incidence of CML in organ transplant recipients observed at a single institution over a 12 year period. Methods: We report all cases of CML diagnosed in adult solid organ transplant recipients at a single institution from 2000–2011. These organ transplant patients were followed at our institution for their transplant related care, which enabled a detailed review of the cases of CML. The observed incidence of CML cases during the 12 year period was compared to the published national CML incidence in the general adult population by the exact binomial test. Results: As reported to the Organ Procurement and Transplant Network, our institution performed 3,223 adult solid organ transplants from 2000–2011. Four of these organ transplant recipients developed CML at various intervals post-transplant ([Table 1][1]). All patients had CML diagnosed in chronic phase after the evaluation of abnormal leukocytosis and splenomegaly. No additional cytogenetic abnormalities besides Philadelphia chromosome t(9;22) were observed in any of these patients. All patients were treated with imatinib and achieved a complete cytogenetic response (CCyR) within 12 months of therapy. Two patients subsequently achieved complete molecular response, one patient remained in CCyR on imatinib and one patient died from septic shock while in CCyR. Conclusion: The observed 12 year incidence of CML was 4 out of 3223 transplant recipients. This incidence significantly exceeds the reported national incidence of 1.6 cases per 100,000 persons per year (p = 0.004, exact binomial test). We hypothesize that the increase in CML incidence in solid organ transplant recipients results from chronic immunosuppression. We also observed that clinical presentation and response of CML to imatinib therapy in solid organ transplant recipients were similar to non-transplant CML patients. | Patient | Age/gender | Transplant Type | Immunosuppressant | Time from transplant to CML diagnosis (years) | CML phase at diagnosis | Best response to imatinib | Time to Best Response (months) | |:-------:| ---------- | -------------------------------- | --------------------------------------- | --------------------------------------------- | ---------------------- | ------------------------- | ------------------------------ | | 1 | 52/male | Liver | Prednisone and tacrolimus | 4 | Chronic | CMR | 18 | | 2 | 48/female | Kidney and pancreatic islet cell | Prednisone and tacrolimus | 6 | Chronic | CCyR | 6 | | 3 | 50/male | Lung transplant | Prednisone, tacroliums and azathioprine | 1.5 | Chronic | CMR | 18 | | 4 | 59/male | Kidney | Sirolimus | 10 | Chronic | CCyR | 6[*][2] | * Abbreviations: CMR- complete molecular response, CCyR- complete cytogenetic response * [↵][3]* - The patient died from septic shock while in CCyR Table 1 Clinical characteristics of solid organ transplant recipients with CML Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #fn-2 [3]: #xref-fn-2-1