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Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Immune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids, rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up in the outpatient setting.

BACKGROUND Anemia is an independent risk factor for hospitalization, readmission, prolonged length of stay (LOS), diminished quality of life, and mortality. A multidisciplinary program was implemented to manage anemia preoperatively as a patient blood management (PBM) initiative. METHODS AND MATERIALS From March 2016 to August 2018, 240 patients were screened for anemia during their preoperative cardiovascular visit. About 52/240 (22%) were found to be anemic and met out inclusion criteria. Also, 45/52 (87%) had iron deficiency anemia and 7 (13%) had anemia without iron deficiency. A similar historical cohort of patients undergoing elective cardiovascular surgery with hemoglobin (Hb)

Introduction: Our previous qualitative studies of immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors revealed that patients did not communicate to their hematologists about residual cognitive and fatigue issues. A way to overcome this communication barrier is implementation of patient-reported outcomes (PROs) in routine care. Integration of PROs into the clinical care of other diseases has resulted in improved patient-provider communication, symptom management, quality of life and overall patient satisfaction. However, decisions about the mode of administration are challenging. Although 92% of the United States population has access to the internet, studies have shown minorities prefer alternative modes of administration. Given that iTTP disproportionately affects Black women, understanding patient preference is critical for integrating PRO instruments into routine care. The primary study goal was to determine the preferred mode of administration of PRO instruments in iTTP. Furthermore, many individuals use the internet as a source of medical information/advice. A study of iTTP literacy reported that only 34% of survivors correctly identified disease relapse risk factors suggesting a critical knowledge gap. A secondary goal was to describe iTTP survivors' behaviors regarding using the internet for medical information or support. Methods: We utilized a cross-sectional study design. iTTP survivors were recruited from August 2019 until present. Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Multi-center recruitment of survivors included: Oklahoma University, Ohio State University, University of Minnesota, Johns Hopkins University, University of Rochester, University of Pennsylvania, University of Alabama at Birmingham, University of Utah and the University of Vermont. Following informed consent, survivors were administered the PROMIS ® cognitive function ability, anxiety and fatigue instruments via their preferred mode (online, telephone, or self-administered). Typical internet usage, behaviors regarding searching for health information online and demographics were also obtained. Results: To date, 94 survivors have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). A majority (54%) preferred completing PROMIS ® surveys online vs. self-administered or telephone administered. However, among Black survivors, only 38% preferred online administration and among survivors aged ≥65 years only 22% preferred online administration. Interestingly, there was an overall shift in a preference toward online administration following the onset of the COVID-19 pandemic (45% (21/47) preferred online pre vs 66% (31/47) preferred online post). Ninety-one percent (86/94) of survivors reported at least occasional internet use vs 8 (9%) reported none. Similarly, 82% (70/85) had searched the internet for health/medical information for themselves in the past year. Also 62% (53/86) of the survivors selected 'strongly agree' or 'agree' to the statement that the internet helps them determine if symptoms are important enough to see a doctor. Likewise, 62% used the internet to interpret doctor's recommendations. Additionally, 47% (40/86) 'strongly agree/agree' the internet helped determine if they would take a medication/seek alternative treatment. Moreover, 64% (55/86) agreed the internet was a good way to find others experiencing similar health problems. However, when asked about behaviors over the past year, only 42% (36/85) used online social networking sites like Facebook to look for health information or find others with iTTP and only 36% (31/85) had actually participated in online iTTP support groups. Conclusions: Overall iTTP survivors preferred online PRO administration; however, Black and older survivors preferred other methods. Recognizing these preferences is a vital step toward integrating PROs into routine care. Furthermore, iTTP survivors are using the internet as a source of medical support and information. Therefore, it is critical to not only educate iTTP survivors about credible online resources but also to create additional content. Also, future studies are needed to further explore the impact of the COVID-19 pandemic on online health behaviors. Disclosures Terrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Cuker: Spark Therapeutics: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy. Chaturvedi: Dova: Other: Advisory board member; UCB: Other: Advisory board participation; Argenx: Other: Advisory board member; Alexion: Other: Advisory board member; Sanofi Genzyme: Other: Advisory board member. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria. Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Cataland: Alexion: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy.

Introduction: Patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) describe cognitive concerns years after acute episodes. However, these concerns are not routinely addressed during hematology visits. The Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function abilities survey is an easy to administer, valid, reliable, generic instrument that has not been evaluated in iTTP patients from the United States (US). Therefore, the first aim of this study was to compare PROMIS scores of iTTP patients in remission to the normative US population. Also, research in other disorders reported that a barrier to integrating PROMIS into routine care was physician uncertainty related to interpreting results. PROMIS instruments utilize normative scoring, which lacks clinical meaning. Therefore, creation of clinical severity cut-points ('mild', 'moderate', 'severe') is critical to facilitate clinical interpretation. The second aim was to create clinical severity thresholds for the PROMIS instrument. Methods: iTTP patients were recruited from 9 US centers (8/2019 to present). Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Following informed consent, patients were administered the PROMIScognitive survey via their preferred mode (online, telephone, or self-administered). The instrument focused on cognitive function over the last 7 days. Responses were a 5-point Likert scale ranging from 'not at all' (indicating poor function) to 'very much' (no current problem). Demographics and the PROMIS global health question ('In general, would you say your health is') were also obtained. Descriptive statistics summarized patient scores relative to the US population (mean 50, SD 10) with lower scores indicating worse function. Additionally, we determined the T-score ranges for patients who reported 'not at all/a little bit' on all cognitive items and for those who reported 'quite a bit/very much' on all cognitive items. The upper end of the T-score range for patients reporting 'not at all/a little bit' determined the threshold for 'Severe' impairment and the lower end of the T-score range for those reporting 'quite a bit/very much' determined the threshold for 'No/Mild' impairment. Scores greater than the threshold for 'Severe' but lower than the threshold for 'No/Mild' were considered 'Moderate' cognitive impairment. Patients were then classified into a severity category based on their T-scores. As a descriptive validity check, we compared the proportion of patients reporting 'excellent/very good' on the global health question between the 'Severe' and 'No/Mild' impairment classifications. Results: To date, 94 patients have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). Overall the mean cognitive score was 45 (SD 9) compared to the US mean 50 (SD 10). Patients who preferred online administration had a mean score of 47 (SD 9) vs patients who preferred telephone or self-administered (mean score of 43 [SD 9]). T-scores for patients reporting 'not at all/a little bit' on all items ranged from 23.4-35.1. Based on T-scores, 14 patients (15%) were then classified as having 'Severe' cognitive impairment with T-scores < 35.1 (Figure 1). Only 14% of patients classified as having 'Severe' cognitive impairment reported their general health as 'excellent/very good'. T-scores for patients reporting 'quite a bit/very much' on all items ranged from 49.2-68.9. Thirty-one (33%) patients were classified as 'No/Mild' impairment with T-scores >49.2 (Figure 1) and 52% of these patients classified their health as 'excellent/very good'. Conclusion: iTTP patients in remission have descriptively lower cognitive scores versus the US population. Our results are similar to those reported from a cohort of iTTP patients from the United Kingdom (PROMIS cognitive mean 40, SD 8). Further, results showed that patients with cognitive T- scores 49, who have no/mild cognitive impairment. This is the first study to create clinical severity thresholds for the PROMIS cognitive function abilities instrument. Our data provide clinical meaning for PROMIS which should facilitate clinical use in iTTP by identifying patients with severe impairment who need referral to specialists. Figure 1 Figure 1. Disclosures Terrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: LFB: Honoraria; HEMA Biologics: Honoraria. Mazepa: Sanofi Aventis: Other; Answering TTP Foundation: Research Funding. Cuker: Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Takeda: Research Funding. Chaturvedi: Sanofi Genzyme: Other: Advisory board member; Alexion: Other: Advisory board member; Dova: Other: Advisory board member; Argenx: Other: Advisory board member; UCB: Other: Advisory board participation. Lim: Hema Biologics: Honoraria; Dova Pharmaceuticals: Honoraria; Sanofi Genzyme: Honoraria. Gangaraju: Sanofi Genzyme: Consultancy; Alexion: Consultancy. Cataland: Ablynx/Sanofi: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Takeda: Consultancy; Alexion: Consultancy, Research Funding.

Introduction The United States Thrombotic Microangiopathy (USTMA) Consortium consists of high-volume US referral centers that are committed to collaborative research in TMAs. The USTMA Immune Thrombotic Thrombocytopenic Purpura (iTTP) registry has compiled retrospective data on demographics, treatments and outcomes in patients with iTTP to create the world's largest database of patients with this rare disease. While there is consensus on the use of therapeutic plasma exchange (TPE) for treatment of iTTP, there are no large randomized trials on which to base use of rituximab. The drug is frequently used for refractory or relapsed iTTP, but is currently being used more frequently for de novo (first episode) iTTP. We queried the USTMA iTTP registry to determine whether relapse free survival (RFS) is superior when rituximab is added to TPE and corticosteroids for treatment of iTTP. We hypothesized that the addition of rituximab would improve RFS at 5 years in both de novo and relapsing iTTP. Methods Following IRB approval at each institution, investigators independently reviewed individual patient records to confirm diagnostic criteria and entered demographic, treatment and outcomes data into the REDCap database housed at the University of North Carolina. The diagnosis of iTTP was defined as ADAMTS13 < 10% or ADAMTS13 < 20% with an inhibitor or antibody detected at any point or a clinical diagnosis of iTTP based on presenting characteristics, response to treatment and/or relapsing phenotype before ADAMTS13 testing became available (N=173). Relapse was defined as a recurrence of iTTP after at least 30 days of remission (recurrence within 30 days was considered an exacerbation, or continuation of the prior episode). To explore the effect of rituximab added to TPE and corticosteroids, we first assessed the treatment effect in de novo iTTP patients and then separately in relapse. We constructed Kaplan-Meier curves to compare RFS for patients treated with rituximab plus corticosteroids versus corticosteroids alone in both groups, and compared RFS at specific time points using the Klein method. To better understand whether other patient variables had an effect on RFS in both de novo episodes and relapses, ordinary (time-to-event) and mixed-effects (recurrent time-to-event) Cox proportional hazards models were used to examine the relationships of treatment, race/ethnicity, sex, age, treatment year, and presenting signs/symptoms with the outcome. Analyses were conducted using R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Results As of July, 2019, the USTMA database contains 775 unique study patients with a confirmed diagnosis of iTTP with 1397 unique iTTP episodes. The treatment of patients' de novo iTTP episode was available for analysis in 375 patients, 188 of whom were treated with corticosteroids alone, 131 with corticosteroids plus rituximab, and 56 with other therapies. RFS was significantly higher in patients treated with corticosteroids and rituximab compared to those treated with corticosteroids alone at 1 year (0.93 vs. 0.78, p=0.0002) and 3 years (0.82 vs. 0.66, p=0.004) but not 5 years (0.60 vs. 0.56, p=0.39). In addition, the risk of relapse decreased with later treatment year for de novo iTTP (hazard ratio (HR) 0.95, 95% CI 0.92-0.99, p=0.03), consistent with rituximab use increasing over time, and was increased in African Americans compared with Caucasians (HR 1.83, 1.10-3.06, p=0.02). We then explored the treatment effect in all iTTP relapses (743 relapses in 426 patients). Here, a significant (p=0.0007) interaction between treatment and race was found. Among African Americans, we found no difference in RFS when rituximab was added (HR 1.15, 0.81-1.62, p=0.43). However, among Caucasians, RFS was significantly improved when rituximab was added (HR 0.15, 0.06-0.35, p Conclusions For de novo iTTP, adding rituximab to corticosteroids for immunosuppression likely delays but does not prevent relapse. Unlike in de novo disease, in patients with relapsed iTTP, we found a novel and significant interaction between race and treatment: while Caucasians had significantly improved RFS with the addition of rituximab, there was no effect on RFS in African Americans. Further investigation is warranted to determine the mechanisms of this difference in the response to rituximab in relapsed iTTP to improve outcomes in African Americans. Figure Disclosures Marshall: Sanofi: Membership on an entity's Board of Directors or advisory committees. Farland:Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Imara: Other: PI on Clinical trial- Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Zheng:Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding; Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau. Cataland:Ablynx/Sanofi: Consultancy, Research Funding; Alexion: Consultancy, Research Funding. Off Label Disclosure: rituximab for immunosuppression in TTP.

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683], sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806]. Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures Farland: Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.

While hematopoietic stem cells (HSCs)-intrinsic effects of aging have been explored, less is known about how HSC support is altered by the aged bone marrow microenvironment (BMME). To assess the role of the BMME in HSC aging, we compared the BMME in young (6-12 weeks) and aged (20-24 months) male mice and young (50 YO) human volunteers. Aged mice had remodeling of the BMME, with expansion of the marrow cavity and vascular volume compared to young mice. BMME constituents were redistributed within two distinct anatomic regions, namely endosteal bone-associated (BA) and marrow-associated (MA) cells. BA cells in aged mice contained fewer phenotypic mesenchymal/osteoblastic progenitors, with reduction in their ability to constitute colony forming units (CFUs). CFU loss was also observed in aged human volunteers. Aged murine MA had significant expansion of dysfunctional mesenchymal stem cells (MSCs) and activated macrophages (MΦ). Increased MΦ were also detected in aged human marrows. Following this in vivo characterization, we developed an ex vivo co-culture system to determine if aged murine BMME cells could impart aging characteristics to young HSCs. Young murine HSCs co-cultured with aged MA cells acquired phenotypic properties of aged HSCs, including increased CD41+ expression. Single cell RNA sequencing of Long Term-HSCs (LT-HSCs) from young and aged mice also identified upregulation of integrin-β3 (CD61) as a novel marker of aged LT-HSCs. Subsequent flow cytometry analysis confirmed the increase in CD61+ expression in vivo in aged HSCs. Importantly, aged MA - but not BA cells - also increased CD61+ expression in young HSCs ex vivo, highlighting the region-specific remodeling of the BMME that occurs with age. We then used a reductionist approach to identify targetable cellular and molecular regulators of the region-specific BMME-induced HSC aging. CD45+ and Ter119+ depletion in aged MA cells did not induce CD41+ expression in young HSCs, suggesting that a critical BMME component responsible for non-cell-autonomous HSC aging is present within the hematopoietic pool. Since marrow MΦ can regulate HSCs, we co-cultured aged MA MΦ with young MA and found that aged MΦ were sufficient to increase CD41+ expression in young HSCs. The addition of aged MΦ also expanded young MSCs, demonstrating that MΦ orchestrate both BMME remodeling and HSC aging. We next aimed to explore mechanisms by which aged MA MΦ impart aging characteristics to HSCs. Transcriptional analysis of murine MA MΦ demonstrated an increase in inflammatory activation in aged mice compared to young mice. This finding was also present in aged human MΦs. Among the inflammatory signals, interleukin-1β (IL-1β) was identified to be necessary and sufficient to mediate the aging effect of aged MA MΦ on young HSCs. Transcriptional analysis also revealed downregulation of phagocytic programs in aged MA MΦ compared to young MA MΦ. Supporting the transcriptional data, aged MA MΦs cultured in vitro demonstrated impaired ability to engulf senescent neutrophils compared to young MA MΦ. Bone marrow MΦ continuously remove large quantities of senescent neutrophils through phagocytosis, a process also known as efferocytosis. Complementing the in vitro findings, in vivo testing demonstrated that young MA MΦ are primarily responsible for engulfing senescent neutrophils and that aged MA MΦ had reduced engulfment of senescent neutrophils. No phagocytic defect was identified in aged BA MΦ, highlighting the regionalization of MΦ function within the BMME that is differentially impacted with age. Consistent with the systemic impact of the efferocytic defect of aged MA MΦ, aged mice had increased levels of circulating senescent neutrophils and. Moreover, neutrophils from aged mice had increased caspase-1 activity, a signal required for IL-1β activation. Together, these data provide evidence that aging differentially remodels two anatomically distinct BMMEs. Regional specialization of marrow MΦ was differentially impacted by aging and induced aging characteristics in HSCs. We propose that impaired removal of senescent neutrophils by aged MA MΦ increases IL-1β production, leading to local inflammation and disrupted BMME and HSC function in aged mice. Strategies aimed at restoring healthy efferocytic activity as well as diminishing IL-1β production or function could therefore reduce the aging effect on HSCs by rejuvenating the BMME. Disclosures Liesveld: Onconova: Honoraria; Seattle Genetics: Honoraria.

The natural history of the chronic phase (CP) of chronic myeloid leukemia (CML) and the high response rates achieved with BCR-ABL inhibitor therapy necessitate long-term evaluation of survival-based outcome measures. Prior to the availability of long-term BCR-ABL inhibitor data, short-term surrogate end points predictive of longer-term outcomes have been identified using data from clinical trials of patients with CML-CP treated with interferon-α-based therapy and approved BCR-ABL inhibitors. In patients with newly diagnosed CML-CP treated with imatinib, achieving a complete cytogenetic response (CCyR) by 12 months has been associated with more favorable outcomes, and both CCyR and major cytogenetic response have been used as surrogate end points for regulatory approval. Following approval of second-generation BCR-ABL inhibitors in the first-line setting (nilotinib, dasatinib), which have significantly faster and deeper response rates than imatinib, molecular-based surrogate markers at earlier time points of 3 and 6 months are also being explored, although longer follow-up is needed. As patients who achieve early responses show the greatest long-term benefit, these end points may help to identify patients with suboptimal responses early in treatment who might benefit from switching to a different, more effective therapy.

Osteoprogenitor cells (OPCs) are marrow microenvironmental cells known to modulate hematopoietic stem and progenitor cells (HSPCs). Specifically, OPCs regulate HSPCs in response to Parathyroid hormone (PTH) treatment in murine models. However, the role of OPCs in human HSPC regulation and whether human OPCs can be manipulated is poorly understood. Niche stimulation is an appealing strategy to aid in the treatment of hematopoietic dysfunction. Myelodysplastic syndromes (MDS) are clonal disorders with ineffective hematopoiesis resulting in cytopenias and risk of transformation to acute leukemia (AML). In mouse models, disruption of the osteolineage cells can contribute to initiation of ineffective hematopoiesis with phenotypic features of MDS. Our long term goal is to utilize microenvironmental stimulation as a therapeutic tool to improve hematopoietic disorders. We hypothesized that human cells isolated from the marrow fraction containing spicules harbor HSPC supportive cells, which can be manipulated to improve HSPC support. Moreover we hypothesized that OPC number and function is impaired by dysplasia-initiated microenvironmental disruption as a potential mechanism for reduced support of HSPCs and ineffective hematopoiesis. Our objective was to isolate human bone marrow spicule associated cells (SACs) and define their ability to support HSPCs, determine the impact of PTH treatment of SAC/HSPCs interactions and characterize dysplasia-induced osteolineage changes in human MDS and AML bone marrow. To achieve this objective, we used normal as well as MDS/AML patient-derived OPCs using a mouse-human co-culture system. Human bone marrow SACs isolated by collagenase digestion were either used for co-culture, analyzed with flow cytometry or cultured in mineralization media in limited dilutions. To assess the potential impact of PTH on human OPC interaction with HSPCs, we developed a 7 day co-culture of human bone marrow SACs treated with either vehicle or PTH, with mouse Lineage- Sca1+ c-Kit+ (LSK) hematopoietic progenitor cells. At the end of the co-culture, all cells present were used for competitive transplantation. Transplant experiments demonstrated that PTH treatment of the human bone marrow SACs leads to improved function of the co-cultured LSK cells as demonstrated by significantly improved engraftment of the LSK cells after transplant into irradiated C57/bl6 recipient mice when sampled at pre-specified time points over a 20-week period (N=12, 2-way ANOVA; p < 0.05). Flow cytometry analysis showed that mature (Lin- CD31- CD146+ CD105-) and immature osteolineage (Lin- CD31- CD146+ CD105+) cells were present in SACs and more abundant compared to within BMMCs (1% vs 0.1% and 0.24% vs 0.12% for the same patient). Notably, the putative HSC-supportive MSC pool was increased in SACs vs BMMCs (0.052% vs 0.019%). The presence of OPCs was functionally confirmed using colony forming unit osteoblasts (CFU-OBs). CFU-OB frequency was calculated using L-Calc TM (StemCell technologies). Among normal donors the frequency of CFU-OBs was low in marrow donors >50 years old compared to These data demonstrate that human SACs contain HSPC-supportive cells which can be stimulated to improve HSPC function. Human SACs comprise MSCs and osteolineage cells including osteoprogenitor cells. Aging decreases OPC pools in SACs. Our data in our small sample also suggest that dysplastic bone marrow microenvironment may negatively impact OPCs, which may in turn decrease OPC support of HPSCs. PTH treatment in our in-vitro model shows the potential to improve the interaction between the OPCs and HSPCs, resulting in amelioration of HSC function. Together these data suggest a strategy where targeting the MDS microenvironment may add to the currently available treatment modalities. Disclosures Calvi: Fate Therapeutics: Patents & Royalties.

Abstract 5250 Background: VTE is a public health burden in hospitalized patients, affecting the length of hospital stay and overall cost of care. Recent studies suggest increasing incidence of VTE among cancer patients, but contemporary data regarding proportion of VTE attributable to cancer and non-cancer populations are lacking. Methods: Hospital-acquired VTE is a reportable event to New York State and we studied all reported VTE events among patients hospitalized at the University of Rochester Medical Center from January 2003 through April 2009. We utilized electronic medical records to identify additional information including demographics and diagnosis of malignancy. Results: We identified 2031 patients with 2185 documented VTE events during the study period. Of these, 1102 (54.3%) were men and 929 (45.7%) were women. VTE events included deep vein thrombosis (DVT) (N=1428, 65 %), pulmonary embolism (PE) (N=757, 34.6%), and concurrent DVT and PE (N=153, 7 %). Of the 2031 hospitalized patients with VTE, 492 (24.2%) had a concurrent diagnosis of cancer and 1539 (75.8%) did not. Of 492 cancer-related VTE, 167 (34%) were associated with hematologic malignancies, and 324 (66%) with solid tumors. The proportion of cancer-associated VTE varied by year, ranging from 21% to 31%. Conclusions: Approximately one-fourth of all VTE in hospitalized patients occurred in patients with cancer, including a substantial proportion with hematologic malignancy. Public health efforts to reduce hospital-associated VTE should focus on improving compliance with thromboprophylaxis for this population. Disclosures: No relevant conflicts of interest to declare.