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We follow a patient with Diamond-Blackfan anemia (DBA) mosaic for a pathogenic RPS19 haploinsufficiency mutation with persistent transfusion-dependent anemia. Her anemia remitted on eltrombopag (EPAG), but surprisingly, mosaicism was unchanged, suggesting that both mutant and normal cells responded. When EPAG was withheld, her anemia returned. In addition to expanding hematopoietic stem/progenitor cells, EPAG aggressively chelates iron. Because DBA anemia, at least in part, results from excessive intracellular heme leading to ferroptotic cell death, we hypothesized that the excess heme accumulating in ribosomal protein-deficient erythroid precursors inhibited the growth of adjacent genetically normal precursors, and that the efficacy of EPAG reflected its ability to chelate iron, limit heme synthesis, and thus limit toxicity in both mutant and normal cells. To test this, we studied Rpl11 haploinsufficient (DBA) mice and mice chimeric for the cytoplasmic heme export protein, FLVCR. Flvcr1-deleted mice have severe anemia, resembling DBA. Mice transplanted with ratios of DBA to wild-type marrow cells of 50:50 are anemic, like our DBA patient. In contrast, mice transplanted with Flvcr1-deleted (unable to export heme) and wild-type marrow cells at ratios of 50:50 or 80:20 have normal numbers of red cells. Additional studies suggest that heme exported from DBA erythroid cells might impede the nurse cell function of central macrophages of erythroblastic islands to impair the maturation of genetically normal coadherent erythroid cells. These findings have implications for the gene therapy of DBA and may provide insights into why del(5q) myelodysplastic syndrome patients are anemic despite being mosaic for chromosome 5q deletion and loss of RPS14.

Chronic lymphocytic leukemia (CLL) occurs in 2 major forms: aggressive and indolent. Low miR-29b expression in aggressive CLL is associated with poor prognosis. Indiscriminate miR-29b overexpression in the B-lineage of mice causes aberrance, thus warranting the need for selective introduction of miR-29b into B-CLL cells for therapeutic benefit. The oncofetal antigen receptor tyrosine kinase orphan receptor 1 (ROR1) is expressed on malignant B-CLL cells, but not normal B cells, encouraging us with ROR1-targeted delivery for therapeutic miRs. Here, we describe targeted delivery of miR-29b to ROR1+ CLL cells leading to downregulation of DNMT1 and DNMT3A, modulation of global DNA methylation, decreased SP1, and increased p21 expression in cell lines and primary CLL cells in vitro. Furthermore, using an Eμ-TCL1 mouse model expressing human ROR1, we report the therapeutic benefit of enhanced survival via cellular reprograming by downregulation of DNMT1 and DNMT3A in vivo. Gene expression profiling of engrafted murine leukemia identified reprogramming of cell cycle regulators with decreased SP1 and increased p21 expression after targeted miR-29b treatment. This finding was confirmed by protein modulation, leading to cell cycle arrest and survival benefit in vivo. Importantly, SP1 knockdown results in p21-dependent compensation of the miR-29b effect on cell cycle arrest. These studies form a basis for leukemic cell–targeted delivery of miR-29b as a promising therapeutic approach for CLL and other ROR1+ B-cell malignancies.

Dysregulated cellular differentiation is a hallmark of acute leukemogenesis. Phosphatases are widely suppressed in cancers but have not been traditionally associated with differentiation. In this study, we found that the silencing of protein phosphatase 2A (PP2A) directly blocks differentiation in acute myeloid leukemia (AML). Gene expression and mass cytometric profiling revealed that PP2A activation modulates cell cycle and transcriptional regulators that program terminal myeloid differentiation. Using a novel pharmacological agent, OSU-2S, in parallel with genetic approaches, we discovered that PP2A enforced c-Myc and p21 dependent terminal differentiation, proliferation arrest, and apoptosis in AML. Finally, we demonstrated that PP2A activation decreased leukemia-initiating stem cells, increased leukemic blast maturation, and improved overall survival in murine Tet2−/−Flt3ITD/WT and human cell-line derived xenograft AML models in vivo. Our findings identify the PP2A/c-Myc/p21 axis as a critical regulator of the differentiation/proliferation switch in AML that can be therapeutically targeted in malignancies with dysregulated maturation fate.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Background: Chimeric antigen receptor T (CAR-T) cell therapy is a recent treatment option for triple-class exposed relapsed refractory multiple myeloma (RRMM) patients, who have previously received proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. In addition to CAR-T cell therapy acquisition costs, there are expected CAR-T healthcare costs separate from the cost of the CAR-T cell therapy itself. Identification and quantification of these costs have not previously been fully investigated. Healthcare payers, hospitals, and physicians need this important cost information in order to make informed healthcare decisions. Objective: The objective of this study was to quantify CAR-T therapy associated healthcare costs, i.e., costs aside from CAR-T therapy acquisition costs, associated with use of CAR-T therapy in RRMM patients. Methods: RRMM CAR-T clinical trial data and published literature, including peer-reviewed publications and conference presentations, were used for identification of these additional healthcare cost components. Inclusion/exclusion of additional cost components was based on previously published oncology pharmacoeconomic studies and input from key opinion leaders (KOLs) with expertise in the treatment of RRMM patients. The study categorized costs for RRMM patients who receive the CAR-T infusion. Costs were categorized as pre-infusion, peri-infusion (excluding CAR-T therapy acquisition costs), and post-infusion costs. Pre-infusion costs included evaluation costs, apheresis costs, bridging therapy costs, and conditioning therapy costs. Peri-infusion costs included either inpatient or outpatient infusion costs. Post-infusion costs included 100-day post-infusion monitoring costs, additional infusion monitoring costs in the first year, and management of serious adverse event (AE) costs associated with the CAR-T therapy. Serious AEs included AEs that require or prolong hospitalization or result in death. CAR-T acquisition costs are known and readily accessible, but this is not the case for other costs associated with CAR-T therapy, i.e., the pre-, peri-, and post-infusion costs. The costs must be individually calculated utilizing CAR-T clinical trial data, medical resource costs and utilization, and AE costs and rates. Based on a targeted literature review, there are sufficient data in the public domain to quantify the component additional costs, however there are no publications quantifying the entirety of these costs specifically in RRMM patients receiving CAR-T. Methodology was developed for derivation of these costs, which comprise an important and consequential portion of the total CAR-T therapy costs. Results: The RRMM patient pre- and peri-infusion CAR-T healthcare cost, aside from CAR-T therapy acquisition costs, was estimated to be $15,478. The components of this cost were apheresis ($112), bridging therapy ($8,570), conditioning therapy ($3,435), and a single day of inpatient infusion ($3,362). The post-infusion costs (including additional inpatient hospital days, AE management, and monitoring costs) are dependent on the types and rates of AEs associated with CAR-T therapy. These results will be presented at the ASH 2021 meeting. Conclusions: This study developed a methodology for the categorization, quantification, and calculation of the important healthcare costs, aside from CAR-T therapy acquisition costs, associated with the use of CAR-T in triple-class exposed RRMM patients. This information has been lacking in the literature and the analysis provides valuable, holistic information that key stakeholders require to make informed decisions. Disclosures Jagannath: Bristol Myers Squibb: Consultancy; Janssen Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Legend Biotech: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Joseph: Johnson and Johnson: Current Employment, Current equity holder in publicly-traded company. Crivera: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Valluri: Janssen: Current Employment, Current equity holder in publicly-traded company. Cost: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Phelps: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Slowik: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Klein: Medical Decision Modeling Inc.: Current Employment. Yu: Medical Decision Modeling Inc.: Current Employment. Smolen: Medical Decision Modeling Inc.: Current Employment. Cohen: GlaxoSmithKline: Consultancy, Research Funding; Janssen: Consultancy; Takeda: Consultancy; Oncopeptides: Consultancy; BMS/Celgene: Consultancy; AstraZeneca: Consultancy; Genentech/Roche: Consultancy; Novartis: Research Funding.

Although myeloablative fludarabine/busulfan (FluBu4) has been widely adopted in clinical practice, considerable interpatient variability exists in systemic busulfan exposure (AUC) when using body weight or body surface area based-dosing, leading to decreased efficacy (i.e. relapse) or increased toxicity (i.e., mucositis, veno-occlusive disease). This well-defined dose-exposure-outcome relationship has led to the widespread clinical implementation of therapeutic drug monitoring (TDM). However, individualized TDM can be time and labor intensive as well as potentially biased due to the lack of incorporation of any previously established PK data (Bayesian prior). In contrast, Bayesian maximum a posteriori (MAP) PK models consider the Bayesian prior and individualized TDM to generate a revised probability distribution (Bayes conditional posterior) to more accurately and rapidly estimate the AUC with reduced bias. There are a paucity of data comparing busulfan AUCs using individualized PK versus MAP-Bayesian-based models in adults although these more sophisticated approaches may assist in optimizing dosing of busulfan in this vulnerable population. This was a retrospective, single-center study of patients who received FluBu4 with busulfan TDM between January 1999 and September 2019. 109 patients diagnosed with a hematologic malignancy who received either sequential (n=46) or concurrent (n=63) FluBu4 were analyzed. The median age was 48 (range: 18-66), and were Hispanic (n=38), White (n=46) or African-American (n=14). TDM was performed either after a test dose of 0.8 mg/kg (n=52) or after the first dose (3.2 mg/kg) of busulfan administered during the preparative regimen (n=71), with dosing was based on actual or adjusted body weight. For PK analysis, plasma busulfan concentrations were analyzed via gas chromatography with mass selective detection. Individualized PK data were generated using WinNonlin while the MAP-Bayesian approach utilized the Bayesian prior developed from McCune et al (Clin Cancer Res, 2014). An AUC of 4800 µM˖min/24 hours was targeted based on previous literature. Based on individualized PK data, total recommended busulfan doses ranged from 9.3-21.3 mg/kg (-27.1% to +66.7% compared to FDA labeled dose of 12.8 mg/kg). When first-dose busulfan PK was compared between busulfan given sequentially versus concurrently with fludarabine there was a trend towards a higher AUC with concomitant administration (4651 vs. 4988 µM˖min; p=0.13). A strong correlation between the AUC generated from both the individualized PK an MAP-Bayesian models was observed with both the test dose (R2=0.91) and first dose (R2=0.86) of busulfan. Using the MAP Bayesian model, AUC predictions were on average higher (mean AUC 5069 versus 4886 µM˖min, p Our individualized busulfan PK approach generated relatively similar AUC values compared to MAP-Bayesian estimates, although the higher AUC generated via MAP-Bayesian predictions may allow for lower doses of busulfan to be administered thereby potentially reducing toxicity while maintaining efficacy. Further, use of the MAP-Bayesian method may allow for more rapid dose optimization and a decreased number of serum concentrations. Further prospective studies including more patients are warranted to confirm these findings. Figure 1 Disclosures Calip: Flatiron Health: Current Employment. Patel:Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity. Here we investigate OSU-T315, a compound that disrupts the PI3K/AKT pathway in a novel manner. Dose-dependent selective cytotoxicity by OSU-T315 is noted in both CLL-derived cell lines and primary CLL cells relative to normal lymphocytes. In contrast to the highly successful Bruton's tyrosine kinase and PI3K inhibitors that inhibit B-cell receptor (BCR) signaling pathway at proximal kinases, OSU-T315 directly abrogates AKT activation by preventing translocation of AKT into lipid rafts without altering the activation of receptor-associated kinases. Through this mechanism, the agent triggers caspase-dependent apoptosis in CLL by suppressing BCR, CD49d, CD40, and Toll-like receptor 9-mediated AKT activation in an integrin-linked kinase-independent manner. In vivo, OSU-T315 attains pharmacologically active drug levels and significantly prolongs survival in the TCL1 mouse model. Together, our findings indicate a novel mechanism of action of OSU-T315 with potential therapeutic application in CLL.

The receptor tyrosine kinase ROR1 is uniquely expressed on and required for many hematological malignancies such as t(1;19) positive acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). The t(1;19) is one of the most frequent translocations in B-ALL, observed in both adult and pediatric patients. The translocation has intermediate prognosis on its own, but is associated with a poor prognosis in the unbalanced der(19)t(1;19) form in pediatric ALL, and in the context of hyperdiploid B-ALL. While leukemic cell dependence on ROR1 is known, ROR1 lacks kinase activity making it difficult to target therapeutically. However, we have previously shown that ROR1 can be targeted to deliver therapeutic payload specifically to leukemic cells in CLL, sparing the normal cells from toxic side effects. This encouraged us to develop ROR1 directed immunoliposomal nanoparticles encapsulating a novel small molecule OSU-2S. OSU-2S is a non-immunosuppressive derivative of the sphingosine analogue FTY720, with potent anti-tumor activity against multiple hematological malignancies including CLL, mantle cell lymphoma (MCL) and canine B-cell lymphoma. OSU-2S demonstrated potent dose dependent cytotoxicity in patient derived B-ALL samples with different cytogenetic backgrounds including translocations t(4;11), t(9;22) and t(1;19) as well as hyperdiploid, hypodiploid and normal cytogenetic background [n=7, p= 0.0032 (0 vs 2.5µM), mean decrease in relative viability= 44.51±12.12%] as assessed by Annexin V/Propidium Iodide staining. We confirmed ROR1 expression on t(1;19) translocated patient samples by flow cytometry, and synthesized ROR1 targeted OSU-2S immunoliposomal nanoparticles (2A2-OSU-2S-ILP) (mean size= 186.9 +/- 0.8 nm, mean concentration= 1.38*1013 particles/ml). 2A2-OSU-2S-ILP was selectively cytotoxic to t(1;19) translocated ALL, including unbalanced der(19)t(1;19), from relapsed patients aged 29-37, but not ROR1-ve, t(1;19) non translocated ALL, as compared to control IgG-OSU-2S-ILP, or 2A2/IgG immunoliposomes without OSU-2S [n=3, p= 0.04, mean decrease in relative viability (IgG-OSU-2S-ILP vs 2A2-OSU-2S-ILP)= 35.14±7.36%]. Similar results were seen in ROR1+ve 697 cells, a B-ALL cell line carrying t(1;19) translocation, where 2A2-OSU-2S-ILP showed selective cytotoxicity [n=8, p=0.004, mean decrease in relative viability (IgG-OSU-2S-ILP vs 2A2-OSU-2S-ILP)= 61.62±14.63%]. To assess the effect of 2A2-OSU-2S-ILP on t(1;19) positive ALL in-vivo, we used a disseminated cell line derived xenograft model. Immunocompromised NSG mice were engrafted with 697 cells, treated with 2A2-OSU-2S-ILP or IgG-OSU-2S-ILP for 14 days and tumor burden was assessed in the spleen and bone marrow. 2A2-OSU-2S-ILP treatment significantly reduced the number of human CD45+CD19+ cells in the bone marrow as compared to IgG-OSU-2S-ILP cohort (n=6 per cohort, p=0.022, mean decrease in 697 cells in marrow= 1.751 ± 0.6372 million cells/ femur). There was also a trend towards decreased tumor burden in spleen (mean decrease in 697 cells in spleen= 1.883 ± 0.9729 million cells). Together, these data show the ability of ROR1 targeted liposomal nanoparticles to selectively deliver its payload to leukemic cells in t(1;19) translocated B-ALL, sparing toxicity to the normal cells. Ongoing studies are directed towards understanding the mechanistic basis of OSU-2S mediated therapeutic benefit in B-ALL in-vitro and in-vivo. [This work was supported by NIH-R01-CA197844-01. SG is supported by Pelotonia Graduate Fellowship] Disclosures Baskar: NIH: Patents & Royalties: ROR1 mAb 2A2. Rader:NIH: Patents & Royalties: ROR1 mAb 2A2. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau. Bhatnagar:Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Muthusamy:Ohio State University: Patents & Royalties: OSU-2S.

In this issue of Blood , Tout and colleagues add another layer of personalization to rituximab therapy in patients with diffuse large B-cell lymphoma (DLBCL) by demonstrating the relationship between baseline total metabolic tumor volume (TMTV 0 ), rituximab exposure, and outcomes from therapy. 1

Background: Vitamin B1 (Thiamine) deficiency might result in Wernicke's encephalopathy (WE); the latter was reported in clinical studies with the JAK2 inhibitor fedratinib resulting in disruption of clinical development, despite efficacy in patients with myelofibrosis (MF) (JAMA Oncol, 2015, 5). Our objectives were i) to determine the incidence of thiamine deficiency in patients with myeloproliferative neoplasms (MPN), ii) assess clinical correlations of thiamine level and iii) determine the impact of JAK2 inhibitor therapy on thiamine level in MPN. Methods: After Institutional review board approval, patients referred with a suspected diagnosis of MPN were enrolled. All clinical and laboratory variables including treatment details were collected at the time of referral. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of thiamine diphosphate in whole blood was performed at the time of referral. Reference range for thiamine level in whole blood was 70-180 nmol/L. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all statistical analysis. Results: A total of 115 patients were prospectively enrolled and included 28 patients without MPN and 87 with MPN. 87 MPN patients (median age, 65 years, 52% males) included 32 with primary myelofibrosis (PMF), 17 with polycythemia vera (PV), 17 with essential thrombocythemia (ET), 11 with post PV MF, 8 with post ET MF, and 2 with MPN-U. The MPN and non-MPN patients were similar in their gender distribution, pattern of alcohol use, malnutrition and multivitamin use (p=0.24, 0.12, 0.54 and 0.78 respectively), although the former were older (p=0.09). Median thiamine level of the study patients was 167 nmol/L (range; 60-442 nmol/L) with only two (1.7%) female patients displaying level below the normal reference range. One belonged to the non-MPN group (thiamine level 68 nmol/l); a 26 year old female with erythroid leukemia in the absence of alcohol use or malnutrition; the second patient (thiamine level 60 nmol/l) was a 38 year old female with ET, CALR type 2 mutated on hydroxyurea, without a history of alcohol use or malnutrition. Overall, both MPN and non-MPN patients displayed similar thiamine level (p=0.89). Clinical correlations of thiamine level in MPN Median thiamine level was similar amongst post ET MF, ET, PMF, PV, and post PV PMF patients (127, 162, 166, 190 and 209 nmol/L respectively, p=0.13). No significant effect on thiamine level was apparent for age, gender, hemoglobin, platelet count, dynamic international prognostic scoring system (DIPSS) score, unfavorable cytogenetics, palpable splenomegaly, or constitutional symptoms. Interestingly, thiamine level was significantly higher in JAK2 mutated cases (median 177 nmol/L vs 145 nmol/L in unmutated cases, p=0.03). Furthermore, when analysis was restricted to PMF patients, thiamine level positively correlated with JAK2V617F mutant allele burden (p=0.01) and leukocyte count > 10 x 109/L (p=0.03). JAK2 mutated PMF patients with leukocyte count > 10 x 109/L depicted significantly higher thiamine levels (median 313 nmol/L) compared to JAK2 mutated patients without leukocytosis (median 164 nmol/L) and JAK2 unmutated patients with or without leukocytosis (median 192 nmol/L and 143 nmol/L respectively)(p=0.004, Figure 1a). Impact of treatment on thiamine level Treatment with hydroxyurea was documented in 35 patients with no significant impact on thiamine level (p=0.28). 27 patients were on JAK inhibitors (median duration at referral; 41 months); 12 patients on ruxolitinib and 15 MF patients on momelotinib as part of a clinical trial. Thiamine level was similar amongst JAK inhibitor treated vs untreated patients (median 166 vs 169.5 nmol/L respectively, p=0.72). Annual thiamine measurements were performed on 15 patients treated with momelotinib (median duration 52 months, range 18-60 months). Despite fluctuations in thiamine levels, only two patients were noted to have thiamine level below normal (65 and 69 nmol/L at year 3), which subsequently improved to 101 and 121 nmol/L by year 4, while still on treatment (Figure 1b). Conclusions: The current study confirms the rarity of subnormal thiamine levels in MPN and the limited impact of treatment on thiamine levels, including with JAK2 inhibitors. Our novel observation regarding the correlation of thiamine level with JAK2V617F mutant allele burden and leukocyte count requires further exploration. Disclosures No relevant conflicts of interest to declare.

Graft-versus-host disease (GVHD) is characterized by an impairment of mechanisms that underlie the development of immunologic tolerance. Although the cytokine storm associated with GVHD leads to expression of cell surface markers on both effector and regulatory T cells, regulatory CD4+ T cells that play an instrumental role in the maintenance of tolerance appear to uniquely express the Foxp3 transcriptional repressor. Foxp3 mRNA expression was significantly decreased in peripheral blood mononuclear cells from patients with either allogeneic GVHD or autologous GVHD compared with patients without GVHD. Expression of Foxp3 negatively correlated with the severity of GVHD but positively correlated with recent thymic emigrants. The results suggest that defective thymic function contributes to the impaired reconstitution of immune regulatory mechanisms following transplantation. The decrease in regulatory mechanisms after transplantation appears to provide an environment permissive to the development of GVHD. (Blood. 2004;104:2187-2193)

The risk of hepatitis B virus (HBV) transmission by transfusion in sub-Saharan Africa is considered to be relatively low, and testing of blood donors is often not done or is done relatively poorly. To re-examine this attitude, we identified HBV chronically infected blood donors from a major hospital in Ghana with a range of hepatitis B surface antigen (HBsAg) assays. Test efficacy was estimated using HBV DNA as a gold standard, and the risk of HBV infection in blood recipients was estimated for different testing strategies. Particle agglutination, dipstick, and enzyme immunoassay (EIA) HBsAg screening detected 54%, 71%, and 97% of HBV infectious donors, respectively. The risk of HBV transmission to recipients less than 10 years old ranged between 1:11 and 1:326 with blood unscreened and screened by EIA, respectively. For older recipients, the risk decreased a further 4-fold because of the high frequency of natural exposure to HBV. A total of 98% of HBsAg-confirmed positive samples contained HBV DNA. HBV DNA load was less than 1 × 104 IU/mL in 75% of HBsAg-reactive samples, most of them anti-HBe reactive. Approximately 0.5% of HBsAg-negative but anti-HBc-positive samples contained HBV DNA. The use of sensitive HBsAg tests is critical to prevent transfusion transmission of HBV infection to young children in a population with a 15% prevalence of chronic HBV infection in blood donors. However, this will not have much effect on the prevalence of this infection unless other strategies to protect children from infection are also advanced in parallel.

Background Venous thromboembolism (VTE) is the second leading cause of mortality in cancer patients. National guidelines recommend treatment with a low-molecular-weight heparin (LMWH) for at least 6 months following a cancer-associated thrombosis (CAT). The direct oral anticoagulants (DOAC) have become attractive options for the management of CAT as they are orally administered and require no routine monitoring. However, current guidelines do not support the routine use of DOAC for CAT, given the lack of direct comparison between LMWH and DOAC. The objective of this study was to compare the efficacy and safety of LMWH to DOAC for the treatment of CAT. Methods This was a retrospective, single-center study conducted at the Ohio State University. Adult cancer patients with confirmed VTE treated with therapeutic doses of either a LMWH or DOAC between December 2010 and January 2016 were included. Patients were excluded if they had a history of thrombophilia, heparin-induced thrombocytopenia, creatinine clearance (CrCl) < 30mL/min, required mechanical or pharmacologic thrombolysis, or anticoagulation started > 3 months after the initial VTE date. Medical records were reviewed for 6 months following the start of anticoagulation or until the occurrence of the primary outcome, death, or cessation of therapy. Predefined data were systematically collected, including patient demographics, treatments, risk factors, recurrent VTE, bleeding events, and death. The primary efficacy outcome was VTE recurrence at 6 months and the primary safety outcome was major bleeding at 6 months. Secondary outcomes included clinically-relevant-non-major bleeding (CRNMB), overall mortality, and risk factors for recurrent VTE or bleeding. Major bleeding and CRNMB were defined in accordance with the International Society on Thrombosis and Hemostasis criteria. Baseline characteristics were compared by t-test, Wilcoxon rank sum test, or chi-square test, as appropriate. The VTE and major bleeding outcomes were assessed by univariable logistic regression for LMWH versus DOAC and for other potential risk factors. One multivariable logistic regression model was fit to each outcome. Results Two hundred ninety patients treated with LMWH and 190 patients treated with DOAC were included. The majority of patients were treated with enoxaparin (n=287) and rivaroxaban (n=167). Mean age was 58 years, 16% had a history of VTE, 7% had a history of bleeding, and 53% had metastatic disease. Statistical differences in baseline characteristics included: high thrombotic risk cancers (57% LMWH vs 43% DOAC), hematologic cancers (19% LMWH vs 32% DOAC), vena cava filters (20% LMWH vs 12% DOAC), baseline hemoglobin and plateletcounts(10.9g/dL vs 11.4g/dL and 237 K/µL vs 252 K/µL for LMWH vs DOAC respectively). The median follow up time was 160 days and 153 days for the LMWH and DOAC groups respectively. There was no difference in the rate of recurrent VTE at 6 months between groups. Patients treated with LMWH experienced more major bleeding and CRNMB episodes and had more deaths at 6 months (Table 1).A majority of patients died from cancer progression (67% LMWH, 73% DOAC), however, 3 patients died of a major bleed (2 LMWH, 1 DOAC), and 1 LMWH patient died from recurrent PE. We used the multivariable analysis to identify several risk factors associated with increased risk of recurrent VTE: platelet count < or = 150 K/µL, younger age, vena cava filter insertion after VTE, and history of warfarin failure. Risk factors associated with bleeding included the presence of vena cava filter and baselineCrCl< 50 mL/min. In adjusted analysis, the use of LWMH showed a trend toward a higher risk of major bleeding (Table 2). Discussion In patients with CAT, we found no difference in VTE recurrence in patients treated with DOAC compared to LMWH, while LMWH was associated with increased bleeding. Baseline demographics were unbalanced and increased cancer related mortality in the LMWH group suggests more advanced disease in this group. To account for these confounding factors, we used the multivariable logistic regression model and found that LWMH is associated with a trend towards increased bleeding, although not statistically significant. Conclusion In our cohort of patients with CAT, treatment with DOAC appears to be as effective and potentially safer when compared to LMWH. Randomized controlled trials for direct comparison are ongoing and results are highly anticipated. Disclosures No relevant conflicts of interest to declare.

Introduction: For fit multiple myeloma (MM) patients, autologous hematopoietic stem cell transplant (HSCT) is standard of care as part of first line therapy, demonstrating longer progression-free survival when compared to upfront bortezomib, lenalidomide, and dexamethasone (IFM/DFCI 2009, ASH 2015). The use of granulocyte colony stimulating factor (G-CSF) after HSCT accelerates time to neutrophil recovery by 1 - 6 days when compared with control (Klumpp TR et al, JCO, 1995 & Schmitz N et al, BMT 2004). The American Society of Clinical Oncology guidelines recommend that G-CSF should be initiated 1-5 days after administration of high-dose chemotherapy and should be continued until the absolute neutrophil count (ANC) is 2000-3000/mm3 (Smith TJ, JCO, 2015). We have evaluated the role of G-CSF starting day +1, day +5, and day +7 post-transplant in three sequential cohorts of MM patients focusing on the duration of severe neutropenia (rather than the time to neutrophil engraftment), infections, and mucositis. Methods: As part of changes in the standard of care institutional protocols for autologous HSCT of myeloma patients at Ohio State University, three sequential cohorts of myeloma patients were identified that received G-CSF daily post-transplant until ANC>1500/mm3 or WBC>5/mm3. Two hundred twenty-six (226) patients received G-CSF on day +1 (n=43), day +5 (n=78), and day +7 (n=105) from May 2012 to August 2015. The majority of the patients received levofloxacin, acyclovir and fluconazole as prophylaxis. We evaluated the duration of severe neutropenia (ANC Results:The cohort of patients receiving G-CSF on day +5 had a shorter median follow up (455 days versus 979 days in the day +1 and 1355 days in the day +7 cohorts), since the patients were enrolled at a later timepoint. No statistically significant difference was noted in terms of age, gender, cytogenetic or ISS stage distribution, number of infused cells per kg, and melphalan dose among the three cohorts of patients. The duration of severe neutropenia was significantly increased for patients receiving G-CSF on day +7 (mean 153.4 hrs, SD 36.9) compared to those receiving G-CSF on day +1 (mean: 104.8 hrs, SD 19.4; p-value of 5 x 106 cells). Patients who received G-CSF on day +1 or day +5 had a significantly decreased incidence of grade 2 or higher mucositis (4.65% vs 10.3%) for day +1 and day +5 versus 21.9% for day +7 (fisher-test, p = 0.014 and 0.0255). Similarly, the incidence of bacteremia was decreased in those patients treated with G-CSF on days +1 and +5 versus day +7 (21.8%, 23.2%, and 33.3% for those treated on days +1, +5, and +7, respectively; p = 0.09). The group of patients who received G-CSF on day +5 had a longer length of stay, with two patients with prolonged hospitalization (mean 17.7 days, SD 5.6 days, range 12-49) when compared to the other groups (day +1 group mean 13.88 days, SD 2.8 days, range 10-21 versus day +7 group mean 15.2 days, SD 2.7 days, range 11-21 days; Two-tailed t-test p = 0.012). Lastly, our data indicates a trend, though not statistically significant, toward a longer time to biochemical progression in patients who received G-CSF on day +1 when compared to the other two groups. Conclusion: We conclude that starting G-CSF injections the day after stem cell infusion (day +1) decreases the duration of severe neutropenia, infections, and mucositis in comparison to day +5 and day +7 in patients receiving autologous transplant for MM. A prospective trial would definitively test this, but a multi-institution meta-analysis via CIBMTR would be more cost-effective, acknowledging that differing anti-infective prophylaxis regimens would prevent effective between institution comparisons of infection. Disclosures No relevant conflicts of interest to declare.

Background: Patients (pts) with CLL/SLL that have del11q tend to have relatively short remission durations and shorter overall survival (OS) with standard chemotherapy regimens. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton's tyrosine kinase (BTK) is indicated by the US FDA for the treatment of pts with CLL/SLL and allows for treatment without chemotherapy. In phase 3 studies, treatment with single-agent ibr was superior to treatment with ofatumumab (ofa) in relapsed/refractory (R/R) CLL/SLL (RESONATE; Byrd, N Engl J Med 2013) or chlorambucil (clb) in treatment-naïve (TN) CLL/SLL (RESONATE-2; Burger, N Engl J Med 2015); treatment with ibr + bendamustine/rituximab (BR) was also superior to treatment with BR in R/R CLL/SLL (HELIOS; Chanan-Khan, Lancet Oncol 2016). We examined the outcome of pts in these 3 studies who did or did not have del11q to determine the impact of del11q on clinical outcomes. Methods: In RESONATE, pts with R/R CLL/SLL received ibr 420 mg/day until progressive disease (PD) or unacceptable toxicity (tox) vs ofa for up to 24 weeks (300 mg week 1, 2000 mg weekly for 7 weeks, 2000 mg every 4 weeks for 16 weeks). In RESONATE-2, pts ≥65 years of age with TN CLL/SLL (excluding del17p) received ibr 420 mg/day until PD or tox vs clb 0.5 mg/kg (up to max of 0.8 mg/kg) on days 1 and 15 of each 28-day cycle (≤12 cycles). In HELIOS, pts with R/R CLL/SLL (excluding del17p) received BR (≤6 cycles) with or without ibr 420 mg/day (starting on day 2 of cycle 1) followed by single-agent ibr or placebo continued until PD or tox. Data from pts in the 3 studies were pooled (ibr pool, comparator pool) and analyzed based on whether or not their CLL/SLL had del11q. We performed a multivariate analysis to examine for risk factors prognostic for survival (del11q del17p, age, sex, race, current Rai stage, baseline ECOG PS, number of prior therapies, cytopenias; no multiplicity adjustment). Results: A total of 1210 pts with del11q data were included in the analysis: 609 in the ibr pool (179 with del11q, 430 without del11q) vs 601 in the comparator pool (149 with del11q, 452 without del11q). Demographics and baseline characteristics were generally similar in pts regardless of del11q status; differences of more than 10% included proportions with bulky disease ≥5 cm (63% vs 49%) and unmutated IGHV (88% vs 72%) in pts with or without del11q, respectively. Median lymphadenopathy and absolute lymphocyte counts were also higher in pts with del11q. At the time of the primary analysis, median treatment durations in the ibr pool were 20.0 mo with del11q and 18.7 mo without del11q; in the comparator pool 5.3 mo with del11q and 8.5 mo without del11q. Overall, ibr-treated pts had higher overall response rate (ORR) and complete response (CR) rates and longer progression-free survival (PFS, Figure) and OS than comparator-treated pts regardless of del11q status. In the ibr pool, the presence of del11q was associated with a trend of longer PFS and OS while in the comparator pool, pts with del11q had shorter PFS (Figure, Table), as compared to pts without del11q. Results were similar when excluding pts with del17p (10% of ibr pool [6%/11% with/without del11q] and 9% of comparator pool [8%/10% with/without del11q]; Table). By multivariate analysis, in the comparator pool, del11q, male sex, >1 prior therapy, presence of cytopenias, and unmutated IGHV (in R/R only) were associated with shorter PFS. However, these differences were not found in the ibr pool. The presence of del11q did not unfavorably impact the tempo of reductions in lymphadenopathy for ibr-treated pts, but did for comparator-treated pts. Adverse events leading to discontinuation were similar in ibr- and comparator-treated pts (12% [9% vs 13% with/without del11q] vs 13% [12% vs 13% with/without del11q]). Deaths within 30 days of last dose occurred in 31 pts (5% [3% vs 6% with/without del11q]) in the ibr pool and 28 pts (5% [6% vs 4% with/without del11q]) in the comparator pool. Conclusions: Treatment with ibr was superior to comparator regardless of del11q status; the benefit of ibr was most marked for pts with CLL/SLL with del11q. Presence of del11q was associated with a trend of longer PFS and OS in ibr-treated pts and shorter PFS and lower ORR in comparator-treated pts. By multivariate analysis, presence of del11q was a prognostic factor for shorter PFS for comparator-treated pts, but not for ibr-treated pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Demirkan:Amgen: Consultancy. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding. Barrientos:Gilead: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Cramer:Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Mundipharma: Other: Travel, Accommodations, Expenses; Astellas: Other: Travel, Accommodations, Expenses; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Stilgenbauer:Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Solman:Pharmacyclics LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses; AbbVie: Equity Ownership. Cheng:Johnson & Johnson: Equity Ownership; AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment. Phelps:Johnson & Johnson: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment; Amgen, Inc.: Equity Ownership; AbbVie: Equity Ownership. Howes:Janssen: Employment, Other: Leadership; Johnson & Johnson: Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Acute myeloid leukemia (AML) is an incurable disease with 5 year survival rates of 10% in patients over 60 years. Poor tolerance to chemotherapy, chemo resistance and high rate of relapse warrants less toxic and more effective regimens in AML. OSU-2S is a novel non-immunosuppressive derivative of FTY720, a sphingosine analogue. The promising in-vitro and in-vivo activity of OSU-2S against a number of leukemias and lymphomas, and other malignancies such as hepatocellular carcinoma, impelled us to evaluate the activity of OSU-2S in AML. The potent cytotoxic activity of the OSU-2S (5µM, 24hrs) in AML cell lines HL-60, MV411 and MOLM13 (n=3; HL-60: p=0.008; MV411: p=0.04; MOLM13: p=0.0094) encouraged us to evaluate the effect of OSU-2S in primary leukemic cells from AML patients. OSU-2S (5µM, 24 and 48 hrs) demonstrated significant cytotoxic activity against AML cells, including high risk FLT3-ITD mutated AMLs, (n=13, p Interaction of AML cells with the bone marrow stromal environment plays a critical role in leukemic cell survival and proliferation, thus contributing to resistance to chemotherapy. To effectively mimic this interactive environment which would be encountered in the patients, bone marrow stromal cells (MSCs) were cultured and expanded from AML patients to develop autologous co-culture systems with AML cells. The autologous stromal cells mediated significant protective effect on AML cells (n=3, p=0.022, mean difference in viability with MSC=21.05), which was compromised in the presence of OSU-2S (5µM) (n=3, p=0.01, mean difference in viability= -64.36), indicating lack of stromal protection mediated resistance to OSU-2S. To circumvent any unintended off target effects of OSU-2S on normal cells, we synthesized an immunoliposomal (ILP) nanoparticle formulation targeting CD33 (SIGLEC-3), a transmembrane receptor which is highly expressed on myeloid progenitor cells and AML. OSU-2S encapsulated immunoliposomes (OSU-2S-CD33-ILP) showed significant cytotoxicity as compared to empty-CD33-ILPs in primary cells (n=5 AML, p=0.0005, mean difference in viability= -48.63) as well as AML cell lines (n=3, MOLM13: p=0.002; MV411: p=0.004). Importantly, OSU-2S-CD33-ILP selectively depleted CD33 positive myeloid population (n=3, p=0.0011, mean difference in % viable population= -43.39) without compromising the CD33 negative non targeted lymphoid population (n=3, p=0.013, mean difference in % viable population= 29.56) in primary AML cell cultures. Similarly, selective cytotoxicity ablated CD33+ MOLM13 and MV411 AML cell lines but not CD33 non targeted Jurkat cell line, which is sensitive to the free (naked) drug. In summary, OSU-2S mediated potent cytotoxic activity against primary AML cells that is not compromised in the presence of autologous bone marrow stromal cells from AML patients. Further, CD33 targeted delivery of OSU-2S has promising selective activity against CD33+ but not CD33- cells. Ongoing studies are evaluating the efficacy of free OSU-2S and OSU-2S-CD33-ILP formulations in-vivo. [This work was supported by NIH-R01-CA197844-01, P50-CA140158, Lauber Funds for Immunotherapy in AML and Robert J. Anthony Leukemia Fund] Disclosures Chen: The Ohio State University: Patents & Royalties: OSU-2S patent.

Fetal hemoglobin (HbF) potently corrects red cell pathology caused by β-globin (HBB) mutations in β-hemoglobinopathies (e.g., sickle cell disease, SCD). DNA methyltransferase (DNMT1) is a central component of the chromatin-modifying enzyme network that represses the gene for HbF, ƴ-globin (HBG), in adult erythropoiesis. Thus, DNMT1 has been scientifically validated as a molecular target to increase HbF. The generic deoxycytidine analogue decitabine (Dec) can incorporate into DNA without terminating chain elongation (the sugar in Dec is natural) and deplete DNMT1 without cytotoxicity. Unfortunately, Dec is very rapidly metabolized by cytidine deaminase (CDA) in vivo into uridine counterparts that do not deplete DNMT1. Moreover, the uridine degradation products can mis-incorporate into DNA and cause cytotoxicity. Also, solid tissues, e.g., intestine/liver, highly express CDA, severely limiting Dec tissue distribution, oral bioavailability and exposure time. To address these barriers to clinical translation, which have as a common cause CDA, we evaluated the combination of oral Dec with a CDA-inhibitor, tetrahydrouridine (THU). Pre-clinical in vivo studies indicated improved distribution and oral bioavailability (~10-fold increase) with the low Cmax but extended Tmax desired for non-cytotoxic DNMT1-depletion. Here we report the first-in-man clinical translation (NCT01685515). Patients: This Phase 1 clinical trial enrolled adult SS or S-b-thal patients with multiple, clinically significant complications of SCD and risk of early death despite standard of care hydroxyurea. The primary objective was to identify the dose of oral Dec that can be safely co-administered 2X/week with oral THU. Treatment: Fixed dose oral THU 10mg/kg was ingested 60 minutes before oral Dec at 0.01, 0.02, 0.04, 0.08 or 0.16 mg/kg (mpk) in 5 cohorts of 5 pts, randomized 3/2 THU-Dec/placebo (Fig.1). Repeat dose administration 2X/wk for 8 wks was used to assess safety, increasing the likelihood that the identified dose would be safe for the intended application of chronic disease modification. Pharmacokinetics: Samples were obtained at 0, 2, 4 and 24 hrs from 12 of 15 THU-Dec subjects (dictated by venous access). Dec was detected (standard LCMS/MS method) at the lowest dose 0.01 mpk, and a dose-dependent increase was observed. Dec 0.08 and 0.16 mpk produced Cmax 9-21 and 39-54 nM respectively, levels that produced clinical pharmacodynamic effects (described below). Adverse events (AE):AE were similar in placebo and THU-Dec cohorts. No significant AE, including no significant gastro-intestinal AE, were attributed to study drug. There were no Grade 4 AE. No subjects discontinued placebo or THU-Dec. Hematology: HbF was measured by HPLC and in individual red cells by flow cytometry (F-cells). Dec 0.08 and 0.16 mpk substantially increased HbF (~2-fold increase in F-cells at 0.16 mpk) (Fig.1). In parallel, total hemoglobin (hb) increased (e.g., by 1.9, 1.8 and 1.2 g/dL at 0.16mpk) while LDH, t.bilirubin and D-dimers decreased (improvement in hemolysis and thrombophilia biomarkers) (Fig.1). Non-cytotoxic DNMT1-depletion alters hematopoietic differentiation and is expected to simultaneously increase platelet counts and decrease absolute neutrophil counts. This was seen at Dec 0.08 and 0.16 mpk. The HbF and Hb increases and biomarker improvements were produced within boundaries of platelet and neutrophil counts that did not require treatment holds. Discussion: Combining oral Dec with oral THU to inhibit CDA thus produced the Dec tissue distribution and wide concentration-time profile that is a basic requirement for clinical translation of observations regarding the safety and value of DNMT1 as a molecular target for therapy, moreover with the accessibility of oral administration. Platelet count increases by non-cytotoxic DNMT1-depletion were not linked with increases in thrombophilia biomarkers here or in previous trials of Dec in SCD. This impression is consistent also with clinical experience after standard of care splenectomy, which increases platelet counts even more drastically. Multi-organ damage in SCD incorporates the bone marrow, causing a decline in reticulocytosis/hb that contributes to early death. This underscores the import in further evaluation of this non-cytotoxic, normal stem cell sparing, rationally targeted approach to disease modification of SCD. Figure 1 Figure 1. Disclosures Lavelle: Acetylon: Research Funding. Hsu:Gerson Lehman Group: Consultancy; Mast Therapeutics: Research Funding; Eli Lilly: Research Funding; Astra Zeneca: Consultancy, Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; EMMI Solutions: Consultancy; Purdue Pharma: Research Funding; Hilton Publishing: Consultancy, Research Funding; Sancilio: Research Funding; Pfizer: Consultancy, Research Funding. DeSimone:EpiDestiny: Consultancy, Other: patents around decitabine and tetrahydrouridine. Saunthararajah:EpiDestiny: Consultancy, Other: patents around decitabine and tetrahydrouridine.