Background: Viral infection remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (Bollard/Heslop Blood 2016). Anti-viral agents for treatment of viral infection in immunocompromised patients are limited in efficacy and are associated with significant toxicities (Gerdemann BBMT 2004; Sili Cytother 2012). The use of virus-specific cytotoxic T-lymphocytes (VST) for immunocompromised patients with viral infections has been associated with therapeutic benefit and improved OS (Bollard/Heslop Blood 2016; Sutrave Cytother 2017). Methods of VST production include ex-vivo expansion and direct selection (Gottlieb Cytother 2017). Ex-vivo expansion requires prolonged manufacturing time, is associated with T-cell exhaustion, and results in a limited donor pool. Direct selection is rapid (12-24 hours), can be done locally, allows for expanded HLA matching, permits a low degree of HLA match to the recipient, and can be adapted for many viruses. A multicenter consortium, the Viral Cytotoxic T-Lymphocyte Consortium (VIRCTLC) was created to investigate the safety and efficacy of VST manufactured by direct selection using the IFN-g Cytokine Capture System process automated on the CliniMACS® Prodigy device (Miltenyi Biotec) for immunocompromised patients with viral infection (Figure 1). Objective: Determine the safety and efficacy of VST for the treatment of immunocompromised child, adolescent and young adult (CAYA) patients with refractory, systemic viral infection and/or viral infection and intolerance to appropriate anti-viral medical therapy. Design/Methods: CAYA patients after allo-HSCT, solid organ transplantation (SOT), or with primary immunodeficiency (PID) with refractory adenovirus (ADV), cytomegalovirus (CMV), Epstein Barr virus (EBV) or BK virus (BKV) infections as evidenced by increasing serum RT-PCR DNA (by 1 log) after 7 days or persistent quantitative RT-PCR DNA copies after 14 days of appropriate anti-viral therapy, and/or known resistance to anti-viral agents, and/or intolerance to anti-viral agents were eligible. Related donors with ≥1 HLA A, B, or DR match to recipient and with an adequate T-cell response to virus specific MACS® PepTivators were eligible. Donors were screened with viral specific antigen (PepTivator®) to predict successful VST manufacturing. Peripheral blood mononuclear cells (PBMC) were collected from eligible related donors using non-mobilized apheresis. VST were isolated using the CliniMACS® Prodigy following stimulation of PBMC with specific viral MACS PepTivator® pools, generously provided by Miltenyi Biotec. Production of CD4+ and CD8+ VST was performed as previously described (Feuchtinger Blood 2010). The target cell dose was 0.5x104 CD3+/kg for HLA mismatched haploidentical related donors and 2.5x104 CD3+/kg for matched related donors. Based on response and safety, VST were given every 2 weeks for a maximum of 5 infusions. Results: Eleven patients have been enrolled to date. Seven patients were treated for ADV, 2 for BKV, 1 for CMV, and 1 for EBV. There were 8 males and 3 females enrolled, aged 1-38 years. There were 10 patients post allo-HSCT and 1 patient post SOT. There were 8 haploidentical, related, original allo-HSCT donors and 3 haploidentical, related, third party donors. There have been no matched related donors enrolled to date. The mean±SEM %CD4+ IFN-g+ of total CD4+, %CD8+ IFN-g+ of total CD8+, and %CD3 cells recovered in the final product were 21.5±4.8, 25.0±7.0, and 50.4.2±7.2, respectively. The median number of VST infusions was 2 (1-5). The mean±SEM CD3+ cell dose was 0.49±0.001x104. Ten patients achieved complete response (PCR negative) and 1 patient achieved partial response (PCR≥1 log decrease). The overall response and complete response rates were 100% and 90.9%, respectively. The median time to maximal response was 34 days (7-141) (Table 1). No patient developed aGVHD, cGVHD, infusion reaction or CRS associated with VST. Conclusion: Preliminary results of this pilot study demonstrate that VST are safe, well tolerated and efficacious in CAYA with refractory viral infections after allo-HSCT, SOT or with PID. Manufacturing utilizing the CliniMACS® Prodigy device is rapid, reproducible and effective. Accrual is ongoing. This research is supported by FDA RO10063-01A1. Disclosures Flower: Lentigen Technology Inc/Miltenyi Biotec: Research Funding. O'Donnell:Kiadis Pharma: Other: Licensing of intellectual property. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Johnson:Cell Vault: Research Funding; Miltenyi Biotec: Research Funding. Cairo:Technology Inc/Miltenyi Biotec: Research Funding; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Reduction of peripheral blood stem cell collection sessions with extended-hour operation of the apheresis center Submit Manuscript | http://medcraveonline.com Abbreviations: BV, blood volume; PB CD34+, peripheral blood CD34+ cell count; MM, multiple myeloma; G-CSF, granulocyte colony stimulating factor; PY, product yield; PBSC, peripheral blood stem cell IntroductionAs healthcare expenses continue to increase, and healthcare funding becomes heavily reduced, hospitals are faced with the challenge of providing quality care while curtailing costs.1 Since nursing salaries account for the highest percentage of healthcare expenditure, many hospitals have restricted the size of their nursing workforce and restructured their rosters in a manner that would adequately allocate staff to meet patient needs, while simultaneously increasing operational efficiency.1,2 At the Mount Sinai Hospital Apheresis Center, full-time apheresis nurses previously worked on an 8.5-hour shift (8:00 am-4:30 pm), five days a week. Following the recommendation of a proposed guideline for autologous PBSC collection, the previous daily maximal processing volume for each patient was increased from 3 to 4 blood volumes (BV), except when the initial peripheral blood CD34+ cell count (PB CD34+) was >120 cells/mL. 3 The time required to process the 4 BVs varies between patients, and between collection sessions, based upon flow rate, health condition of the patient, and mobilization efficiency. Four BVs was usually the maximal blood volume that could be processed within the 8.5-hour limit of daily operation of the Apheresis Center.Autologous PBSC transplantation is performed to restore hematopoietic recovery in patients with hematological malignancies, including lymphomas, multiple myeloma (MM), Amyloidosis, and certain solid tumors, 4 after high dose chemotherapy. PBSC collections are done in preparation for an autologous transplant, in which the stem cells are infused back into the patient. PBSC collection involves the collection of mobilized stem cells in the patient's blood that are used for hematopoietic reconstitution in stem cell transplantation. To maximize collection, patients undergo stem cell mobilizing regimens that consist of chemotherapy and/or granulocyte colony stimulating factor (G-CSF; filgrastim), with or without additional mobilizing agent, plerixafor, to mobilize the highest possible population of stem cells into blood circulation.4-6 the collection procedure is to process several blood volumes in an apheresis instrument, in order to reach an optimal target number of cells collected. 7 The PBSC collection product yield (PY) rises with the increase of BVs processed. The number of collection days varies among patients, depending on the peripheral blood stem cell concentration and daily BV processed. AbstractBackground: With the rising cost of healthcare, and nurses' salaries accounting for a large percentage of hospital expenses, it is crucial to maximize the efficiency of nursing services, while minimizing operational cost and impr...

In patients with Sickle Cell Disease (SCD), transfusion therapies have shown to reduce the risk of strokes in patients with abnormal cerebral blood flow. The current guidelines for pediatric patients with SCD recommend monthly transfusions using red cell exchange (RCE) to maintain the pediatric patient's sickle hemoglobin (HbS) below 30% between treatments. However, it is not clear how much RCE is needed to achieve this goal. Our objective was to find a target post-RCE HbS (post-HbS) level, following which our patients' HbS would remain below 30% between monthly RCE. We identified RCE events for pediatric patients ≤ 20 years old with the HbSS genotype and receiving monthly RCE therapy. HbS results were categorized into post-HbS and follow-up RCE HbS (F/u-HbS) from twenty two to forty days later. Two hundred and seventy two complete sets of data from 14 patients were identified from 2000 to 2015. No particular level of post-HbS accurately predicts the exact level of F/u-HbS. Of patients with post-HbS of 5-10%, 67% had F/u-HbS < 30%. Additionally only 20% of patients with post-HbS of 10-15% had F/u-HbS < 30%. Reduction of post-HbS to 5-10% was found to be the most effective in maintaining the HbS level < 30% between monthly RCE.

The tumor microenvironment (TME) can mediate resistance of acute leukemias to chemotherapy, however few therapies targeting this niche interaction are available. This Research Topic highlights recent findings regarding "Microenvironment and Therapy-Resistance in Leukemias".In the review by Hellmich et al. the authors focus on the role of senescence in the aging bone marrow (BM) microenvironment in acute myeloid leukemia (AML) and multiple myeloma. Senescence is the irreversible arrest of stem cell proliferation. Through senescence, the senescence associated secretory phenotype (SASP) is activated, causing manipulation in growth and proliferation by pro-inflammatory cytokines, chemokines, proteases and growth factors. Though evolutionarily protective as an anti-cancer mechanism promoting repair, the system of senescence can become maladaptive, and instead create a pro-inflammatory, pro-tumor growth, and chemotherapy resistant environment. The prior publication by this group (Blood 2019) (1), demonstrated that AML cells induce a senescent phenotype in BM stromal cells (BMSCs) resulting in the secretion of SASP supporting the survival and proliferation of leukemic blasts. In-vivo studies demonstrated that deletion of BMSCs slowed tumor progression and prolonged animal survival. This supports the role in development of anti-senolytic agents which can selectively eliminate senescent cells and reduce chemoresistance.In the review by Tabe et al., the authors present the role of fatty acid metabolism as a targetable mechanism of AML chemoresistance in adults whose BM content is progressively replaced by adipocytes. Oxidative phosphorylation (OXPHOS) is utilized by Leukemic stem cells (LSCs) as an energy source to promote growth and survival of the tumor cells. The authors describe the potential for combinatorial regiments utilizing fatty acid oxidation (FAO) inhibitors to target the critical energy source for the chemo-resistant leukemia cells and LSCs. FAO produces twice as much ATP per mole compared to the oxidation of glucose, making it a more effective energy source. LSCs obtained from relapsed AML patients acquire a compensatory ability to overcome the loss of amino acid metabolism (targeted by chemotherapies) by increasing FAO. While FAO inhibition sounds promising, tumor cells have several mechanisms for adapting to nutrient deprivation. Therefore, FAO alone is unlikely to be useful; rather combination with chemotherapy or targeted therapies have potential for synergistic effect.