Use Of Umbilical Cord Blood Research Articles

Knowledge and attitude of donating and using cord blood for transfusion among patients attending Nnamdi Azikiwe University Teaching Hospital, Nnewi, South East Nigeria.

BACKGROUND:Allogeneic blood for transfusion is in short supply in most parts of the developing world. Cord blood for transfusion can be a significant source of blood supply to our health institutions.AIMS:This study aims to investigate the knowledge and attitude to the donation and use of umbilical cord blood (UCB) for transfusion among the patients receiving services in a tertiary health institution in South-East Nigeria.MATERIALS AND METHODS:This was a cross-sectional study; an anonymous structured questionnaire was used. A total of 549 consenting patients randomly selected from the antenatal, postnatal, sickle cell clinics, and wards were the subjects. Statistical analysis of the data was done using SPSS version 20.0.RESULTS:The mean age of the participants was 31.9 ± 9.5 years. The majority were females (77.2%), married (86.4%). About 26.2% of the respondents were willing to accept UCB for transfusion to them or their child. Following counseling, the acceptance rate increased to 71.5%. Most of the respondents (80.0%) were willing to donate the UCB of their baby; or be tested for HIV (93.3%), if necessary. Educational level was significantly associated with knowledge of UCB. After logistic regression, occupation, and gender were significantly associated with acceptance of UCB for transfusion. Up to 52% belonged to low income family background, approximately 150 US dollars monthly family income (50,000 naira).CONCLUSION:The knowledge and acceptance of UCB for transfusion are low in our environment. However, proper counseling and public enlightenment could change this attitude.

Clinical Studies of Ex Vivo Expansion to Accelerate Engraftment After Umbilical Cord Blood Transplantation: A Systematic Review.

Cell dose limits greater use of umbilical cord blood (UCB) in hematopoietic cell transplantation. The clinical benefits of ex vivo expansion need clarity to understand its potential impact. A systematic search of studies addressing UCB ex vivo expansion was conducted. Fifteen clinical studies (349 transplanted patients) and 13 registered trials were identified. The co-infusion of an expanded unit and a second unmanipulated unit (8 studies), the fractional expansion of 12% to 60% of a single unit (5 studies), and the infusion of a single expanded unit (2 studies) were reported. More recently, published studies and 12 of 13 ongoing trials involve the use of novel small molecules in addition to traditional cytokine cocktails. Higher total cell number was closely associated with faster neutrophil engraftment. Compared with historical controls, neutrophil engraftment was significantly accelerated in more recent studies using small molecules or mesenchymal stromal cells (MSC) co-culture, and in some cases, platelet recovery was also statistically improved. Recent studies using nicotinamide and StemRegenin-1 reported long-term chimerism of the expanded unit. No significant improvement in survival or other transplant-related outcomes was demonstrated for any of the strategies. Ex vivo expansion of UCB can accelerate initial neutrophil engraftment after transplant. More recent studies suggest that long-term engraftment of ex vivo expanded cord blood units is achievable. Results of larger randomized controlled trials are needed to understand the impact on patient outcomes and health care costs.

MDS disease characteristics, not donor source, predict hematopoietic stem cell transplant outcomes.

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological malignancies with considerably variable prognoses and curable only with hematopoietic cell transplantation (HCT). Few studies comparing MDS HCT outcomes between sibling and umbilical cord blood (UCB) donors exist. Using the University of Minnesota Blood and Marrow Transplant (BMT) database, we retrospectively analyzed HCT outcomes among 89 MDS patients undergoing either sibling or double UCB HCT in 2000–2013. We observed similar survival, relapse and non-relapse mortality between sibling and UCB donor sources. Relapse was increased in those with monosomal karyotype (P=0.04) and with reduced intensity conditioning (P<0.01). In summary, our data highlight similar MDS HCT outcomes regardless of donor source and support the use of UCB as an alternative donor when a sibling is unavailable.

Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients

Background aimsDespite widespread use of umbilical cord blood (UCB) transplantation and distinct practice preferences displayed by individual UCB banks and transplant centers, little information exists on how processing variations affect patient outcomes. MethodsWe reviewed 133 adult double UCB transplants performed at a single center: 98 after reduced-intensity and 35 after myeloablative conditioning. Processing associated with contributing UCB banks and units was surveyed to identify differences in practice. We analyzed effect of selected variables on clinical outcomes of engraftment, dominance, transplant-related mortality, and survival. ResultsEighty-eight percent of banks queried currently practice red blood cell (RBC) depletion before cryopreservation. This reflects a shift in practice because previously 65% of banks employed RBC-replete processing methods (i.e., cryopreservation or plasma/volume reduction). Neither neutrophil nor platelet engraftment was affected by processing conditions analyzed. RBC depletion was not associated with clinical outcomes, except in 17 recipients of 2 RBC-replete units, where survival was better than that observed in 116 recipients of ≥1 RBC-depleted units (hazard ratio 3.26, P = 0.004). When analyzed by attributes of the dominant unit, RBC depletion, time in storage, bank years in existence, and inventory size did not affect clinical outcomes. Postthaw viability and CD34 dose were factors impacting engraftment. Notably, all RBC-replete units in this cohort were washed in dextran-human serum albumin before infusion. DiscussionThese findings support continued utilization of the entire existing pool of cord blood units, despite recent trends in processing, and have important implications for banking resources and UCB selection practices.

Infusion of Umbilical Cord Blood-Derived Natural Killer Cells in Immune-Deficient Mice for the Treatment of Resistant Acute Myeloid Leukaemia

Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against acute myeloid leukaemia (AML). Success of this NK cell immunotherapy is dependent on obtaining high numbers of functional NK cells that have the potential to survive in vivo. The use of umbilical cord blood (UCB) CD34+ cells as a source of allogenic NK cells is an interesting method that can generate a readily available, non-invasive, off the shelf cellular product.We developed a cytokine-based culture method for the generation of NK cell products derived from CD34+hematopoietic progenitor cells (HPC) isolated from fresh UCB units. Immuno-phenotyping of ex vivo expanded NK cells showed typical inhibitory and activating NK receptors except for CD16 and the KIR receptors.UCB-derived NK cells displayed good cytolytic activity against NK-sensitive K562 cells with a percentage of specific lysis varying from 30 to 50%. Cytolysis was directly correlated to CD94 expression since CD94-sorted NK cells were responsible for all the in vitro cytolytic function of differentiated NKs against K562 cells. There was an inconstant susceptibility of patient-derived primary AML cells to UCB-derived NK lysis in vitro with a specific lysis ranging from 0 to 25%.We further characterized UCB-derived NK cells by investigating their toxicity, biodistribution, and anti-leukemic potential in vivo. As adoptive transfer of NK cells is an attractive approach for treating refractory leukemia, immune deficient mice were engrafted with a patient derived AML strain resistant to NK-mediated lysis and doxorubicin.After successful engraftment and randomization, leukemic mice were injected with either UCB- derived NK cells or NK cells from healthy donors (NKhds) or doxorubicin, with one control group that didn't receive any treatment. Mice were sacrificed after 2 weeks of treatment and leukemia load along with NK distribution were evaluated by flow cytometry in the blood, bone marrow (BM) and spleen.There was no evidence of toxicity of UCB-derived or healthy donors NK cells in mice. Both types of cells were preferentially found in the blood and in the spleen, even though NKhds reached much higher levels than UCB-derived NKs.As for treatment efficacy, none of our treatment showed anti-leukemic potential based on the absence of decrease of leukemic cells in BM, blood, and spleen. In vivo microenvironment didn't overcome resistance of the patient derived AML cell to NK lysis or to doxorubicin.Remarkably, all of the UCB derived NK cells founded in vivo expressed the CD94 whereas not more than 20% of the injected cells were positive for this marker. Whether it was by in vivo selection or by in vivo differentiation must be investigated.Interestingly, a small cell population with CD56 and CD34 double staining was distinguished in UCB-derived NK and NK healthy donor treated leukemic mice suggesting in vivo interaction between leukemic and NK cells. Further characterization of this population may help to understand the molecular mechanism of leukemic recognition by NK cells and resistance of leukemic cells to cytolysis.In conclusion, UCB-derived NK generation is feasible. Investigation of the role of CD94 in these cells is needed, as cell sorting by CD94 selection in addition to the CD56 could be an interesting approach in the future to select highly functional expanded NK cells before therapeutic use. Furthermore, infusion of UCB-derived NK cells into immune-deficient mice is achievable and non-toxic. However, in vivo environment didn't overcome primary in vitro resistance of AML cells despite an established interaction. Additional elucidation of AML resistance mechanisms to NK lysis is mandatory before therapeutic application. DisclosuresNo relevant conflicts of interest to declare.

INFECTIOUS COMPLICATIONS AFTER UMBILICAL CORD-BLOOD TRANSPLANTATION FROM UNRELATED DONORS

Umbilical cord-blood (UCB) is a well-recognized alternative source of stem cells for unrelated donor hematopoietic stem cell transplantation (HSCT). As compared with other stem cell sources from adult donors, it has the advantages of immediate availability of cells, absence of risk to the donor and reduced risk of graft-versus-host disease despite donor-recipient HLA disparity. However, the use of UCB is limited by the delayed post-transplant hematologic recovery due, at least in part, to the reduced number of hematopoietic cells in the graft and the delayed or incomplete immune reconstitution. As a result, severe infectious complications continue to be a leading cause of morbidity and mortality following UCB transplantation (UCBT). We will address the complex differences in the immune properties of UCB and review the incidence, characteristics, risk factors, and severity of bacterial, fungal and viral infectious complications in patients undergoing UCBT.

Immunotherapy after hematopoietic stem cell transplantation using umbilical cord blood-derived products.

Umbilical cord blood (UCB) is being increasingly used as a source of hematopoietic stem cells (HSC) for transplantation. UCB transplantation (UCBT) has some advantages such as less stringent HLA-matching requirements, fast availability of the graft and reduced incidence and severity of graft-versus-host disease. However, UCBT is also associated with a higher incidence of infection, graft failure, slow engraftment and slow immune reconstitution. UCB is mainly used as a source of HSC; however, it is also rich in immune cells that could be used to treat some of the main complications post-UCBT as well as other diseases, thus implicating the use of UCB for immunotherapy. Here, we aim to describe some of the therapies currently developed that use UCB as a cell source, focusing in particular on regulatory T cells and natural killer cells.

Quality and exploitation of umbilical cord blood for cell therapy: Are we beyond our capabilities?

There is increasing interest in identifying novel stem cell sources for application in emerging cell therapies. In this context, umbilical cord blood (UCB) shows great promise in multiple clinical settings. The number of UCB banks has therefore increased worldwide, with the objective of preserving potentially life-saving cells that are usually discarded after birth. After a rather long and costly processing procedure, the resultant UCB-derived cell products are cryopreserved until transplantation to patients. However, in many cases, only a small proportion of administered cells engraft successfully. Thus, can we do any better regarding current UCB-based therapeutic approaches? Here we discuss concerns about the use of UCB that are not critically pondered by researchers, clinicians, and banking services, including wasting samples with small volumes and the need for more reliable quality and functional controls to ensure the biological activity of stem cells and subsequent engraftment and treatment efficacy. Finally, we appeal for collaborative agreements between research institutions and UCB banks in order to redirect currently discarded small-volume UCB units for basic and clinical research purposes. Developmental Dynamics 245:710-717, 2016. © 2016 Wiley Periodicals, Inc.

Use of Umbilical Cord Blood to Treat Non-Fatal Submersion Events

Use of Umbilical Cord Blood to Treat Non-Fatal Submersion Events

Umbilical Cord Blood Transplantation Is a Feasible Rescue Therapeutic Option for Patients Suffering from Graft Failure after Previous Hematopoietic Stem Cell Transplantation

Objective: Umbilical cord blood (UCB) is an important graft source for hematopoietic stem cell transplantation (SCT). Due to less stringent human leukocyte antigen (HLA) matching criteria compared to bone marrow or peripheral blood stem cells, UCB enables patients lacking an HLA-matched donor to receive potentially curative SCT. Methods: We retrospectively analyzed the efficacy and safety of UCB transplantation (UCBT) at our center. Results: Between June 2009 and June 2015, 27 UCBT were performed in 25 patients. Reasons for the use of UCB were lack of adequate related or unrelated stem cell donor (n = 20) and graft failure after previous SCT (n = 7). Median time to neutrophil engraftment was 22 days. Four patients experienced primary graft failure. Thirteen patients developed acute graft-versus-host disease (GVHD), whereupon 6 subsequently also developed chronic GVHD. After a median follow-up time of 19 months, 9 patients relapsed and 12 patients died. Cause of death was relapse in 8 and transplant-related events in 4 patients. Median overall survival and progression-free survival have not been reached yet. Conclusion: In our experience, UCBT is an alternative graft source for patients lacking a suitable related or unrelated donor and a feasible treatment option for patients experiencing graft failure after previous SCT.

Defining Parameters That Can Guide Public Cord Blood Units (CBUs) in Korea

Background: It is well known that Total Nucleated Cell (TNC) and CD34 are the greatest limiting factor in the use of umbilical cord blood (UCB) for transplantation. To enhance high UCB quality, it is important that how the factors will affect the UCB. This study is to identify maternal, neonatal, obstetric factors that influence the suitability for banking and transplantation of UCB units collection.Study design and methods: This study examined 6534 UCB (3712 at the Catholic Hematopoietic Stem Cell Bank and 2822 at the Daegu Fatima Hospital Public Umbilical Cord Bank) collected at two banks from October 2003 to June 2015. The variables were collected from retrospective records at the time of donation. The associations between TNC, CD34+ and variables including maternal age (MA), gestational age (GA), fetal body weight (FBW), time from collection to processing (T), collecting volume (CV), preTNC, and delivery type were analyzed by logistic regression.Results: In our study cohort (n=6534, male 2988, female 2991, unkown 555, all Koreans), the median values of TNC, numbers of CD34+, MA, GA, FBW, T, preTNC, and CV were 9.24úI108/unit (range, 3.02-35.64), 2.0úI106/unit(range, 0.04-29.2), 31.0 years(range, 15-46), 277 days (range, 202-382), 3330g (range, 1740-4970), 19 hours (range, 1-54), 11.69úI108/unit (range, 3.41-50.32), and 83.5ml (range, 26.0-218.2) respectively.In univariate analysis, variables that were associated with high TNC (defined as a TNC of > 9.24úI108/unit) included GA (defined as GA > 277 days) [OR 1.29 (95% CI 1.16-1.42 p < 0.001)], FBW (defined as FBW > 3330g) [OR 1.52 (95% CI 1.37-1.68 p < 0.001)])], CV (defined as > 83.5mL) [OR 2.61 (95% CI 2.36-2.88 p < 0.001)], preTNC [OR 25.45 (95% CI 22.34-29.00 p < 0.001)], and T (defined as T> 19 hours) [OR 0.87 (95% CI 0.79-0.96 p < 0.005)]. Variables that were associated with high CD34+ (defined as a number of CD34+ > 2.0úI106/unit) included MA (defined as MA > 31.0 years) [OR 0.90 (95% CI 0.82-0.99 P=0.036)], GA [OR 0.74 (95% CI 0.67-0.82 p < 0.001)], FBW [OR 1.41 (95% CI 1.27-1.56 p<0.001)], preTNC [OR 3.38 95% CI 3.06-3.74 p < 0.001]], and CV [OR 1.41 (95% CI 1.28-1.60 p<0.001)]In multivariate analysis of TNC, preTNC [OR 20.71 (95% CI 17.87-24.00) p < 0.001]] was the best predictor of followed by normal delivery [OR 1.77 (95% CI 1.48-2.11 P<0.001)], FBW [OR 1.35 (95% CI 1.17-1.56 p<0.001)], CV [OR 1.31 (95% CI 1.13-1.53 p<0.001)], and female gender [OR 1.21 (95% CI 1.05-1.39 p=0.01)]. In multivariate analysis of CD34, was preTNC [OR 3.39 (95% CI 3.00-3.83 p < 0.001)] was the best predictor of followed by FBW [OR 1.41 (95% CI 1.25-1.58 P<0.001)], GA [OR 0.59 (95% CI 0.52-0.66 p<0.001)], MA [OR 0.84 (95% CI 0.75-0.94 p=0.003)], and female gender [OR 0.89 (95% CI 0.78-0.98 p=0.02)].Conclusions: We established referential values of cord blood using large scaled CB units in Korea. In multivariate analysis, maternal/donor characteristics were associated with preTNC, FBW, and gender for both high TNC and CD34+. Our results confirm that is similar values to those reported in previous data. These associations could be used to prioritize donations, collections, optimizing resource utilization and financial modeling in Korean cord blood banks. We are focusing on collection education using the standard operation procedure to facilitate of high cells as well as on more recruits of healthy mothers. DisclosuresNo relevant conflicts of interest to declare.

ETHICAL ASPECTS ABOUT INFORMED CONSENT IN CORD BLOOD COLLECTION FOR DIAGNOSTIC PURPOSES

Deepening the knowledge about genetic and epigenetic mechanisms studies (environmental caused) regarding atopy, brought revelations about intrauterine onset of allergies, proven by the presence of IgE in umbilical cord blood. Detection of these newborns and their inclusion in a specific care program further reduces the morbidity of allergic march with the undeniable effects on quality of life and healthcare costs. The dramatic increase in the prevalence of atopy in recent decades suggests the importance of IgE in umbilical cord determinations. The use of umbilical cord blood for diagnostic purposes requires clear laws and rules and this is the subject we suggest to debate in this paper.

Proportional-Integral-Derivative (PID) Control of Secreted Factors for Blood Stem Cell Culture.

Clinical use of umbilical cord blood has typically been limited by the need to expand hematopoietic stem and progenitor cells (HSPC) ex vivo. This expansion is challenging due to the accumulation of secreted signaling factors in the culture that have a negative regulatory effect on HSPC output. Strategies for global regulation of these factors through dilution have been developed, but do not accommodate the dynamic nature or inherent variability of hematopoietic cell culture. We have developed a mathematical model to simulate the impact of feedback control on in vitro hematopoiesis, and used it to design a proportional-integral-derivative (PID) control algorithm. This algorithm was implemented with a fed-batch bioreactor to regulate the concentrations of secreted factors. Controlling the concentration of a key target factor, TGF-β1, through dilution limited the negative effect it had on HSPCs, and allowed global control of other similarly-produced inhibitory endogenous factors. The PID control algorithm effectively maintained the target soluble factor at the target concentration. We show that feedback controlled dilution is predicted to be a more cost effective dilution strategy compared to other open-loop strategies, and can enhance HSPC expansion in short term culture. This study demonstrates the utility of secreted factor process control strategies to optimize stem cell culture systems, and motivates the development of multi-analyte protein sensors to automate the manufacturing of cell therapies.

Reprint of: Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases

Background aimsCord blood (CB) transplantation slows neurodegeneration during certain inherited metabolic diseases. However, the number of donor cells in the brain of patients does not appear to be sufficient to provide benefit until several months after transplant. We developed the cell product DUOC-01 to provide therapeutic effects in the early post-transplant period. MethodsDUOC-01 cultures initiated from banked CB units were characterized by use of time-lapse photomicroscopy during the 21-day manufacturing process. Antigen expression was measured by means of flow cytometry and immunocytochemistry; transcripts for cytokines and enzymes by quantitative real-time polymerase chain reaction; activities of lysosomal enzymes by direct biochemical analysis; alloreactivity of DUOC-01 and of peripheral blood (PB) mononuclear cells (MNC) to DUOC-01 by mixed lymphocyte culture methods; and cytokine secretion by Bioplex assays. ResultsDUOC-01 cultures contained highly active, attached, motile, slowly proliferating cells that expressed common (cluster of differentiation [CD]11b, CD14 and Iba1), M1 type (CD16, inducible nitric oxide synthase), and M2-type (CD163, CD206) macrophage or microglia markers. Activities of 11 disease-relevant lysosomal enzymes in DUOC-01 products were similar to those of normal PB cells. All DUOC-01 products secreted interleukin (IL)-6 and IL-10. Accumulation of transforming growth factor-β, IL-1β, interferon-γ and TNF-α in supernatants was variable. IL-12, IL-2, IL-4, IL-5 and IL-13 were not detected at significant concentrations. Galactocerebrosidase, transforming growth factor-β and IL-10 transcripts were specifically enriched in DUOC-01 relative to CB cells. PB MNCs proliferated and released cytokines in response to DUOC-01. DUOC-01 did not proliferate in response to mismatched MNC. ConclusionsDUOC-01 has potential as an adjunctive cell therapy to myeloablative CB transplant for treatment of inherited metabolic diseases.

Preclinical characterization of DUOC-01, a cell therapy product derived from banked umbilical cord blood for use as an adjuvant to umbilical cord blood transplantation for treatment of inherited metabolic diseases

Background aimsCord blood (CB) transplantation slows neurodegeneration during certain inherited metabolic diseases. However, the number of donor cells in the brain of patients does not appear to be sufficient to provide benefit until several months after transplant. We developed the cell product DUOC-01 to provide therapeutic effects in the early post-transplant period. MethodsDUOC-01 cultures initiated from banked CB units were characterized by use of time-lapse photomicroscopy during the 21-day manufacturing process. Antigen expression was measured by means of flow cytometry and immunocytochemistry; transcripts for cytokines and enzymes by quantitative real-time polymerase chain reaction; activities of lysosomal enzymes by direct biochemical analysis; alloreactivity of DUOC-01 and of peripheral blood (PB) mononuclear cells (MNC) to DUOC-01 by mixed lymphocyte culture methods; and cytokine secretion by Bioplex assays. ResultsDUOC-01 cultures contained highly active, attached, motile, slowly proliferating cells that expressed common (cluster of differentiation [CD]11b, CD14 and Iba1), M1 type (CD16, inducible nitric oxide synthase), and M2-type (CD163, CD206) macrophage or microglia markers. Activities of 11 disease-relevant lysosomal enzymes in DUOC-01 products were similar to those of normal PB cells. All DUOC-01 products secreted interleukin (IL)-6 and IL-10. Accumulation of transforming growth factor-β, IL-1β, interferon-γ and TNF-α in supernatants was variable. IL-12, IL-2, IL-4, IL-5 and IL-13 were not detected at significant concentrations. Galactocerebrosidase, transforming growth factor-β and IL-10 transcripts were specifically enriched in DUOC-01 relative to CB cells. PB MNCs proliferated and released cytokines in response to DUOC-01. DUOC-01 did not proliferate in response to mismatched MNC. ConclusionsDUOC-01 has potential as an adjunctive cell therapy to myeloablative CB transplant for treatment of inherited metabolic diseases.

Advances in umbilical cord blood manipulation-from niche to bedside.

The use of umbilical cord blood (UCB) as an alternative haematopoietic cell source in lieu of bone marrow for haematopoietic reconstitution is increasingly becoming a mainstay treatment for both malignant and nonmalignant diseases, as most individuals will have at least one available, suitably HLA-matched unit of blood. The principal limitation of UCB is the low and finite number of haematopoietic stem and progenitor cells (HSPC) relative to the number found in a typical bone marrow or mobilized peripheral blood allograft, which leads to prolonged engraftment times. In an attempt to overcome this obstacle, strategies that are often based on native processes occurring in the bone marrow microenvironment or 'niche' have been developed with the goal of accelerating UCB engraftment. In broad terms, the two main approaches have been either to expand UCB HSPC ex vivo before transplantation, or to modulate HSPC functionality to increase the efficiency of HSPC homing to the bone marrow niche after transplant both of which enhance the biological activities of the engrafted HSPC. Several early phase clinical trials of these approaches have reported promising results.

Successful Haploidentical Hematopoietic Stem Cell Transplant for GATA2 Deficiency

▪Background: GATA2 deficiency results in a clinical syndrome known variably as: MonoMAC for the lack of monocytes and atypical mycobacterial infections (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger’s syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Reconstitution of the deficient cell compartments in GATA2 deficiency with allogeneic hematopoietic stem cell transplant (HSCT) results in reversal of the infection susceptibility and represents the only curative therapy for both the myeloid disease and the virally driven malignancies seen in this disorder. However, only about one-half of patients that require HSCT will have an HLA-matched related or unrelated donor. Moreover, the use of umbilical cord blood has been reported to be suboptimal in this cohort of patients in whom infection susceptibility underlies much of the need for a transplant.Methods: We performed haploidentical, related donor HSCT with high dose post-transplant cyclophosphamide (PT/CY) in 3 patients with GATA2 deficiency in whom a suitable HLA matched donor was not available. All three patients had a first degree relative (sibling) who shared at least 1 HLA-haplotype. The first patient, a 21 year-old Chinese woman presented with Hydroa Vacciniforme like T-cell lymphoma involving her lung, bowel (resulting in multiple small bowel resections and ileostomy), and skin (with large ulcerative lesions); multiple thrombotic cerebral events; and macrophage activation syndrome requiring etoposide and high dose prednisone in the intensive care unit (ICU). The second patient, a 20 year-old Hispanic female, presented with myelodysplasia (MDS), profound neutropenia, an invasive fungal sinusits due to Fusarium sp., and recurrent bacteremias. The third patient, a 45 year-old woman, presented with Emberger’s Syndrome, multiple episodes of bacterial and fungal sepsis and hypocellular MDS. All three patients received cyclophosphamide 14.5mg/kg on day’s -6 and-5; fludarabine 30mg/m2 on day’s -6 through -2; 200cGy of total body irradiation (TBI) on day -1. Patients 2 and 3 also received busulfan 3.2 mg/kg on day’s -4 and -3 because of MDS. All 3 patients received high dose PT/CY 50mg/kg on day’s +3 and +4, and mycophenolate mofetil and tacrolimus starting on day +5.Results: All 3 patients engrafted at a mean of 18 days and all are alive at a median follow-up of 9 months (range, 5 to 13 months). All three patients achieved 100% donor myeloid and lymphoid chimerim by day +100 post-transplant. The first patient had complete resolution of her T-cell lymphoma and macrophage activation syndrome, the second patient has had complete reversal of her hematopoietic and infectious phenotype, and the third patient has had resolution of her infectious complications that required continuous IV Daptomycin for 5 years prior to transplant. In addition, all three patients had complete reconstitution of the monocyte, NK cell, and B-lymphocyte compartments that were severely deficient prior to transplant. The main toxicity was mucositis, which required intravenous narcotics in all three patients. Lastly, the first patient developed late grade I liver graft-versus-host disease (GVHD) that was responsive to cyclosporine, the second patient developed grade I acute GVHD of skin that was responsive to topical steroids, and the third patient had no evidence of acute or chronic GVHD.Conclusions: Haploidentical, related donor HSCT represents a safe and effective viable alternative for patients with GATA2 deficiency who lack an HLA-matched donor, including patients such as our first patient who was in the ICU at the time of transplant. DisclosuresNo relevant conflicts of interest to declare.

Improving umbilical cord blood processing to increase total nucleated cell count yield and reduce cord input wastage by managing the consequences of input variation

Background aimsWith the rising use of umbilical cord blood (UCB) as an alternative source of hematopoietic stem cells, storage inventories of UCB have grown, giving rise to genetically diverse inventories globally. In the absence of reliable markers such as CD34 or counts of colony-forming units, total nucleated cell (TNC) counts are often used as an indicator of potency, and transplant centers worldwide often select units with the largest counts of TNC. As a result, cord blood banks are driven to increase the quality of stored inventories by increasing the TNC count of products stored. However, these banks face challenges in recovering consistent levels of TNC with the use of the standard protocols of automated umbilical cord processing systems, particularly in the presence of input variation both of cord blood volume and TNC count, in which it is currently not possible to process larger but useable UCB units with consequent losses in TNC. MethodsThis report addresses the challenge of recovering consistently high TNC yields in volume reduction by proposing and validating an alternative protocol capable of processing a larger range of units more reliably. ResultsThis work demonstrates improvements in plastic ware and tubing sets and in the recovery process protocol with consequent productivity gains in TNC yield and a reduction in standard deviation. ConclusionsThis work could pave the way for cord blood banks to improve UCB processing and increase efficiency through higher yields and lower costs.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia during first complete remission: a clinical perspective.

Allogeneic hematopoietic cell transplantation (HCT) is the most potent therapy for preventing relapse of acute myeloid leukemia (AML). Although its efficacy is compromised by a high risk of treatment-related morbidity and mortality, an accumulating body of evidence has led to the general recommendation favoring allogeneic HCT from a matched sibling donor during first complete remission (CR1) for younger patients with cytogenetically intermediate- or high-risk AML. Over the past few decades, this field has seen a great many advancements. The indications for allogeneic HCT have been refined by taking into account the molecular profiles of leukemic cells and the degree of comorbidities. The introduction of high-resolution human leukocyte antigen-typing technology and advances in immunosuppressive therapy and supportive care measures have improved outcomes in alternative donor transplantation, while the parallel growth of unrelated donor registries and greater use of umbilical cord blood and haploidentical donors have considerably improved the chance of finding an alternative donor. The development of reduced-intensity and non-myeloablative conditioning has made it possible to receive allogeneic HCT for patients who might once have been considered ineligible due to advanced age or comorbidities. Thanks to these advances, the role of allogeneic HCT during CR1 has become progressively more important in the treatment of AML.

Hospital Length of Stay in the First 100 Days after Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia in Remission: Comparison among Alternative Graft Sources

Several studies have shown comparable survival outcomes with different graft sources, but the relative resource needs of hematopoietic cell transplantation (HCT) by graft source have not been well studied. We compared total hospital length of stay in the first 100 days after HCT in 1577 patients with acute leukemia in remission who underwent HCT with an umbilical cord blood (UCB), matched unrelated donor (MUD), or mismatched unrelated donor (MMUD) graft between 2008 and 2011. To ensure a relatively homogenous study population, the analysis was limited to patients with acute myelogenous leukemia and acute lymphoblastic leukemia in first or second complete remission who underwent HCT in the United States. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation. For children who received myeloablative conditioning, the median time alive and out of the hospital in the first 100 days was 50 days for single UCB recipients, 54 days for double UCB recipients, and 60 days for MUD bone marrow (BM) recipients. In multivariate analysis, use of UCB was significantly associated with fewer days alive and out of the hospital compared with MUD BM. For adults who received myeloablative conditioning, the median time alive and out of the hospital in first 100 days was 52 days for single UCB recipients, 55 days for double UCB recipients, 69 days for MUD BM recipients, 75 days for MUD peripheral blood stem cell (PBSC) recipients, 63 days for MMUD BM recipients, and 67 days for MMUD PBSC recipients. In multivariate analysis, UCB and MMUD BM recipients had fewer days alive and out of the hospital compared with recipients of other graft sources. For adults who received a reduced-intensity preparative regimen, the median time alive and out of the hospital during the first 100 days was 65 days for single UCB recipients, 63 days for double UCB recipients, 79 days for MUD PBSC recipients, and 79 days for MMUD PBSC recipients. Similar to the other 2 groups, receipt of UCB was associated with a fewer days alive and out of the hospital. In conclusion, length of stay in the first 100 days post-transplantation varies by graft source and is longer for UCB HCT recipients. These data provide insight into the resource needs of patients who undergo HCT with these various graft sources.