Umbilical Cord Blood Stem Cell Transplantation Research Articles

Effect of nutritional status on outcomes in children receiving umbilical cord blood stem cell transplantation.

The impacts of nutritional status on clinical outcomes in children receiving umbilical cord blood stem cell transplantation (UCBT) are not fully described. We evaluated the risk for malnutrition before transplantation admission and influence of weight loss during hospitalization on short-term clinical outcomes in children with UCBT. We conducted a retrospective study of pediatric patients up to age 18 years who received UCBT and were treated at the Children's Hospital of Fudan University between January 2019 and December 2020. The mean age of the 91 patients was 1.3 years, with 78 (85.7%) men and 13 (14.3%) women (p<0.001). UCBT was performed mostly for primary immunodeficiency disease (PID) (83, 91.2%). The weight loss differences among children with different primary diseases were statistically significant (p=0.003). Children with a large amount of weight loss during hospitalization (n = 24) had higher risks of skin graft-versus-host disease (GVHD) (multivariate OR=5.01, 95% CI: 1.35-18.65), intestinal GVHD (multivariate OR=7.27, 95% CI: 1.74-30.45), a longer median hospital stay (p=0.004), higher antibiotic costs (p=0.008) and higher total hospitalization costs (p=0.004). Malnutrition on admission was significantly positively correlated with longer parenteral nutrition (PN) time (p=0.008). Early nutritional intervention effects on clinical outcomes need further assessment. Underweight recipient child and excessive weight loss during transplantation increases the length and cost of hospital stay, and is associated with a high incidence of GVHD, which affects the prognosis of transplantation and medical resources consumption.

Analysis of risk factors and prognosis of cytomegalovirus infection post umbilical cord blood stem cell transplantation in children with primary immunodeficiency diseases

Objective: To investigate the risk factors and outcomes of cytomegalovirus (CMV) infection post umbilical cord blood stem cell transplantation (UCBT) in children with primary immunodeficiency diseases (PID). Methods: Clinical data of 143 PID children who received UCBT in the Children's Hospital of Fudan University from January 2015 to June 2020 were collected retrospectively. CMV-DNA in the plasma was surveilled once or twice a week within 100 days post-UCBT. According to the CMV-DNA test results, children were divided into the CMV-infected group and the CMV-uninfected group. The incidence and risk factors of CMV infection were analyzed. At 1-month post-UCBT, the absolute lymphocyte count, ratio of lymphocyte subsets and immunoglobulin levels were compared between those whose CMV infection developed 1-month later post-UCBT and those not. Mann-Whitney U test and chi-squared test were used for comparision between groups. Kaplan-Meier survival analysis was used to analyze the impact of CMV infection on survival. Results: Among 143 patients, there were 113 males and 30 females, with a age of 14 (8, 27) months at UCBT. Chronic granulomatosis disease (n=49), very-early-onset inflammatory bowel disease (n=43) and severe combined immunodefiency (n=29) were the three main kinds of PID. The rate of CMV infection was 21.7% (31/143), and the time of infection occurring was 44 (31, 49) days post-UCBT. The incidence of recurrent CMV infection was 4.2% (6/143) and refractory CMV infection was 4.9% (7/143).There was no significant difference in the first time CMV-DNA copy and peak CMV-DNA copy during treatment between the recurrent CMV infection group and the non-recurrent CMV infection group (32.8 (18.3, 63.1)×106 vs. 22.5 (13.2, 31.9)×106 copies/L, Z=-0.95, P=0.340;35.2 (20.2, 54.6)×106 vs. 28.4 (24.1, 53.5)×106copies/L, Z=-0.10, P=0.920), so were those between the refractory CMV infection group and non-refractory CMV infection group (21.8 (13.1, 32.2)×106 vs. 25.9 (14.2, 12.2)×106copies/L, Z=-1.04, P=0.299; 47.7 (27.9, 77.6)×106 vs. 27.7 (19.7,51.8)×106copies/L, Z=-1.49, P=0.137). The CMV-infected group accepted more reduced-intensity conditioning (RIC) regimen than the CMV-uninfected group (45.2% (14/31) vs. 25.0% (28/112), χ2=4.76, P<0.05). The rate of CMV-seropositive recipients and Ⅱ-Ⅳ acute graft versus host diseases (aGVHD) are significantly higher in the CMV-infected group than the CMV-uninfected group (100% (31/31) vs. 78.6% (88/112), 64.5% (20/31) vs. 26.8% (30/112), χ2=7.98,15.20, both P<0.05). The follow-up time was 31.6 (13.2, 45.9) months, CMV infection had no effect on overall survival (OS) rate (χ2=0.02, P=0.843). There was significant difference in the survival rate among three groups of refractory CMV infection, non-refractory CMV infection and the CMV-uninfected (4/7 vs.95.8% (23/24) vs. 86.6% (97/112), χ2=5.91, P=0.037), while there was no significant difference in the survival rate among three groups of recurrent CMV infection, non-recurrent CMV infection and the CMV-uninfected (5/6 vs. 88.0% (22/25) vs. 86.6% (97/112), χ2=0.43, P=0.896). Children who developed CMV infection after 30 days post-UCBT had lower absolute count and rate of CD4+ T cells and immunoglobulin G (IgG) level than those in the CMV-uninfected group (124.1 (81.5, 167.6) ×106 vs. 175.5 (108.3, 257.2) ×106/L, 0.240 (0.164, 0.404) vs. 0.376 (0.222, 0.469), 9.3 (6.2, 14.7) vs. 13.6 (10.7, 16.4) g/L, Z=-2.48, -2.12,-2.47, all P<0.05), but have higher rate of CD8+T cells than those in CMV-uninfected group (0.418 (0.281, 0.624) vs. 0.249 (0.154, 0.434), Z=-2.56, P=0.010). Conclusions: RIC regimen, grade Ⅱ-Ⅳ aGVHD and CMV-seropositive recipients are the main risk factors associated with CMV infection in PID patients post-UCBT. Survival rate of children with refractory CMV infection after UCBT is reduced. Immune reconstitution in children after UCBT should be regularly monitored, and frequency of CMV-DNA monitoring should be increased for children with delayed immune reconstitution.

Successful Umbilical Cord Blood Stem Cell Transplantation for Pelizaeus Marzbacher Leukodystrophy

Introduction Pelizaeus-Merzbacher Disease (PMD) is a rare X-linked recessive leukodystrophy caused by mutations in the proteolipid protein-1 (PLP-1) gene on the Xq22 chromosome affecting myelination of neurons. Clinical phenotype varies from mild motor deficits to severe spasticity and death at very young age. There is no definitive curative treatment. We report here a successful umbilical cord blood stem cell transplantation (UCBT) for PMD in a 2-year-old boy. Methods A 2-year-old Russian boy, first child of non-consanguineous parentage, presented to us with global developmental delay. Child had a history of prolonged seizures at 1½ yrs of age and was symptomatically managed in his native country. Subsequently child had total 5 episodes of right sided focal seizures. On examination, he had hypotonia and developmental delay with no evidence of dysmorphism or neurocutaneous markers. MRI brain revealed changes of leukodystrophy. CT scan head showed agenesis of corpus callosum & cerebellar vermis along with moderate ventriculomegaly. Genetic testing showed PLP-1 gene duplication. Child development quotient was approximately 70. He then underwent an UCBT from a 10/10 matched unrelated cord at our centre. Parents gave written informed consent before transplant. Myeloablative conditioning was used with Busulfan day-9 to -6 (3.2mg/kg/day), Cyclophosphamide day-5 to -2 (50mg/kg/day), Rabbit ATG day-3 to -1 (2.5mg/kg/day) and Rituximab on day-8 (100mg/m2). Cord blood stem cell (CD34+) dose was 0.2 million/kg. MMF and Cyclosporine were used for graft-vs-host disease (GVHD) prophylaxis. Results His neutrophil engrafted on day+29 and platelets on day+33. Post-transplant on day+30 he had reactivation of CMV and BK virus along with haemorrhagic cystitis which was managed successfully. On day+53, he had an episode of hematemesis and malena with sudden drop in hemoglobin. Upper and lower Gastrointestinal endoscopies were performed. Biopsies were suggestive of MMF induced enterocolitis which resolved after discontinuation of MMF. Chimerism on day+32, day+56 and day+100, 1-year and 2-years was fully donor. There was no evidence of acute or chronic GVHD. His further post-transplant period was uneventful. Neurodevelopmental assessment was done at 12 months and 24 months post-transplant which showed overall good improvement in all domain of developmental. His motor skills improved, he can walk independently and run for few meters with infrequent falls. Child could speak in sentences and better social communications skills. No further seizures were recorded post transplant. At present child is more than two years post-transplant and is doing fine. Conclusion PMD is a rare metabolic leukodystrophy with sparse treatment options. It appears that UCBT is feasible and beneficial treatment option for children with PMD.

Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation

Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC+ T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3-4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3-4 infections.

Wnt3a protein reduces growth factor-driven expansion of human hematopoietic stem and progenitor cells in serum-free cultures.

Ex vivo expansion of hematopoietic stem and progenitor cells (HSPC) is a promising approach to improve insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT). Although culturing HSPC with hematopoietic cytokines results in robust proliferation, it is accompanied with extensive differentiation and loss of self-renewal capacity. Wnt signaling has been implicated in regulating HSPC fate decisions in vivo and in promoting HSPC self-renewal by inhibition of differentiation, but the effects of Wnt on the ex vivo expansion of HSPC are controversial. Here, we demonstrate that exogenous Wnt3a protein suppresses rather than promotes the expansion of UCB-derived CD34+ cells in serum free expansion cultures. The reduced expansion was also observed in cultures initiated with Lin-CD34+CD38lowCD45RA-CD90+ cells which are highly enriched in HSC and was also observed in response to activation of beta-catenin signaling by GSK3 inhibition. The presence of Wnt3a protein during the culture reduced the frequency of multilineage CFU-GEMM and the long-term repopulation ability of the expanded HSPC. These data suggest that Wnt signaling reduces expansion of human HSPC in growth factor-driven expansion cultures by promoting differentiation of HSPC.

StemEx®(Copper Chelation Based) Ex Vivo Expanded Umbilical Cord Blood Stem Cell Transplantation (UCBT) Accelerates Engraftment and Improves 100 Day Survival In Myeloablated Patients Compared To a Registry Cohort Undergoing Double Unit UCBT: Results Of a Multicenter Study Of 101 Patients With Hematologic Malignancies

BackgroundUCBT has proven effective in treating patients with hematologic malignancies (HM),but engraftment is slower and graft failure rates higher compared to other unrelated transplants. We have previously shown that incubation of UCB CD133+ cells with cytokines and the copper chelator TEPA (5µM), inhibits stem cell differentiation and results in a median of 89 and 30 fold expansion of CD34+ and CD34+CD38- cells, respectively (Cytotherapy 2004;6:344). Using this technology (StemEx®) we performed a prospective multicenter myeloablative UCBT trial in patients with HM. MethodologyPatients were transplanted with a single CBU of which CD133+ cells from a segregated portion of the CBU (20-50%) were cultured for 21 days with hematopoietic cytokines and TEPA and transplanted along with a minimum of 107nucleated cells (NC)/kg from the un-manipulated (UM) portion of the same unit (NCT00469729). The primary endpoint of this study was 100 day overall survival. Using an intent to treat design, outcome was compared to a 2006-2010 double UCBT (dUCBT) control group (n = 295) collected from and by the CIBMTR and Eurocord registries using identical eligibility criteria to the StemEx® study: lack of a 5/6 or 6/6 matched sibling donor, age 12-55 years with high risk AML or ALL in 1stCR or subsequent, advanced CML or after failing TKI, MDS with Int-2 or high risk features or chemosensitive relapsed lymphoma. GvHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil. Comparison of the primary endpoint was based on a logistic regression model that adjusts the treatment comparison for imbalance between the groups in important prognostic factors found to impact mortality: age, sex, CMV status and disease risk. Results25 centers in US, EU and Israel enrolled 101 eligible patients between Oct 2007-Feb 2012 with AML-43, ALL-30, MDS and CML-8 each, and lymphoma-12. Median age was 37 (12.6-55.8); median weight was 68 kg (42.5-128.5). The baseline NC and CD34 cell dose/kg were 3.06 (1.29-11.0) x 107 and 1.64 (0.24-9.23) x 105. 70% of the units were matched at 4/6 loci. Median NC and CD34 fold expansion were 400 (0-764) and 77 (6-280), respectively. StemEx yielded a median of 14-fold increase in the number of CD34+ infused, in comparison to the number of CD34+ cells the patients could have received from the entire UM CBU. In total, patients received a median dose of 2.2 x 107 NC/kg and 9.7 x 105CD34/kg. No significant acute toxicity was seen with the expanded cell infusions.The primary endpoint of this study has been met: 100 day survival was significantly higher in the StemEx® vs control group; 84.2 vs 74.6 % [95% CI 0.5 (0.26-0.95); p = 0.035]. Neutrophil and platelet engraftment rates were faster in the StemEx® vs control group: 21 vs 28 days (p< 0.0001) and 54 vs 105 days (p = 0.008), respectively. There was a trend in the reduction of engraftment failure from 14.4% in the control to 8.1% in the StemEx® group, p=0.086. Early engraftment (EE) (ANC ≤ day 20 and platelets ≤ day 60) was achieved more frequently in StemEx® (39.4%) than in the control arm (12.4%) , p<0.001. EE was associated with improved 100 day survival (p = 0.0028). Grade III/IV aGvHD and cGvHD rates did not differ between the study and control groups (19.4 vs 16.9%; p = 0.107) and 18.4 vs 16.0% (p = 0.731), respectively. Of the 101 patients, 16 patients died in the first 100 days. Causes of death were infection (5), multiorgan failure/ARDS (4), VOD (2) and relapse, acute GvHD, graft failure, hemorrhagic CVA and DIC (1 each). Importantly, the CD34+ cell dose from the StemEx expanded fraction was associated with time to ANC and platelet engraftment (p<0.001, 0.011, respectively) and inversely associated with grade III/IV infections during 100 day post-transplant (p = 0.023). ConclusionsThis multi-international study demonstrated the advantage of StemEx® over dUCBT historical controls,measured by a significant improvement in day 100 survival and faster engraftment of ANC and platelets. The robust associations obtained between CD34+ cell dose derived from the expanded portion and graft functionality provide additional support for the clinical benefit obtained over the dUCBT historical control arm. This technology holds the promise of increasing the number of UCBT being performed while potentially reducing its short term morbidity and mortality. Disclosures:Stiff:Gamida Cell Ltd: Consultancy, Honoraria, Research Funding. Peled:Gamida Cell: Employment. Landau:Gamida Cell Ltd: Employment. Rosenheimer:Gamida Cell Ltd: Employment. Mandel:Gamida Cell LTd: Employment. Hasson:Gamida Cell Ltd: Employment. Olesinski:Gamida Cell Ltd: Employment. Glukhman:Gmaida Cell Ltd: Employment. Snyder:Gamida Cell Ltd: Employment. Galamidi Cohen:Gamida Celll Ltd: Employment. Kidron:Gamida Cell Ltd: Employment. Bracha:Gamida Cell Ltd: Employment. Harati:Gamida Cell Ltd: Employment. Ben-Abu:Gamida Cell Ltd: Employment. Freind:Gamida Cell Ltd: Employment. Freedman:Gamida Cell Ltd: Consultancy. Olmer:Gamida Cell Ltd: Consultancy. Barishev:Gamida Cell Ltd: Consultancy. Nagler:Gamida Cell Ltd: Consultancy, Research Funding. Sanz:Gamida Cell Ltd: Consultancy, Honoraria, Research Funding.

Fatal Immune Hemolytic Anemia Following Allogeneic Stem Cell Transplantation: Report of 2 Cases and Review of Literature

Immune hemolytic anemia is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). There are 4 possible causes for this complication. First, antibodies present in the recipient destroy donor cells. Second, donor red cell antibodies at the time of stem cell infusion are transferred to the recipient. Third, sometimes, engrafted donor lymphocytes cause active production of red cell antibodies. Fourth, another cause of hemolysis after allogeneic HSCT is autoimmune hemolytic anemia (AIHA). It is thought to be due to antibodies produced by the donor's immune system against antigens on red cells of donor origin. Autoimmune hemolytic anemia after allogeneic HSCT is rare, it is still not well characterized, and it represents a life-threatening situation. We describe 2 patients with acute myeloid leukemia treated with intensive chemotherapy and umbilical cord blood stem cell transplantation (UCBT). One patient developed AIHA at day +182 and the other at day +212 after receiving UCBT. Patients received 5 and 7 line treatment options, respectively, including continuous corticosteroids, intravenous immunoglobulin, splenectomy, cyclophosphamide, plasma exchange, rituximab, bortezomib, and eculizumab. However, both patients died because of massive hemolysis after 85 and 106 days of intensive treatment, respectively. These cases reflect the extreme difficulty in the therapeutic management of patients with AIHA following UCBT. After an extensive review of the literature, the exact physiopathologic mechanisms of AIHA after allogeneic HSCT in general, and after UCBT in particular, and therefore an effective treatment remain unknown.

Quality control measures in cord blood banking in India - critical appraisal and recommendations.

Umbilical cord blood (UCB) is a potential source of primitive hematopoietic stem and progenitor cells (HSPC) available for clinical application to reconstitute the hematopoietic system in patients lacking conventional stem cell donors. In the last decade because the frequency of UCB stem cell transplantation has increased, the quality of UCB available in banks has become an important criterion for the success of any UCB stem cell transplant. Moreover, with the growing numbers of cord blood banks there is not only a need to improvise quality issues but to also develop a more homogenous approach in setting standards and regulations for assessing them. The present article provides an insight on the importance of cord blood banking in India and the impending requirement to provide clarity on certain issues regarding UCB banking. Furthermore, the article discusses about certain practical approaches which could perhaps be referred to as guidelines (and by no means be solely adopted as the only measures) by cord blood banks in India for establishing or maintaining a standard for quality control (QC) measures.

A Possible Role for Wnt3a in Enhancing StemRegenin1-Mediated Expansion of Hematopoietic Stem Cells

AbstractAbstract 4130Insufficient engraftment after umbilical cord blood stem cell transplantation (UCB-SCT) may be improved by the administration of ex vivo expanded UCB-derived hematopoietic stem cells (HSC). Although culturing HSC with cytokines such as SCF, Flt3L and TPO results in robust proliferation, it is accompanied with extensive differentiation and loss of self renewal capacity. Inhibition of the Aryl hydrocarbon Receptor (AhR) leads to potent expansion of hematopoietic progenitor cells (HPC) (Boitano et al. Science 2010). Reportedly, Wnt3a inhibits differentiation in different types of stem cells including hematopoietic stem cells(Reya et al. Nature 2003, Ten Berge et al. Nature Cell Biology 2011). Here, we evaluated possible additive or synergistic effects of combining the AhR antagonist StemRegenin1 (SR1) with recombinant purified Wnt3a to expand hematopoietic stem cells ex vivo.UCB-derived CD34-selected cells were cultured in serum-free Glycostem Basal Growth Medium (GBGM) supplemented with the early-acting growth factors SCF, Flt3L and TPO (SFT medium) with or without the addition of SR1 and Wnt3a. Cell number, viability and subset composition within the CD34+ cells were measured using flowcytometry. The multilineage differentiation potential and self renewal capacity of expanded CD34+HPC were evaluated in stroma-supported long-term culture-initiating cell (LTC-IC) assays.Culturing CD34+ cells in SFT medium resulted in a mean 10.2-fold increase in CD34+ cells after 1 week of culture (n=3). Addition of SR1 to the SFT-medium resulted in a 16-fold increase of CD34+ input cells within 7 days, while on the other hand, addition of Wnt3a alone to the SFT-medium resulted in a 7-fold increase in CD34+ cells. However, combining SR1 and Wnt3a in the SFT medium resulted in a 20-fold expansion of CD34+ cells compared to input. The early additive effect of Wnt3a on SFT+SR1-induced expansion of CD34+ cells, however, disappeared upon prolonged culture up to 2–3 weeks.Approximately 3–10% of UCB-derived CD34+ cells could be characterized as phenotypic HSC, as was defined by CD34+CD38lowCD45RAlowCD90+ cells. After culture, we sorted different CD34+-populations to evaluate their functional capacity. Evaluation of LTC-IC frequencies yielded a frequency of 1/23 LTC-IC in the phenotypic HSC-subset (CD34+CD38lowCD45RAlowCD90+) after 28 days of culture in SFT medium with SR1. However, no LTC-IC appeared to be present in the multipotent progenitor subset (MPP, CD34+CD38lowCD45RAlowCD90low). These results indicate that phenotypic HSC maintain their functional LTC-IC capacity after expansion culture.Collectively, our results confirm that SR1 expands HSC with preservation of self-renewal capacity and ability to differentiate into various hematopoietic lineages. In addition, we show that Wnt3a initially enhances SFT+SR1-driven expansion of CD34+ HPC, but reduces the increase in number of CD34+ cells at later stages of culture. These data may suggest that the period of expansion needed for clinical application may be shortened by combining SR1 and Wnt3a. Disclosures:Spanholtz:Glycostem Therapeutics: Employment. Groenewegen:Glycostem Therapeutics: Equity Ownership.

Effect of Serotherapy dose on Immunoreconstitution Following Umbilical Cord Stem Cell Transplant for Primary Immunodeficiency

Background: Severe Primary Immunodeficiencies (PID) have high morbidity and mortality. Umbilical cord blood stem cell transplantation (UCSCT) is curative. Conditioning regimens aid engraftment and long-term thymopoiesis. Modification of cyto-reductive chemotherapy with or without anti-lymphocyte serotherapy may alter immunoreconstitution and outcome.Aims: To examine speed of immunoreconstitution with respect to dose of serotherapy.Methods: A retrospective review of time to neutrophil and platelet engraftment, ≥200 T cells/µl, thymopoiesis, and lymphocyte subsets at 2,4,6 and 12 months in 33 PID patients who received UCSCT between 1999-2010 in one centre.Results: 12 patients received high dose (>0.6mg/kg), 10 low dose, and 8 no serotherapy. Overall median time to neutrophil and platelet engraftment was 21 and 38 days respectively. There were significant differences in median lymphocyte counts between dosages of serotherapy at specific time periods post UCSCT, with a general trend of low dose resulting in higher counts than high dose or no serotherapy. Exceptions were CD3+ and CD4+ counts at 2 months when no serotherapy led to significantly higher counts. No serotherapy led to a significantly shorter time to ≥200 CD3 cells/µl (17.5 days, range 10-88, p=0.001) but not to thymopoiesis. 6 evaluable patients achieved viral clearance by a median of 103 days post-UCSCT. Survival was 81%.Conclusions: This study shows that no serotherapy leads to higher lymphocyte counts by 2 months post UCSCT, but that higher lymphocyte counts are achieved with low dose serotherapy in the longer term. Further studies to determine mechanism are needed.

Acute Myeloid Leukemia Presenting as Subcutaneous and Epidural Granulocytic Sarcoma Inside and Outside of the Frontal Bone

An 18 year-old male was admitted to our hospital suffering from a large tumor which was located at the right frontal bone. He was diagnosed to have acute myeloid leukemia (AML) with granulocytic sarcoma (GS). A chromosomal analysis showed t (8 ; 21), and a flow cytometric analysis demonstrated the leukemic cells to be positive for CD56. Systemic chemotherapy and radiation therapy to the GS, but the patient experienced a relapse in the lumbar vertebrae. He underwent an umbilical-cord blood stem cell transplantation, however, he died 7 months thereafter. GS is a localized tumor consisting of leukemic myelolasts, which is generally observed as a complication of either AML, myelodysplastic syndrome, or myelobproliferative disorders. We herein report this case due to its rarity, even though various sites of GS have been reported.

Umbilical Cord Blood (UCB) Graft T-Cells Correlate with Myeloid Recovery in Adults with Hematologic Malignancies Treated with Reduced Intensity Conditioning (RIC) and Single Unit Infusion.

Experience with unrelated allogeneic UCB stem cell transplantation in the non-myeloablative setting is limited because of concerns of graft failure due to limited cell content. Dual UCB graft infusion has been explored to overcome cell dose limitations, but influence on engraftment is unclear. This single institution phase I trial examined RIC followed by single UCB transplantation for patients unable to tolerate fully myeloablative regimens and lacking a matched adult donor. Conditioning consisted of TBI 200 cGy, fludarabine 175 mg/m², cyclophosphamide 2 gm/m², ATG 60 mg/kg. Trial design specified selection of UCB grafts to be matched at 4/6 HLA loci or better with one unit infused if cryopreserved nucleated cell dose exceeded 2.5 x 107/kg recipient weight. If no adequate single UCB unit to meet these criteria was available, study patients received 2 UCB units containing a combined cell dose exceeding 1.5 x 107/kg. Grafts were analyzed via flow cytometry post thaw for stem cell and lymphocyte expression of surface antigens, among them CD4, CD8, CD7, CD34, CD38, CD45RA, CD45RO. 23 patients have been enrolled, the majority diagnosed with AML (n=17). Median age was 47 (range 25–68) years. Single UCB units meeting stated criteria were identified for all but one study patient, who was excluded from graft analysis. The time to engraftment was measured from the date of transplantation to the date of 3 successive days ANC≥500/μL attained. In addition, we assessed time to peripheral blood donor lymphocyte chimerism ≥ 60%. Patients were censored at the date of last follow-up or the date of death. 94% (95%CI: 77-.99%) of patients achieved ANC≥500/μL by T+36 with median of 26.5 ( range 11–55) days. 68% (95%CI: 48–85%) of patients (n=15) achieved >60% donor derived chimerism by median of 22 (range 14–35) days. Median cryopreserved and infused total nucleated cell dose was 2.85 x 107 and 2.5 x 107 cells/kg, respectively. Median infused CD34 cell dose was 1.71 (range 0.21–5.39) x 105 cells/kg. By univariate analysis the dose of infused UCB graft T-cells including CD4 and CD8 T-cells co-expressing CD45RO, and CD34 stem cells co-expressing CD7 and CD38 correlated with neutrophil recovery, p=0.046, 0.008, and 0.033, respectively. Median overall survival at this early interim analysis has not been reached; with 86% and 65% survival at 3 and 24 months, respectively. Event free survival is 78% and 44.5% at 3 and 24 months, respectively. In summary, in this heavily pretreated group of advanced age patients, RIC and single unit unrelated allogeneic UCB stem cell transplantation is safe. Identification of a single UCB graft of HLA match 4/6 meeting cell dose requirement 2.5x107/kg is identified in the vast majority of full size adult patients. Engraftment and survival rates are higher than reported in single UCB transplants following administration of myeloablative regimens and similar to recent reports for RIC with double UCB graft infusion. The potential benefit of infusion of 1 vs. 2 UCB units after RIC in adult patients remains to be fully evaluated.

Stem Cell Transplantation in Thalassemia

The beneficial results of stem cell transplantation from HLA identical family members for patients with severe thalassemia are clear. Class I patients have a very high probability of cure with a very low early and late morbidity and mortality. Delay of transplantation until the patient is in a risk category beyond class I substantially reduces the probability of transplant success and jeopardizes the reversibility of liver and cardiac damage. It is reasonable to suggest that patients with β-thalassemia who have HLAidentical donors should be transplanted as soon as possible. Umbilical cord blood (UCB) has been shown to be capable of reconstituting the bone marrow of the patient with thalassemia after myeloablated pre-conditioning treatment. The major advantage of UCB over other sources of stem cells is the ability to cross HLA barriers, and there is evidence of less GVHD. The use of related –donor UCB stem cells with HLA mismatches at one to three antigens needs to be considered. It would be worth while to do a prospective study to evaluate the role of UCB stem cell transplantation in the treatment of the thalassemias and hemoglobinopathies.