Single Mismatched Expanded Cord Blood Transplantation for the Treatment of Hematological Diseases.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4056-4056
Author(s):  
Zimin Sun ◽  
Huilan Liu ◽  
Jian Wang ◽  
Zuyi Wang ◽  
Liangquan Geng ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Cord Blood ◽  
Ex Vivo ◽  
Cord Blood Transplantation ◽  
Free Medium ◽  
Platelet Recovery ◽  
Blood Transplantation ◽  
Cd34 Cells ◽  
Cord Blood Unit

Abstract Umbilical cord blood transplantation (UCBT) is increasingly used as an alternative stem cell source for therapy in place of bone marrow or peripheral blood stem cell transplantation. However, the low yield of transplantable cells limits the application of a single cord blood unit to patients, particularly with adults and high body weight children. Currently, different cytokines and serum-and-stroma-free medium are used to increase the number of hematopoietic stem/progenitor cells in a single cord blood unit. The ex vivo expanded cord blood transplantation results from phase I trials of clinical therapies have been reported. Here, we report our preliminary data using single HLA mismatched UCBT expanded ex vivo and transplanted for treatment of patients with hematological disease in China. Three patients suffering from chronic myelocytic leukemia (CML, accelerated phase), severe aplastic anemia (SAA, type II), or acute lymphocytic leukemia (ALL) (age range 10–35 years; Body weight range 37.0–76.5. kg) were given ex vivo expanded HLA mismatched (4/6 or 5/6) UCBT. Myeloablative conditioning regimens were used (busulfanum/cyclophosphamide (BU/CY), and anti-thymus globulin (ATG) for CML, cyclophosphamide and ATG for SAA-II, and BU/CY, ATG, and 1,3 -bis(2-chloroethyl)- 1- nitrosourea for ALL-CR2). All patients used cyclosporine A (CsA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. After thawing, a 5/6 fraction of the cord blood was infused on day 0 and the remaining 1/6 was expanded for 7 days in serum-and-stroma-free medium containing stem cell factor (SCF), thrombopoietin (TPO), Flt3-L, and IL3. This expaded fraction was infused on day 7. After incubation, the number of total nuclear cells (TNC) increased by 1.86-, 1.91-, 1.81- fold in the CML-Ap, SAA-II, and ALL patients, respectively, while CD34+ cells in these cord blood units increased 7.60-, 0-, 7.46- fold in the CML-Ap, SAA-II, and ALL patients, respectively. The TNC of the three grafts reached 2.4, 4.73, 3.72 ×107/kg; CD34+ cells reached 4.37, 2.69, 8.46×105/kg and colony-forming cells (CFC) reached 5.16, 2.43, 6.87×104/kg in the recipients respectively. One patient (CML-Ap) died of hepatic veno-occlusive disease (HVOD) and multi-organ failure (MOF). In the other two cases, neutrophils were engrafted on day 16 and day 17. In one patient (SAA-II), the cord blood was rejected on day 60. The genotype of 16 STR markers in the ALL patient changed on day 30, as detected by STR-PCR and the blood group changed on day 62. Platelet recovery (>20× 109/L) occurred on day 34. Both patients were still alive after 10–12 months follow up. We found that TNC and CD34+ cells were increased after incubation for seven days in the serum-and-stroma-free medium including SCF, TPO, Flt3-L, IL-3. After infusion of the expanded UCBT fraction, the time required for neutrophil recovery in the patients was significantly shortened, although there was no influence on platelet recovery. Therefore, these data indicate that it is safe and feasible to use a 1/6 expanded fraction of UCBT combined with a 5/6 unmanipulated fraction of UCBT for the treatment of hematological cancers.

Double Cord Blood Transplantation in Bone Marrow Failure Syndromes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2018-2018
Author(s):  
Regis Peffault de Latour ◽  
Vanderson Rocha ◽  
Marie Robin ◽  
Celso A. Rodrigues ◽  
Delphine Rea ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Bone Marrow Failure ◽  
Cord Blood Transplantation ◽  
Blood Transplantation ◽  
Bone Marrow Failure Syndromes ◽  
Cord Blood Unit ◽  
Grade Ii

Abstract The outcome of severe aplastic anemia, refractory to immunosuppressive therapy or observed in case of Fanconi anemia (FA), is usually poor in the absence of Hematopoietic Stem Cell Transplantation (HSCT). Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit is associated with high transplant related mortality due to the low cell dose infused in previous highly transfused patients. We have driven the hypothesis that double cord blood transplantation (dCBT) could circumvent the cell dose problem. For the purpose of this study, we have studied 13 patients with bone marrow failure syndromes given 2 partially matched dCBT from 2004 to 2007. The diagnoses were FA (n=9), SAA (n=4) and PNH (n=1). Among those patients, 5 (39%) received a dCBT as a rescue of previous rejected transplants (2 SAA and 3 FA). All patients received a fludarabine-based regimen, with TBI (2 Gy) for 4 patients. Cord blood units were a 4/6 or 5/6 HLA A, B and DR match with the patient except one which was 3/6. Graft versus host disease (GVHD) prophylaxis consisted in CSA+MMF. Steroids were given from day 7 to day 14 and stopped in case of no GVHD. Five male (39%) and 8 female (61%) with a median age of 16 years (range 7–31) were treated. The cell doses infused were a median of 5.0 × 107 NC/Kg (4–9) and 5.3 × 105 CD34+ cells/Kg (2–8). Graft rejection was seen in 5 patients (2 previously allotransplanted). Among those patients, one displayed a temporary mixed chimerism before rejection and another presented an autologous reconstitution. Among the remaining 8 patients, the median time to an absolute neutrophils count > 500 was 25 days (range 14–42) and the median time to a platelet count > 20,000 was 39 days. In these last patients, we observed a complete donor chimerism with one cord blood unit during 100 days after dCBT. Acute GVHD grade II–III was scored in 9 patients (69%) (7 grade II, 2 grade III). No patients presented acute GVHD grade IV. Four patients out of 8 developed Chronic GVHD (3 limited and 1 extensive). Four patients died (1 GVHD, 2 fungal infection, 1 thrombotic microangiopathy). With a median follow-up of 13 months (range 1 to 19 months), the overall survival was 55% (±15%) for all patients. The median survival of patients who were transplanted twice was 50% (±25%). In conclusion, dCBT seems to be an option to treat patients with bone marrow failure syndromes and without a suitable compatible HLA donor. Those results need to be established on a large number of patients to warrant the inclusion of dCBT in the treatment strategy of diseases with high risk of rejection.

Differences in the Kinetics of Hematopoietic and Stem Cell (SC) Engraftment Following Murine Newborn/Cord Blood (NB) and Bone Marrow (BM) Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4949-4949
Author(s):  
Tao Du ◽  
George F. Atweh ◽  
Yelena Galperin ◽  
Rona Singer Weinberg
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cord Blood ◽  
Mononuclear Cells ◽  
Cord Blood Transplantation ◽  
Platelet Recovery ◽  
Platelet Counts ◽  
Blood Transplantation ◽  
Cell Counts ◽  
Kinetics Of

Abstract Cord blood is being used at an increasing frequency as a source of stem and progenitor cells in human hematopoietic transplantation. However, very little is known about the kinetics of engraftment of cord blood relative to bone marrow derived stem cells. We have used a murine model of newborn/cord blood transplantation to address this question. Our studies demonstrated that murine NB can provide long-term engraftment in primary, secondary, and tertiary transplant recipients. Although NB engrafts more slowly than BM, at one year, engraftment was similar in both types of recipients. We compared the rate of recovery of blood counts, hematopoietic progenitor counts and putative stem cell [SC] counts (i.e. Sca-1+, c-kit+, Lin- cells) in recipients of NB and BM transplantation. Interestingly, the SC ratio in mononuclear cells from donor NB/donor BM was 3.25 ± 0.8 (range = 2.45 – 4.75, n=15). Similarly, donor NB mononuclear cells contained approximately 30% of the number of megakaryocytic progenitors, 12% of the myeloid progenitors and 5% of the erythroid progenitors of donor BM mononuclear cells. The repopulation kinetics in recipients of donor BM and NB transplantation were analyzed at regular intervals, up to 8 months after transplantation. During the first two weeks, NB recipients had lower hemoglobin, WBC and platelet counts than BM recipients. However, by 1 month, the hemoglobin and WBC counts were at similar levels in NB and BM recipients. In contrast, NB transplantation recipients required 2 to 3 months to achieve platelet counts similar to those in BM recipients. These results are reminiscent of the well-known delayed platelet recovery following human cord blood transplantation. Progenitor cell counts in the bone marrow of recipients paralleled the hematological recovery described above. At 2 weeks post-transplantation, progenitor counts of all lineages in NB recipients were 25 to 35% of those in BM recipients. By 1 month, erythroid and myeloid progenitor numbers were similar in NB and BM recipients. In contrast, the appearance of megakaryocytic progenitors was delayed following NB transplantation and did not reach the same level as BM recipients until about 2 months after transplantation. During recovery, the number of SC in the bone marrow of both types of recipients increased gradually over time. At one month after transplantation, the number of SC in BM recipients was significantly greater than that in NB recipients, with a ratio of 4.2 ± 0.2. This SC ratio decreased gradually during the next several months. At 2, 4, and 8 months following transplantation, the ratios of SC in BM recipients/NB recipients were 3.5 ± 0.4, 2.6 ± 0.5, and 2.2 ± 0.3, respectively (n=5). This gradual decrease in the ratio of BM/NB SC suggests that NB SC increase more rapidly than BM SC. In conclusion, these data demonstrate that the kinetics of hematopoietic and stem cell recovery following NB and BM transplantation are significantly different. Although hematopoietic recovery after NB transplantation is slow at first, final engraftment is similar following NB and BM transplantation. Furthermore, the number of SC in NB recipients increases at a faster rate than the number of SC in BM recipients. These differences in SC recovery may be a reflection of differences either in the homing capacity or in the functional maturity of NB relative to BM SC. Further investigation is required to distinguish between these two possibilities.

Ex Vivo Fucosylation Of Cord Blood Accelerates Neutrophil and Platelet Engraftment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 691-691 ◽  
Author(s):  
Uday R Popat ◽  
Betul Oran ◽  
Chitra M. Hosing ◽  
Partow Kebriaei ◽  
Katy Rezvani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Median Time ◽  
Ex Vivo ◽  
Cord Blood Transplantation ◽  
Hematologic Malignancies ◽  
Platelet Recovery ◽  
Equity Ownership

Abstract Background Cord blood transplantation (CBT) is an increasingly used alternative to bone marrow or peripheral blood stem cell transplantation, but is associated with slower neutrophil and platelet recovery. One strategy to overcome the delayed hematopoietic recovery of CB is to correct the decreased fucosylation of CB cell surface molecules which is thought to impair homing to the bone marrow of the limited numbers of stem and progenitor cells in the CB graft. Our pre-clinical murine xenograft models have demonstrated that human CB-derived progenitor cells treated with recombinant human fucosyltransferase-VI (ASC-101:America Stem Cell Inc.) prior to infusion resulted in more rapid and higher levels of human engraftment as compared to untreated CB progenitors (Robinson et al Exp Hematol, 2012). We therefore sought to study this novel strategy in a clinical trial where recipients with hematologic malignancies receive a double CBT where one CB unit is fucosylated prior to infusion. Objective In an effort to improve engraftment following cord transplant, we tested the ability of a 30-minute ex vivo fucosylation treatment to shorten time to neutrophil and platelet recovery. Methods Cell Processing: The unmanipulated CB unit with the highest total nucleated cell (TNC) dose was thawed, washed on the Sepax device (Biosafe) and infused first. The second CB unit which had the smaller TNC dose was thawed and washed using 10% Dextran-40/5% human serum albumin and the cells treated at 106cells/ml for 30 minutes at room temperature with recombinant human fucosyltransferase VI (ASC-101) and substrate GDP-fucose (America Stem Cell Inc). The fucosylated cells were then washed on the Sepax and infused. After the procedure fucosylated (CD34+ CLA+) CD34+ cells increased from a median of 33% to 99%. Clinical 10 patients with AML (5), MDS (2), NHL (2), or HL (1) have been enrolled to date. Three patients are too early to evaluate engraftment; therefore, first 7 evaluable patients are reported here. Median age was 55 (range 26 -62) years and median weight 87 (range 61-97) kg. All patients were conditioned with fludarabine 160mg/m2, melphalan 140mg/m2, and ATG 3mg/kg. Tacrolimus and MMF were used for GVHD prophylaxis. Results Median time to absolute neutrophil count ≥ 0.5 X 109 /L was 14 (range 12-28) days. Median time to platelet count ≥ 20 X 109/L was 33 (range 18-100) days. One patient had secondary graft failure and was rescued with backup autologous stem cells. Four patients had engraftment of the fucosylated unit and 2 of the unfucosylated unit. Two patients developed grade 2 acute graft versus host disease. No infusion related toxicities were seen. Conclusion Ex vivo fucosylation appears to be a safe, simple and rapid approach to enhancing neutrophil and platelet engraftment in the setting of double cord transplantation. Accrual to the trial continues and updated results will be presented. Disclosures: Miller: America Stem Cell Inc: Equity Ownership. Paradiso:America Stem Cell Inc: Equity Ownership. Koh:America Stem Cell Inc: Equity Ownership.

Intrabone Infusion of Umbilical Cord Blood Stem Cells to Improve Hematopoietic Recovery after Allogeneic Umbilical Cord Blood Transplantation in Children

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4334-4334 ◽  
Author(s):  
Henrique Bittencourt ◽  
Marie-France Vachon ◽  
Isabelle Louis ◽  
Ernestine Chablis ◽  
Marion Cortier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Single Unit ◽  
Pediatric Patients ◽  
Cord Blood Transplantation ◽  
Platelet Recovery ◽  
Blood Transplantation ◽  
Hematopoietic Recovery

Abstract Umbilical cord blood transplantation (UCBT) has been used to treat malignant and non-malignant diseases. UCBT offers the advantages of easy procurement, immediate availability, and acceptable partial HLA mismatches. Still, patients treated with UCBT show delayed hematopoietic and immunological recoveries, and have higher rates of infection. The problem of slower hematopoietic recovery post-UCBT has been addressed using different approaches: infusion of two CB units, ex-vivo expansion of CB, transplantation of a UCB combined with a selected CD34+ peripheral stem cell unit from an haplo-identical donor. Intrabone (IB) injection is a known emergency access route for infusion of fluids and drugs in children. Frassoni et al published a study on the IB injection of a single unit of CB into 32 adult patients (Frassoni F, et al. Lancet Oncol. 2008) and showed a neutrophil (0.5x10^9/L) and platelet (20x10^9/L) recoveries with a median of 23 and 36 days, respectively, with a median nucleated cell dose of only 2.6 x 10^7 cells/kg. These results have been confirmed in a retrospective study comparing IB infusion of CB with infusion of two units of CB in adult patients (Rocha V, et al. Transplantation. 2013). The only data of IB infusion in pediatric patients is a case report of 5 patients (Saglio F, et al. J Pediatr Hematol Oncol. 2012). In order to confirm the role of IB infusion of CB to improve hematopoietic reconstitution after UCBT in pediatric patients, we started a Phase II single arm, exploratory clinical trial (NCT01711788). Our primary hypothesis is that use of IB infusion of CB reduces stem cell trapping seen with IV infusion, maximizing the number of stem cells and providing a faster short- and robust long-term engraftment. Inclusion criteria includes age up to 21 years, diagnosis of hematopoietic disorders (malignant or not), availability of a single CB with at least 3 x 10^7 nucleated cells (NCs)/kg at freezing (use of two CB units is allowed provided a single CB unit fulfilling the above criteria is not available), and use of a myeloablative-conditioning regimen. On the day of UCBT, frozen CB unit is thawed, washed and re-suspended in 20 ml of a saline/albumin solution and aliquoted into four 5-ml syringes. Patient is sedated with propofol and ketamine according to the current protocol for sedation in children. After sedation, a first aliquot of CB stem cell suspension is injected into the bone marrow, followed by a of 0.5-1 ml saline solution rinse. This procedure is repeated for all remaining aliquots at different places and can be performed in one or both iliac crests, depending on patient size. Each injection is performed within a 2-minute timeframe. If patient requires two CB units, one unit is infused IB while the second unit is infused IV after recovery from sedation. G-CSF is given from D+7. A total of 12 patients has been included since Nov/2012. Eight were male, and median age was 7 (2 - 15) years. Diagnosis were AML (n=6), ALL (n=4) and sickle cell anemia (n=2). Most UCB were unrelated (n=10) and 6/6, 5/6 and 4/6 HLA matching comprised four, five and three UCBT. Busulfan-based conditioning was used in eight patients. Ten patients received a single unit UCB. Median NC infused was 3.4 (2.17-8.4) x 10^7/kg. There was no toxicity related to IB infusion. Engraftment occurred in 10 out of 12 patients and median time to engraftment (neutrophil ≥ 0.5x10^9/L) was 14.5 days. Platelet recovery (≥ 50x10^9/L) occurred in just 6/12 patients (due mainly to early relapse) and median time to recovery was 41 (28-77) days. Three patients presented a grade II aGVHD. There were three relapses. Ten out of twelve patients are alive, one patient died from UCBT complication (ARDS) and other from relapse. In conclusion, IB infusion of UCB is feasible in pediatric patients without any particular toxicity and there is a positive impact on neutrophil recovery. Inclusion of more patients are needed to confirm the impact of IB-UCBT on platelet recovery, duration of hospitalisation, and survival. IB-UCBT might be a more affordable alternative to improve hematopoietic recovery comparing to other methods of UCB expansion. Disclosures No relevant conflicts of interest to declare.

scholarly journals Optimizing cord blood selection

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 522-531 ◽  
Author(s):  
Annalisa Ruggeri
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Ex Vivo ◽  
Cord Blood Transplantation ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Dose Requirement ◽  
Related Factors ◽  
Blood Transplantation ◽  
Donor Choice

Abstract Nowadays a donor can be found for virtually all patients in need of an allogeneic stem cell transplantation, and the decision whether to use a matched or mismatched unrelated donor, an unrelated donor for umbilical cord blood transplantation (UCBT), or a haploidentical donor depends not only on the availability of the donor but also on patient-, disease-, and center-related factors. This paper summarizes the recent criteria in the selection of cord blood unit, including the cell dose requirement and the HLA typing for the optimal donor choice. The main strategies to optimize the results of UCBT, the conditioning regimens, and the use of antithymocyte globulin and the other platforms of graft-versus-host disease prophylaxis are discussed. The paper describes the results of UCBT in children and adults with malignant and nonmalignant diseases and the comparative analysis with other donor type and stem cell sources. Emerging strategies, focusing on the different platforms of ex vivo expansion and the new applications using cord blood stem cell, are also examined.

Sign in / Sign up

Export Citation Format

Share Document