Post Thaw Colony Forming Units (CFU) Is a Strong Independent Predictor of Engraftment after Unrelated Donor Umbilical Cord Blood Transplantation (UCBT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3282-3282
Author(s):  
Kristin M. Page ◽  
Adam Mendizabal ◽  
Barbara Waters-Pick ◽  
Sophia Avrutsky ◽  
Melissa Reese ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Independent Predictor ◽  
Multivariate Model ◽  
P Value ◽  
Unrelated Donor ◽  
Strong Independent Predictor ◽  
Neutrophil Engraftment

Abstract Background: Unrelated donor umbilical cord blood is an acceptable graft source for patients lacking related donors. However, a non-engraftment rate of approximately 20% despite adequate total nucleated cell (TNC) dose remains a barrier to the overall success of UCBT. Of various patient and graft characteristics that may influence engraftment, identifying an assay predictive of cord blood unit (CBU) potency and overall engraftment would be beneficial. Methods: Pre-cryopreservation (pre-cryo) and post-thaw graft characteristics were available on 423 UCBT performed at our institution between 2/11/2000 and 5/1/2007. The units were obtained from 16 US public cord blood banks and were selected by pre-cryo cell dose and HLA matching. Pre-cryo data (TNC, CD34 cells and CFU) was provided by the cord blood bank as part of routine banking practices. All units were thawed in the Duke Stem Cell Laboratory (SCL). Post-thaw testing (TNC, CD34, CFU) was performed by consistent personnel in the SCL after thaw and washing with Dextran/Albumin as described previously by Rubinstein et al. Univariate and multivariate analyses were performed to identify significant pre-cryo, post-thaw, and baseline factors predictive of neutrophil and platelet engraftment. Results: Of the 423 evaluable patients, 68% had malignancies, 61% were males, 73% were Caucasian and 38% were CMV+. The grafts were HLA (93%), sex (50%) or racially (24%) mismatched with the patients. There was excellent correlation between pre-cryo and post-thaw TNC (r2=0.92) and CD34 (r2=0.68) content, but much weaker correlation for CFUs (r2=0.27). In univariate analysis, age (≤5 years), disease (non-malignant), weight (≤12 kg), CMV status (negative), recipient ethnicity (Caucasian), HLA match (5/6 or 6/6) and pre-cryo/post-thaw TNC (larger), pre-cryo/post-thaw CD34 (larger) and pre-cryo/post-thaw CFU (larger) were predictive of both neutrophil and platelet engraftment. Multivariate analysis of parameters are presented in Table 1. In the overall multivariate analysis of neutrophil engraftment, Male units (p=0.01), 5/6 or 6/6 HLA match (p=0.02), larger post-thaw CD34 (p=0.02) and larger post-thaw CFU (<0.0001) were significant. For platelet engraftment, Caucasian recipients (p=0.006) and larger post-thaw CFU (p=0.002) were the only predictive parameters. Conclusions: Post-thaw CFUs are a strong independent predictor of neutrophil and platelet engraftment after UCBT. This assay could be tested on a CBU segment and used as a marker of potency for graft selection. Factors Predictive of Neutrophil and Platelet Engraftment in Multivariate Analysis of Graft/Recipient Characteristics. Neutrophil Engraftment Platelet Engraftment Pre−Cryopreservation Multivariate Model (p−value) CD34+ (0.0046), Recipient CMV (0.0138), CFU (0.0337), Unit Sex (0.0393) Recipient ethnicity (0.0052), TNC (0.0173), CFU (0.0324) Post−Thaw Multivariate Model (p−value) CFU (<0.0001), CD34 (0.0013), HLA match (0.0065) CFU (<0.0001), HLA match (0.0117), Recipient ethnicity (0.0135) Overall Multivariate Model (p−value) Post thaw CFU (<0.0001), Unit Sex (0.0131), HLA match (0.0186), Post thaw CD34 (0.02) Recipient ethnicity (0.0063), Post thaw CFU (0.002)

Alternative Donor Transplantation for Aplastic Anemia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 43-46 ◽  
Author(s):  
Mary Eapen ◽  
Mary M. Horowitz
Keyword(s):  
Cord Blood ◽  
Aplastic Anemia ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Graft Failure ◽  
Hla Typing ◽  
Unrelated Donor ◽  
Term Survival ◽  
Alternative Donor

AbstractPatients with severe aplastic anemia who do not have a human leukocyte antigen (HLA)-identical sibling generally receive immunosuppressive therapy as a first-line therapy, with allogeneic transplantation being reserved for those who do not have an adequate sustained response. Barriers to the use of unrelated-donor transplantation for aplastic anemia include identifying a suitable alternative donor, and risks of graft failure, regimen-related toxicity, and graft-versus-host disease (GVHD). Despite the more than 14 million adults registered with donor registries worldwide, only approximately 50% of patients of Caucasian descent will have an available and fully HLA-matched unrelated adult donor; the rate is substantially lower for non-Caucasians. While umbilical cord blood allows transplantation with greater donor-recipient HLA disparity (without excessive risk of GVHD), risks of graft failure and transplant-related mortality are higher than after transplantation of adult donor grafts. Among patients with a suitable donor, recent changes in pre-transplant conditioning regimens have lowered the risks of organ toxicity and graft failure. Although advances in donor HLA typing and selection practices and improved GVHD prophylaxis have lowered the risk, GVHD remains an important obstacle to long-term symptom-free survival. Despite these limitations, unrelated-donor transplantation offers the best chance of long-term survival for many patients in whom current immunosuppression strategies are not effective. Wider applicability of alternative-donor transplantation for aplastic anemia will require better approaches to prevent graft failure and GVHD and to expand the pool of unrelated-donor grafts. This includes exploring strategies to effectively use alternative grafts such as umbilical cord blood.

scholarly journals Searching for unrelated donor hematopoietic stem cells: Availability and speed of umbilical cord blood versus bone marrow

2002 ◽  
Vol 8 (5) ◽  
pp. 257-260 ◽  
Author(s):  
Juliet N Barker ◽  
Timothy P Krepski ◽  
Todd E DeFor ◽  
Stella M Davies ◽  
John E Wagner ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Unrelated Donor ◽  
Hematopoietic Stem

scholarly journals INFECTIOUS COMPLICATIONS AFTER UMBILICAL CORD-BLOOD TRANSPLANTATION FROM UNRELATED DONORS

2016 ◽  
Vol 8 ◽  
pp. 2016051 ◽  
Author(s):  
Juan Montoro ◽  
Jaime Sanz
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Infectious Complications ◽  
Unrelated Donor ◽  
Alternative Source ◽  
Hematopoietic Stem ◽  
Blood Transplantation

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.

Culture of CD34+ Umbilical Cord Blood Progenitors with Notch Ligand Results in Enhanced and More Rapid Human Engraftment in a Preclinical NOD/SCID Mouse Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 190-190 ◽  
Author(s):  
Colleen Delaney ◽  
Irwin D. Bernstein
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cultured Cells ◽  
Ex Vivo ◽  
Culture Period ◽  
Unrelated Donor ◽  
Culture Vessel ◽  
Notch Ligand ◽  
Significant Difference

Prior clinical studies have indicated that total nucleated and CD34+ cell dose is a critical determinant of hematopoietic reconstitution and survival after unrelated donor umbilical cord blood (UCB) transplantation. Efforts to overcome the problem of small cell numbers in UCB grafts by ex vivo expansion, primarily by culture with cytokines, have not met with success. We have previously shown that culture of CD34+CD38− UCB progenitors with the Notch ligand, Delta1, results in enhanced generation of NOD/SCID repopulating cells. Here we develop a clinically feasible cGMP method for Notch ligand-based expansion of cord blood precursors. Specifically, we investigated the use of CD34+ versus CD34+CD38− cells as a starting population, optimal cytokines and medium, selection of culture vessel and culture period for effects on generation of NOD/SCID repopulating cells. UCB progenitors were cultured in the presence of a Notch ligand form consisting of the extracellular domain of Delta1 fused to the Fc domain of human IgG1 (Delta 1ext-IgG) or control human IgG. Initial studies demonstrated optimal cytokines consisted of SCF, FL, TPO, IL6 and IL3, together with fibronectin fragments in serum free medium. There was no significant difference seen in the CD34 fold expansion with CD34+ versus CD34+CD38− starting cells, however, upon transplantation into NOD/SCID mice, there was a significant increase in the level of human engraftment seen with the CD34+ starting cell population (6.93% vs 2%; p=0.01). Further results from 5 independent experiments in which cord blood CD34+ progenitor cells were cultured for 17 days with immobilized Delta1extIgG or control resulted in a mean fold expansion of CD34+ cells of 230 (± 53) for the Delta cultured cells versus 65 (±31) for the control cultured cells (p=0.03). Delta cultured cells demonstrated significantly enhanced levels of human engraftment as measured by percent CD45 in the marrow of the animals at both 3 weeks (Delta1 15.5%, control 2.6%, uncultured 0.2%; p<0.0001) and at 9 weeks (Delta1 29.4%, control 8.9%, uncultured 7.3%; p<0.0001). We also found significantly greater numbers of SCID repopulating cells (SRC) detected 3 and 9 weeks following transplantation in the Delta1ext-IgG cultured cells compared to control cultured or non-cultured cells (frequency of SRC per 106: 3 weeks, 125 versus 37 or 8, respectively; p=0.0001; 9 weeks, 99 versus 56 or 15, respectively; p=0.01 and p=0.0001). Additional experiments demonstrated that the 17 day culture period was superior to shorter (10 days) or longer (21 days) periods. Relevant to anticipated administration of cultured cord blood units together with a second non-cultured unit in clinical trials, we determined the relative contribution to engraftment of co-infused expanded versus non-manipulated cells in immunodeficient mice, using tissue culture bags as a closed system. We found increased human engraftment in mice that received co-infusions of cultured and uncultured cells compared to either unit alone. Moreover, studies demonstrated that both units contributed to the observed human engraftment suggesting absence of cross-immunologic rejection. This data demonstrate the ability to ex vivo expand UCB repopulating cells using a clinically relevant Notch ligand-based closed culture system and suggests clinical evaluation of this approach to provide more rapid engraftment to overcome the major disadvantage of UCB transplantation.

Unrelated Umbilical Cord Blood Transplant for Children with Leukemia: Single or Double Unit Transplant

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4422-4422
Author(s):  
Chi Kong Li ◽  
Vincent Lee ◽  
Frankie WT Cheng ◽  
Karen Li ◽  
Kent KS Tsang ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Myeloid Leukemia ◽  
Single Unit ◽  
Mixed Chimerism ◽  
Cell Dose ◽  
Single Donor ◽  
Cord Blood Transplant ◽  
Neutrophil Engraftment

Abstract Unrelated umbilical cord blood transplant (UCBT) was performed in 24 children (16 M, 8 F) with leukemia in a single institution from June 1998 to May 2008. The leukemia types were Acute Lymphoblastic Leukemia (ALL, n=13), Acute Myeloid Leukemia (AML, n=9) and Juvenile Myelomonocytic Leukemia (JMML, n=2). The disease status was CR2 in 13, CR3/4 in 3, refractory or relapse in 8. Fifteen patients received single unit (SU) and 9 patients received double unit (DU) UCBT. The mean age and body weight were 5.7 ± 3.7 year and 19.5 ± 7.9 kg for SU, 7.7 ± 4.0 year and 24.6 ± 9.9 kg for DU, respectively. The sources of cord blood units were from local public CB bank (n=20) and 4 overseas public CB banks (n=4). The cord blood units were not more than 2 HLA antigen mismatches from the patients, and the DU cord blood were also not more than 2 antigen mismatches between each other. The minimal requirement was nucleated cell (NC) dose &gt; 2.5×107/kg for SU, and &gt; 3.7 ×107/kg for DU. The conditioning was TBI based for ALL and busulphan-based for myeloid leukemia. ATG was routinely included except in 5 patients. The engraftment rate was 70.8% for the whole group, and 66.7% and 77.8% for SU and DU, respectively. All the 4 overseas UCBT failed to engraft and the engraftment rate for local CB bank units was 85%. The 2 JMML had failed engraftment, one received SU and 1 DU. There was no significant difference in the transplanted cell dose for SU and DU (combined dose), NC 6.2±3.8×107/kg vs 8.2±3.5×107/kg, CD34 cell 5.0±7.2 ×105/kg vs 3.8±1.3×105/kg, respectively. However patients who had successful engraftment received higher cell dose, NC 7.9±3.9×107/kg vs 4.5±1.8×107/kg (p=0.042), CD34 cell 5.4±6.3 ×105/kg vs 2.2±1.6×105/kg (p=0.073), respectively. All the 9 DU UCBT showed signs of engraftment with donor DNA detected, but two did not achieve neutrophil engraftment and subsequently failed engraftment. On the first chimerism study on Day 7–10, 3 had mixed chimerism (MC, 50–60% vs 40–50%) and 2 became single donor complete chimerism (CC) in the second week study, one had persistent MC up to 1 month but required second transplant for failed neutrophil engraftment. Six patients had CC with single CB unit since the week 1 and were maintained in 5, and another one had failed neutrophil engraftment. Finally 7 DU UCBT had sustained CC with single donor unit, however the finally successfully engrafted unit had lower CD34 cell dose as compared to the non-engrafted unit (1.5±0.5×105/kg vs 2.4±1.1 ×105/kg, p=0.004), and the NC dose of the 2 units in DU was similar (3.6±1.7.×107/kg vs 4.4±1.8×107/kg (p=0.042). There was no difference in the degree of HLA mismatch between the engrafted and non-engrafted units of DU. The neutrophil engraftment was more rapid with SU as compared with DU, 14.5 vs 19.7 days, p=0.021, the platelet engratment and number of red cell and platelet transfusion was not different. All those with engraftment developed acute GVHD, and the incidence of grade III–IV was similar between SU and DU (33.3% vs 28.6%), and none died from AGVHD. Nine patients died of non-engraftment or transplant related mortality, 3 from leukemia relapse and 12 were alive (7 patients &gt; 3 years). The 2-year survival after UCBT was 47%. In conclusion, DU cord blood could achieve a higher NC dose, but the engraftment of DU was always single unit and 33% had transient MC in the very early week of UCBT. The DU approach may enhance the engraftment of the finally engrafted unit even that had a lower CD34 cell dose.

Allele Level HLA Matching On Outcomes After Double Umbilical Cord Blood (dUCB) Transplantation for Hematological Malignancies: Stronger Graft Vs. Leukemia with HLA Mismatch

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1976-1976
Author(s):  
Claudio G Brunstein ◽  
Todd E. Defor ◽  
Harriet Noreen ◽  
David Maurer ◽  
Margaret L. MacMillan ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Treatment Failure ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Hla Typing ◽  
P Value ◽  
Hla Matching ◽  
Transplant Outcomes

Abstract Abstract 1976 Multiple single center and registry reports have documented the critical impact of donor-recipient HLA match on engraftment, transplant-related mortality (TRM) and survival after umbilical cord blood (UCB) transplantation. However, nearly all reports have only considered HLA A and B at antigen level and HLA DRB1 at allele level typing without consideration of HLA C or DQ. Therefore, we retrospectively performed allele level HLA typing for HLA-A, B, C, DRB1, DQB1 for UCB donor-recipient pairs in order to assess the importance of high resolution HLA typing on transplant outcomes. After 2002, most patients received a dUCB transplant in order to achieve the desired cell doses of ≥3, ≥4 and ≥5 × 10e7 NC/kg for grafts that were HLA 6/6, 5/6 and 4/6 matched by original typing resolution, respectively. Therefore, the analysis was limited to 275 recipients of dUCBT for hematological malignancy and whom DNA from both units was available. The effect of HLA match was based on the HLA type of the predominant long term engrafting unit. The median recipient age and weight was 44 years (range, 0.6–69) and 76.9 kg (range, 7.1–148), respectively. Conditioning was myeloablative (40%) consisting of cyclophosphamide (CY) 120 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320 cGy, or non-myeloablative (60%) consisting of CY 50 mg/kg, FLU 200 mg/m2, TBI 200 cGy with 95% receiving cyclosporine A (CsA) and mycophenolate mofetil (MMF) immunosuppression. Patients had acute leukemia (62%), standard risk disease (62%), cytomegalovirus seropositive (59%), and received at least one UCB unit that was sex mismatched to the recipient (78%). Results reported are based on the long-term predominant UCB unit. Notably, survival was not adversely affected by HLA mismatch. The probability of survival at 5 years was 46% (95%CI, 33–58%), 47% (95%CI, 38–54%) and 29% (95%CI, 13–47%) in patients engrafting with a 3–5/10, 6–8/10 and 9–10/10 HLA-matched UCB grafts, respectively (p=.47). In multivariable analysis after adjusting for disease risk, CMV serostatus, and KPS, there was similar risk of overall mortality for all groups regardless of HLA matching level. All other transplant outcomes including the incidence of acute and chronic GVHD were similar for all HLA-matching groups (data not shown). In the subset with acute leukemia (n=174), however, greater HLA mismatch was associated with a significantly lower risk of relapse without a deleterious effect on risk of TRM, resulting in a benefit in LFS (inverse of treatment failure) as shown below. Transplant Outcome for Acute Leukemia HLA 3–5/10 match (n=84) RR (95%CI), p-value HLA 6–8/10 match (n=168) RR (95%CI), p-value HLA 9–10/10 match (n=34) RR (95%CI), p-value TRM at 2 years 1.0 1.1 (0.6–2.4)
 P=.73 1.1 (0.6–2.4)
 P=.73 Leukemia Relapse 1.0 1.9 (0.9–4.3)
 P=.11 3.5 (1.3–9.5)
 P=.01 Treatment failure 1.0 1.4 (0.8–2.4)
 P=.19 2.2 (1.1–4.2)
 P=.02 Together these data indicate that UCB units with greater HLA mismatch may confer greater GVL effect without greater TRM compared to HLA better-matched UCB grafts. These results suggest importance of evaluating allele level HLA typing in the setting of dUCB transplantation. If confirmed, these results could have major implications not only on graft selection (ie avoidance of HLA matched units), but also the target size of the international UCB banking inventory. Disclosures: No relevant conflicts of interest to declare.

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