Single-unit Cord Blood Transplantation Research Articles

Single-Unit Cord Blood Transplantation after Granulocyte Colony-Stimulating Factor–Combined Myeloablative Conditioning for Myeloid Malignancies Not in Remission

High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF–combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF–combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.

Umbilical cord blood transplantation from unrelated donors in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

There are very few disease-specific studies focusing on outcomes of umbilical cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. We report the outcome of 45 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent myeloablative single unit cord blood transplantation from unrelated donors within the GETH/GITMO cooperative group. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 35 patients (78%) were in first complete remission, four (8%) in second complete remission and six (14%) in third or subsequent response. The cumulative incidence of myeloid engraftment was 96% at a median time of 20 days and significantly better for patients receiving higher doses of CD34(+) cells. The incidence of acute grade II-IV graft-versus-host disease was 31%, while that of overall chronic graft-versus-host disease was 53%. Treatment-related mortality was 17% at day +100 and 31% at 5 years. The 5-year relapse, event-free survival and overall survival rates were 31%, 36% and 44%, respectively. Although the event-free and overall survival rates in patients without BCR/ABL transcripts detectable at time of transplant were better than those in whom BCR/ABL transcripts were detected (46% versus 24% and 60% versus 30%, respectively) these differences were not statistically significant in the univariate analysis (P=0.07). These results demonstrate that umbilical cord blood transplantation from unrelated donors can be a curative treatment for a substantial number of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

In Vivo DPP-4 Inhibition to Enhance Engraftment of Single-Unit Cord Blood Transplants in Adults with Hematological Malignancies

Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.

Different effects of HLA disparity on transplant outcomes after single-unit cord blood transplantation between pediatric and adult patients with leukemia

Recent advances in unrelated cord blood transplantation have increased chances and options available in allogeneic stem cell transplantation. The effect of HLA disparity on outcomes after cord blood transplantation was studied recently in mainly pediatric populations. Results showed that HLA matching in combination with total nucleated cell dose positively affects survival. The effect of HLA disparity after single-unit cord blood transplantation may be different in adults because their total nucleated cell dose is much lower compared to pediatric patients. We investigated the effect of HLA disparity on the outcome of single-unit unrelated cord blood transplantation separately in 498 children aged 15 years or under (HLA-A, HLA-B low-resolution, and HLA-DRB1 high-resolution matched [6/6], n=82, and one locus- [5/6], n=222, two loci- [4/6], n=158, three loci- [3/6] mismatched, n=36) and 1,880 adults (6/6, n=71; 5/6, n=309; 4/6, n=1,025; 3/6, n=475) with leukemia. With adjusted analyses, in children, 4/6 showed significantly increased risks of overall mortality (relative risk [RR]=1.61, P=0.042) and transplant-related mortality (RR=3.55, P=0.005) compared to 6/6. The risk of grade 2 to 4 acute GVHD was increased in 5/6 (RR=2.13, P=0.004) and 4/6 (RR=2.65, P<0.001). In adults, the risk of mortality did not increase with the number of mismatched loci (RR=0.99, P=0.944 for 5/6; RR=0.88, P=0.436 for 4/6). The risk of relapse was significantly decreased in 4/6 (RR=0.67, P=0.034). The risk of transplant-related mortality (TRM) or acute GVHD was not increased in 5/6 or 4/6. The effect of HLA disparity on transplant outcome differed between children and adults. In children, an increased number of mismatched HLA loci correlated with an increased risk of mortality. In adults, there was no increase in mortality with an increase in the number of mismatched HLA loci.

Prospective Multicenter Study of Single-Unit Cord Blood Transplantation with Myeloablative Conditioning for Adult Patients with High-Risk Hematologic Malignancies

Although the use of cord blood transplantation (CBT) is increasing, the optimal methods for conditioning and graft-versus-host disease (GVHD) prophylaxis remain to be established. Among previous reports, the Institute of Medical Science, University of Tokyo (IMSUT) has reported remarkably favorable results of CBT for hematologic malignancies as a single-institute experience. The aim of the present multicenter prospective study was to assess the safety and efficacy of CBT performed precisely according to IMSUT transplantation procedures. Thirty-three adult patients with hematologic malignancies, such as acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome, either lacking an HLA-identical sibling/HLA-matched unrelated donor or requiring urgent transplantation were enrolled. Conditioning consisted of total body irradiation (12 Gy), cytarabine, and cyclophosphamide. Cyclosporine A and methotrexate were used for GVHD prophylaxis. Diagnoses were acute leukemia in 26 patients, chronic myelogenous leukemia in 4, and myelodysplastic syndrome in 3; 12 patients were in first complete remission, and the others were in advanced stages at the time of CBT. Thirty-one patients achieved engraftment, and the cumulative incidence of grade II-IV acute GVHD was 45% (95% confidence interval, 28%-62%). With a median follow-up of 46.2 months in 16 surviving patients, the 1-year cumulative incidence of nonrelapse mortality was 15% (95% confidence interval, 5%-30%). Causes of nonrelapse mortality were infection (n = 4) and graft failure (n = 1). The overall and disease-free survival rates were 51% (95% CI, 34%-68%) and 42% (95% CI, 26%-59%), respectively. These results suggest that the IMSUT CBT procedures can safely provide a high disease-free survival rate in patients with high-risk hematologic malignancies.

Donor-Recipient HLA-Matching of Unrelated Cord Blood Units At High-Resolution Reveals High Degrees of HLA-Mismatch and Alters Graft Selection

AbstractAbstract 957 Background:Optimal criteria for cord blood (CB) unit selection are unknown. Traditionally, units are matched to the recipient only at human leukocyte antigen (HLA)-A, B antigens, and DRB1 alleles with up to 2 mismatches permitted. Recently, however, a significant association between intermediate resolution HLA-C matching and transplant-related mortality has been reported in single unit CB transplantation (CBT) (Eapen, M., Lancet Oncol, 2011). Moreover, we have recently demonstrated a decreased day 180 grade III-IV acute graft-versus-host disease incidence if the engrafting unit of a double-unit pair is ≥ 4/6 HLA-A, B, DRB1 allele matched to the recipient (Ponce, D., unpublished, 2012). This suggests that CB donor-recipient match criteria should be upgraded to 6 HLA-alleles or higher. However, how to clinically implement higher resolution HLA-matching and how it could affect CB unit selection are not known. Methods:To examine the extent of HLA-mismatch, we analyzed the HLA-match grade of 96 double-unit CB grafts (units 1a and 1b) and the 1–2 back-up units chosen for each transplant at various HLA-match grades. 362 CB units were selected for 95 patients (one patient was transplanted twice) who underwent CBT from 1/1/2009-6/30/2012 for hematologic malignancies. Units were selected based on cryopreserved total nucleated cell (TNC) dose (initially ≥ 1.5, later increased to ’ 2.0 × 107/kg), donor-recipient 4–6/6 HLA-A, B antigen, DRB1 allele match, and CB bank. Unit-unit HLA-match was not considered. High-resolution typing for 10 alleles was obtained prospectively, although usually did not influence unit selection. Results:The median age was 41 years (range 1–69) and the median weight was 65 kilograms (range 10–125). The median cryopreserved TNC/kg × 107 of units 1a and 1b (n = 192) was 2.89 (range 1.53–17.78), and their median donor-recipient HLA-match was 4/6 (range 1–6/6), 5/8 (range 2–8/8), and 6/10 (range 2–9/10) at 6, 8 and 10 HLA-alleles, respectively. The median (range) of 6/6 HLA-A, B antigen, DRB1 allele matched units (n = 9) was 6/6 (3-6/6), 7/8 (5-8/8) and 9/10 (7-9/10) at 6, 8, and 10 allele resolution, respectively. However, 5/6 HLA-A, B antigen, DRB1 allele matched units (n = 90) were a median (range) of 5/6 (2-5/6), 6/8 (3-7/8) and 7/10 (3-9/10) at allele resolution. Moreover, 4/6 HLA-A, B antigen, DRB1 allele matched units (n = 93) were a median (range) of 3/6 (1-4/6), 4/8 (2-6/8) and 5/10 (2-8/10) at allele resolution. We then evaluated how often the use of higher resolution HLA-match criteria would change graft selection to substitute one or both back-up units over units 1a and/or 1b, and the effect on the graft TNC dose (Table). If a cryopreserved TNC/kg ≥ 2.0 × 107 and a better HLA-match were required for either units 1a or 1b to be substituted, the frequency that graft selection would change was up to 38/96 (40%) of transplants for 10 allele HLA-match. The effect on TNC was minimal (≤ 12% reduction in the total graft TNC dose). Conclusions:Recent data suggest the criteria for CB match should be re-evaluated. However, units currently chosen based on HLA-A, B antigen, DRB1 allele match have a very high degree of mismatch when typed at higher resolution (as low as 3/10 for 5/6 units, and 2/10 for 4/6 units). Adoption of higher match grade criteria will frequently change the selection of the “optimal” graft in both adult and pediatric patients. While both the new lower limit of acceptable HLA-match and how to “trade off” higher resolution HLA-match against TNC dose are unknown, our data suggest that higher resolution HLA-match is possible without significant compromise in graft dose. Ultimately, large studies will be required to understand the impact of higher resolution HLA-match on disease-free survival to further guide clinical practice.TableMatchN (%) Grafts That Would ChangeFor Grafts That Would ChangeGradeMedian (Range) Cryo. TNC: Original Choice for Graft (Larger/Smaller)Median (Range) Cryo. TNC: New Choice Based on Higher Match Grade(Larger/Smaller)6 allele:26/96 (27%)3.7 (2.1-12.0)/2.7 (1.9-6.6)3.0 (2.0-8.0)/2.6 (2.0-6.6)A, B, DRB18 allele:33/96 (34%)3.6 (1.9-10.5)/2.7 (1.9-6.4)3.2 (2.0-7.6)/2.5 (1.9-6.8)A, B, C, DRB110 allele:38/96 (40%)3.6 (2.1-10.5)/2.6 (1.6-6.4)3.1 (2.0-8.7)/2.5 (1.6-7.6)A, B, C, DRB1, DQ Disclosures:Giralt:Celgene: Honoraria, Research Funding.

Graft-Specific HLA-Antibodies Do Not Influence Unit Dominance and Do Not Prevent High Rates of Sustained Donor Engraftment in Recipients of Double-Unit Cord Blood Transplantation

AbstractAbstract 960 Background:Pre-transplant human leukocyte antigen (HLA)-antibodies have an established role in failed engraftment after single-unit cord blood (CB) transplantation (CBT). Their role in double-unit CBT (DCBT) engraftment, however, is more controversial. Some transplant centers advocate pre-transplant screening of the recipient for HLA-antibodies, and avoidance of units with the corresponding antigens if antibodies are detected. Methods:We evaluated the influence of pre-transplant HLA-antibodies on sustained donor neutrophil engraftment and unit dominance in 82 recipients (median 48 years, range 2–69) of 4–6/6 HLA-A, B antigen, DRB1 allele matched double-unit CB grafts, and transplanted for hematologic malignancies at MSKCC from July 2008 to July 2012. HLA-antibodies were measured by the HLA Laboratory of the American Red Cross Blood Service using Single Antigen Luminex beads and analyzed by HLA Fusion software. The cut-off for positive results was a normalized mean fluorescence intensity value > 1000. Results:Overall, 28/82 (34%) patients were positive for HLA-antibodies [16 (19.5%) had antibodies without graft specificity, and 12 (14.5%) had antibodies with graft specificity]. These patients were more likely to be female with acute leukemia and cytomegalovirus seropositive. All patients with graft-specific antibodies received myeloablative conditioning; 5 had antibodies against class I HLA, 6 against class II, and one patient had antibodies to both Class I/II. Moreover, of these 12 patients, 6 had antibodies against one unit, and 6 had antibodies against both units. Neutrophil engraftment according to antibody presence is summarized in the Table. 64 of 66 (97%) evaluable myeloablative DCBT recipients (Table 1A) engrafted at a median of 24 days (range 12–40); one patient without antibodies and one with antibodies against both units had primary graft failure, both in the setting of early onset multi-organ failure. Both patients were 100% donor with one unit but did not recover counts. Of the 6 patients with antibodies to one unit, 3 engrafted with that unit and 3 with the opposite unit. Of the 6 patients with antibodies against both units, one had clinical graft failure as described above, and the 5 others had sustained donor engraftment (4 with one unit and one with both). In engrafting myeloablative recipients, the median time to neutrophil recovery was 8 days slower in patients with graft-specific antibodies, but the engrafting unit in these patients also had the lowest infused dose: median CD34+ cell dose/kg if no antibodies 0.83 × 105/kg, non-specific antibodies 1.09 × 105/kg, and antibodies specific to graft 0.65 × 105/kg. In non-myeloablative recipients, 15/16 (94%) engrafted (Table 1B). The single patient with graft rejection and autologous recovery had HLA-antibodies that were not graft specific. Conclusions:11 of 12 double-unit CBT recipients with graft-specific antibodies engrafted successfully. While myeloablative recipients with graft-specific antibodies engrafted more slowly, this may be explained by a lower infused CD34+ cell dose of their engrafting units. Multivariate analysis of larger patient numbers will be required to further evaluate the effect of graft-specific antibodies on engraftment speed. At this time, however, the presence of graft-specific antibodies should not preclude DCBT, and whether their presence should influence graft selection is not clear. Furthermore, there is no suggestion that the presence of HLA-antibodies influences unit dominance after DCBT.TableSustained Donor Neutrophil Engraftment According to HLA-antibodies1A) Myeloablative Conditioning (n=67)Median (Range) Time to Neutrophil Recovery (> 0.5)N (%) Sustained EngraftmentNo antibodies (n=41)23 days (range 12–38)39/40 (1 non-evaluable)Antibodies: not graft-specific (n=14)23 days (range 12–37)14/14Antibodies: graft-specific (n=12)31 days (range 13–40)11/12Against engrafting unit (n=3)28 days (range 24–31)3/3Against non-engrafting unit (n=3)31 days (range 25–32)3/3Antibodies against both units (n=6)33 days (range 13–40)5/61B) Non-Myeloablative Conditioning (n=15)Median (Range) Time to Neutrophil Recovery (> 0.5)N (%) Sustained EngraftmentNo antibodies (n=13)10 days (range 8–20)13/13Antibodies: not graft specific (n=2)19 days in 1 patient (other had graft failure/autologous recovery)1/2Antibodies: graft specific (n=0)-- Disclosures:Giralt:Celgene: Honoraria, Research Funding.

Rapid T‐cell chimerism switch and memory T‐cell expansion are associated with pre‐engraftment immune reaction early after cord blood transplantation

Rapid <scp>T</scp>‐cell chimerism switch and memory <scp>T</scp>‐cell expansion are associated with pre‐engraftment immune reaction early after cord blood transplantation

Single-unit umbilical cord blood transplantation from unrelated donors in patients with hematological malignancy using busulfan, thiotepa, fludarabine and ATG as myeloablative conditioning regimen

Attempts to optimize outcomes in cord blood transplantation (CBT) by using new conditioning regimens and standardization of cord blood unit selection are warranted. In all, 88 patients (18 children and 70 adults) with hematological malignancy from nine Spanish institutions underwent a single-unit CBT after an i.v. BU-based myeloablative conditioning regimen. All evaluable patients except one engrafted. The overall cumulative incidence (CI) of myeloid engraftment was 94% at a median time of 19 days. In multivariate analysis, nonadvanced disease stage was the only factor with a favorable impact on myeloid engraftment. The CI of acute GVHD grades II-IV and chronic extensive GVHD were 24% each. The CI of nonrelapse mortality at 100 days, 180 days and 5 years was 14, 23 and 44%, respectively. The 5-year CI of relapse was 18%, whereas disease-free survival (DFS) was 46%, 39% and 11% for patients transplanted in early, intermediate and advanced stages of the disease, respectively. Our study shows high rates of engraftment with fast neutrophil recovery in patients undergoing single-unit CBT using a BU-based conditioning regimen. Long-term DFS can be achieved in a substantial number of patients with high-risk hematological malignancies, particularly when transplanted in an early stage of the disease.

Hematopoietic stem cell expansion facilitates multilineage engraftment in a nonhuman primate cord blood transplantation model

The use of umbilical cord blood for allogeneic transplantation has increased dramatically over the past years. However, the limited number of cells available in a single cord blood unit remains a serious obstacle. Here, we wished to establish a nonhuman primate cord blood transplantation model that would allow us to test various hematopoietic stem cell expansion and gene therapy strategies. We implemented HOXB4-mediated expansion based on our previous experience with HOXB4 in autologous cells. Cord blood units were divided into two equal parts; half of the cells were transduced with a yellow fluorescent protein control vector and cryopreserved, and half were transduced with a HOXB4GFP vector, expanded, and cryopreserved. Both fractions of cells were transplanted into Macaca nemestrina subjects. We found that neutrophil recovery occurred within 19 days in all animals, and both neutrophil and platelet recovery were substantially accelerated compared to human single unit cord blood transplants. In addition, HOXB4-transduced and expanded cells resulted in superior engraftment of all hematopoietic lineages in all animals over nonexpanded controls. In conclusion, we have successfully established a nonhuman primate cord blood transplantation model and demonstrated that HOXB4 stimulates expansion and engraftment of repopulating cells. The availability of such a model has significant implications for developing and testing strategies to improve clinical cord blood transplantation, as it will allow comparison of different stem cell expansion methodologies within a single animal. Furthermore, it can be used in long-term follow-up studies to determine how specific expansion techniques affect engraftment of various hematopoietic lineages.

Cord blood transplants: one, two or more units?

This review summarizes the current status of double-unit cord blood transplantation (CBT) to improve engraftment, reduce transplant-related mortality, and improve disease-free survival. Transplantation of cord blood provides a potentially curative therapy for many patients without a suitably human leukocyte antigen-matched related or unrelated donor. Single-unit CBT outcomes have been compromised, however, in adults and larger children by limited cell dose. The introduction of double-unit CBT has improved engraftment and transplant-related mortality in adult patients transplanted for hematologic malignancies, with recent data also suggesting a protection against relapse. These improved outcomes are seen despite only a single unit being responsible for sustained donor hematopoiesis in nearly all patients. The study of double-unit CBT provides unique insights into transplant biology, with emerging data suggesting unit dominance is related to unit viability and unit-versus-unit immune interactions. Multiple unit CBT further serves as a platform to test novel graft manipulations. The development of double-unit CBT now allows the majority of patients, regardless of size or racial/ethnic background, access to transplant therapy. Ongoing investigation will serve to further improve outcomes and expand the role of CBT in the future.

Factors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries

A retrospective analysis was conducted to examine factors affecting early mortality after myeloablative, single-unit cord blood transplantation (CBT) for hematological malignancies in adolescents and adults. Data were collected from the three main CBT registries pooling 514 records of unrelated, single, unmanipulated, first myeloablative allogeneic CBTs conducted in North America or Europe from 1995 to 2005, with an HLA match ≥ 4/6 loci, in patients aged 12-55. Overall 100-day, 180-day and 1-year survival (Kaplan-Meier method) were 56, 46 and 37%, respectively, with no significant heterogeneity across registries. Multivariate analysis showed cell dose < 2.5 × 10⁷/kg (odds ratio (OR) 2.76, P < 0.0001), older age (P = 0.002), advanced disease (P = 0.02), positive CMV sero-status (OR 1.37 P = 0.11), female gender (OR 1.43, P = 0.07) and limited CBT center experience (< 10 records contributed, OR 2.08, P = 0.0003) to be associated with higher 100-day mortality. A multivariate model predictive of 1-year mortality included similar prognostic factors except female gender. Transplant year did not appear as a significant independent predictor. This is the first analysis to pool records from three major CBT registries in the United States and Europe. In spite of some differences in practice patterns, survival was remarkably homogeneous. The resulting model may contribute to better understanding factors affecting CBT outcomes.

A Preclinical Model of Double- versus Single-Unit Unrelated Cord Blood Transplantation

Cord blood transplantation (CBT) with units containing total nucleated cell (TNC) dose >2.5 x 10(7)/kg is associated with improved engraftment and decreased transplant-related mortality. For many adults no single cord blood units are available that meet the cell dose requirements. We developed a dog model of CBT to evaluate approaches to overcome the problem of low cell dose cord blood units. This study primarily compared double- versus single-unit CBT. Unrelated dogs were bred and cord blood units were harvested. We identified unrelated recipients that were dog leukocyte antigen (DLA)-88 (class I) and DLA-DRB1 (class II) allele-matched with cryopreserved units. Each unit contained <or=1.7 x 10(7) TNC/kg. Recipients were given 9.2 Gy total-body irradiation (TBI) and DLA-matched unrelated cord blood with postgrafting cyclosporine and mycophenolate mofetil. After double-unit CBT, 5 dogs engrafted and 4 survived long term with 1 dominant engrafting unit and prompt immune reconstitution. In contrast, 0 of 5 dogs given single-unit CBT survived beyond 105 days (P = .03, log-rank test); neutrophil and platelet recovery was delayed (both P = .005) and recipients developed fatal infections. This new large animal model showed that outcomes were improved after double-unit compared to single-unit CBT. After double-unit CBT, the nonengrafted unit facilitates engraftment of the dominant unit.

Cord Blood Transplantation from Unrelated Donors in Adults with High-Risk Acute Myeloid Leukemia

Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelated donors are limited. We analyzed the outcome and prognostic factors of 49 adults with high-risk acute myelogenous leukemia (AML) receiving single-unit CBT from unrelated donors after myeloablative (MA) conditioning at a single institution. Conditioning regimens were based on the combination of thiotepa, busulfan (Bu), cyclophospamide (Cy), or fludarabine (Flu), and antithymocyte globulin (ATG). Cumulative incidence of myeloid and platelet engraftment was 96% and 73% at a median time of 20 and 62 days, respectively. Engraftment was significantly faster for patients receiving higher doses of CD34(+) cells. Confidence Interval of graft-versus-host disease (GVHD), acute GVHD (aGVHD) grade II-IV, III-IV, and extensive chronic GVHD (cGVHD) were 26%, 15%, and 30%, respectively. Leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse at 2 years were 42%, 39%, and 19%, respectively. Low number of total nucleated cells (TNC) had a negative impact on NRM and LFS. Patients transplanted in first complete remission (CR1) receiving TNC above 2 x 10(7)/kg had a 4-year LFS of 75%. These results show that CBT from unrelated donors is a curative treatment for a substantial number of patients with high-risk AML, particularly if transplant is performed with highly cellular units in patients in first CR.

Impact of hematopoietic chimerism at day +14 on engraftment after unrelated donor umbilical cord blood transplantation for hematologic malignancies

Cord blood transplant is a feasible treatment alternative for adult patients with hematologic malignancies lacking a suitable HLA-matched donor. However, the kinetics of myeloid recovery is slow, and primary graft failure cannot be detected easily early after transplantation. We investigated the impact of hematopoietic chimerism status from unselected marrow cells 14 days after transplantation on predicting engraftment after a cord blood transplant. Seventy-one adult patients with hematologic malignancies undergoing single-unit unrelated donor cord blood transplantation after a myeloablative conditioning regimen were included in the study. All patients received conditioning regimens based on busulfan, thiotepa and antithymocyte globulin. Chimerism status was assessed analyzing short tandem repeat polymorphisms. The cumulative incidence of myeloid engraftment at 1 month was significantly lower in patients with mixed chimerism than in those with complete donor chimerism (55% vs. 94%; p<0.0001). For patients achieving myeloid recovery, the median time of engraftment was 16 days when donor chimerism at day + 14 was higher than 90%, compared with 24 days when donor chimerism was below this level (p<0.001). A donor chimerism level of 65% was found to be the best cut-off point for predicting primary graft failure, with a sensitivity of 97% and a specificity of 80%. The incidence of primary graft failure was 67% for patients with less than 65% donor chimerism at day +14 as compared to only 2% for those with more than 65% donor chimerism (p<0.001). Patients with mixed chimerism also had a lower cumulative incidence of platelet engraftment than those with complete chimerism (62% vs. 89%; p=0.01). Donor-recipient chimerism status at day +14 predicts engraftment after a single-unit cord blood transplant in adults.

Immune reconstitution after cord blood transplants supported by coinfusion of mobilized hematopoietic stem cells from a third party donor

Low severity of GVHD, substantial graft vs tumor (GVT) and slow development of protective immunity are well-documented features of cord blood transplants (CBT). We have evaluated the immune reconstitution of adult recipients of single-unit CBT supported by the coinfusion of third party donor (TPD) mobilized hematopoietic stem cells (MHSC), a procedure-'dual CB/TPD-MHSC transplant'-that results in early recovery of circulating granulocytes, high rates of CB engraftment and full chimerism. Cumulative recovery of natural killer and B cells at or above the median values of normal controls were 1.0 and 0.76 by the sixth and ninth months. Recovery of T cells was much slower, naive cells lagging behind those of memory and effector (committed) immunophenotypes. Serial analyses of signal joint TCR excision circles showed a general pattern of very low levels by the third month after CBT, followed by recovery to levels persistently similar or higher than those observed before transplantation and in normal controls. Our results are consistent with the clinical observations of substantial GVT effect together with low incidence of serious GVHD and slow development of protective immunity and suggest that thymic function contributes substantially to the recovery of T-cell populations in adults receiving dual CB/TPD-MHSC transplants.

Decreased Relapse Rates without Excessive Transplant Related Mortality Following Cord Blood Transplantation (CBT): A Matched Cohort Analysis Comparing Myeloablative Cord, Matched Unrelated, and Mismatched Unrelated Donor Transplants.

We conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving transplants from cord blood, matched unrelated donors, and mismatched unrelated donors following myeloablative conditioning in our center's recent experience. Between April 2006, when our current cord blood protocols opened, and February 2008, 26 consecutive patients underwent CBT following conditioning with 13.2 Gy TBI, 120 mg/kg cyclophosphamide (CY), and 75 mg/m2 fludarabine (FLU) for acute leukemias in morphologic CR (n=24) or chronic myeloid leukemia not in blast crisis (n=2). Twenty-three patients received two units (5 of whom had one of the two units ex vivo expanded) and three received single units. Matching between units and patient was 4/6:4/6 (n=10), 4/6:5/6 (n=5), 5/6:5/6 (n=7), 6/6:6/6 (n=1), and single 5/6 (n=3). For paired analysis with each cord patient, waiver of consent was obtained from the IRB and one matched 10/10 unrelated donor patient (MURD) and one mismatched (9/10 n=23, 8/10 n=3) unrelated donor patient (MMURD) was selected from our center's database on the basis of identical disease status and similar age without knowledge of transplant outcome. All unrelated donor patients underwent myeloablative transplantation following conditioning with CY/TBI or busulfan (BU)/CY between November 2001 and February 2008 (median April 2005). Patients were matched for disease type, cytogenetic risk status, minimal residual disease status (MRD), and, for patients beyond CR1, time from diagnosis to relapse. Specific diseases and disease status were ALL n=10: CR1 n=8 (MRD n=3), CR2 n=1, CR3 n=1 (MRD n=1), Philadelphia chromosome positive n=3; AML n=14: CR1 n=8 (MRD n=1), CR2 n=6 (MRD n=2); CML n=2 (CP1 n=1, CP2 following blast crisis n=1). Median ages and range for patients were: CBT 23 (0.6–42), MURD 25 (1–41), and MMURD 25 (1–48), and median differences in age between the cord recipient and their unrelated donor matched pairs were 7.8 and 4.6 years for MMURD and MURD, respectively. Median follow-up for surviving cord patients is 16 months (range 7.5–26). There has been only 1 relapse among cord patients versus 8 relapses among MURDs and 5 relapses among MMURDs. Transplant related mortality (TRM) between each group is comparable. Cause specific hazard for relapse is significantly decreased when comparing cords to MURDs by logrank test (p=0.014) and trends toward decrease when comparing cords to MMURDs (p=0.068) (Figure 1). Two year cumulative incidence (CI) of relapse is 3.8% (95% CI 0.3–16.4) for cord patients, 31.4% (95% CI 14.9–49.6) for MURDs, and 21% (95% CI 7.6–38.9) for MMURDs. Two year CI of TRM is 21.6% (95% CI 7.5–40.4) for cord patients, 22.9% (95% CI 8.3–41.8) for MURDs, and 31.8% (95% CI 15–50.1) for MMURDs. Previous data suggest that double unit CBT, as compared to single unit CBT, may markedly reduce relapse rates. The majority of CBT patients included in this analysis underwent double unit CBT, and this strategy may contribute to our observations. Additionally, myeloablative MURD and MMURD TBI regimens at our center involve 12 Gy in contrast to the 13.2 Gy in our CBT regimens. This may also account to some degree for lower relapse rates. Larger numbers and longer follow-up will be needed to confirm these observations, but the possibility of decreased relapse rates without increased TRM is promising. Growing inventories of high quality cord blood units coupled with ongoing improvements in supportive care for CBT patients should lead to continued expansion of the role of CBT. [Display omitted]

Cord blood transplants supported by co-infusion of mobilized hematopoietic stem cells from a third-party donor

This open label clinical study provides updated evaluation of the strategy of single unit cord blood transplants (CBTs) with co-infusion of third-party donor (TPD) mobilized hematopoietic stem cells (MHSC). Fifty-five adults with high-risk hematological malignancies, median age 34 years (16-60 years) and weight 70 kg (43-95 kg), received CBTs (median 2.39 x 10(7) total nucleated cell (TNC) per kg and 0.11 x 10(6) CD34+ per kg) and TPD-MHSC (median 2.4 x 10(6) CD34+ per kg and 3.2 x 10(3) CD3+ per kg). Median time to ANC and to CB-ANC >0.5 x 10(9)/l as well as to full CB-chimerism was 10, 21 and 44 days, with maximum cumulative incidences (MCI) of 0.96, 0.95 and 0.91. Median time to unsupported platelets >20 x 10(9)/l was 32 days (MCI 0.78). MCI for grades I-IV and III-IV acute GVHD (aGVHD) were 0.62 and 0.11; 12 of 41 patients (29%) who are at risk developed chronic GVHD, becoming severely extensive in three patients. Relapses occurred in seven patients (MCI=0.17). The main causes of morbi-mortality were post-engraftment infections. CMV reactivations were the most frequent, their incidence declining after the fourth month. Five-year overall survival and disease-free survival (Kaplan-Meier) were 56 % and 47% (63% and 54% for patients <or=40 years). In conclusion, CBT with single units of relatively low cell content and 0-3 HLA mismatches is feasible as a first choice option for adult patients who lack a readily available adequate adult donor.

Unrelated Umbilical Cord Blood Transplantation Using a TBI/FLAG Conditioning Regimen for Adults with Hematologic Malignancies

A combined chemotherapy regimen comprising fludarabine, cytosine arabinoside, and granulocyte colony-stimulating factor (FLAG) has been used in the treatment of relapsed or refractory leukemias. We here report 38 patients with hematologic malignancies who underwent single-unit cord blood transplantation (CBT) with a conditioning regimen comprising 12-Gy total-body irradiation (TBI) and FLAG therapy (TBI/FLAG). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus or cyclosporin A and/or methotrexate. The median nucleated cell dose was 2.43 × 10 7/kg (range: 1.96-3.55 × 10 7/kg). Of 34 evaluable recipients, the cumulative incidence of donor engraftment was 97%. The median time to reach an absolute neutrophil count of 500/μL was 23 days (range: 18-35 days). The median time to an untransfused platelet count of 50,000/μL was 45.5 days (range: 28-208 days). Sixteen patients developed grades II-IV of acute GVHD. Fourteen patients were alive at a median follow-up of 46 months (range: 4-77 months). The estimated event-free survival at 3 years for all patients was 33.5%, with 72.7% in the standard-risk group (n = 11) and 17.7% in the high-risk group (n = 27) ( P = .0075). These results showed that this novel regimen was well tolerated by patients and able to establish sustained donor cell engraftment, indicating the feasibility of TBI/FLAG as a conditioning regimen for CBT in adults with hematologic malignancies.

8: Factors Affecting 100-Day and 1-Year Mortality Following Myeloablative Single-Unit Cord Blood Transplantation in Adults and Adolescents: A Comprehensive Meta-Analysis of CIBMTR, NCBP and Eurocord

8: Factors Affecting 100-Day and 1-Year Mortality Following Myeloablative Single-Unit Cord Blood Transplantation in Adults and Adolescents: A Comprehensive Meta-Analysis of CIBMTR, NCBP and Eurocord