Adult Umbilical Cord Blood Transplantation Following Non-Myeloablative Conditioning; Impact of Increased Cell Dose and 200cGy TBI on Engraftment and Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5399-5399 ◽  
Author(s):  
Mitchell Horwitz ◽  
David Rizzieri ◽  
Gwynn D. Long ◽  
Cristina Gasparetto ◽  
Ashley Morris ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Disease Free Survival ◽  
Free Survival ◽  
Cell Dose ◽  
Blood Transplantation ◽  
Disease Free

Abstract Reliable engraftment following transplantation of partially matched umbilical cord blood is dependent upon adequate immunosuppression and myelosuppression. The lowest intensity conditioning regimen that will provide reliable cord blood engraftment in adult patients has not been determined. 26 adult patients with a contraindication for myeloablative marrow conditioning due to advanced age or comorbidities, underwent non-myeloablative umbilical cord blood transplantation for hematologic malignancies. The first 13 patients (Cohort 1) were conditioned with Fludarabine 120mg/m2, Cyclophosphamide 2g/m2 and horse Antithymocyte globulin 90mg/kg. Cyclosporine and Mycophenolate Mofetil was administered for GvHD prophylaxis. The median cell nucleated dose was 2.1 × 107/kg and median follow-up is 60 months (Chao 2004 BBMT 10:569). After protocol revision, 200 cGy total body irradiation was added to the regimen described above. In addition, the minimum nucleated cell dose provided from up to two cord blood units was increased to 3 × 107/kg (Cohort 2). With a median follow-up of 12 months, we now report the outcome of cohort 2. Fourteen patients with AML CR1 (2), CR≥2 (5), CML (1), MDS/AML (1), MDS (4), or Follicular Lymphoma (1) and a median age of 54 (range 21–72) were transplanted. Eight patients required dual cord blood grafts to achieve the minimum cell dose. All grafts were at least 4/6 HLA matches (antigen level class I, allele level class II) with the patient, and with each other (dual cord blood grafts). The median cryopreserved and infused nucleated cell dose was 3.6 × 107/kg and 3.5 × 107/kg respectively. Two patients were not evaluable for engraftment due to early toxic death. Two patients experienced primary graft failure. Acute GvHD (grade II skin) was observed in 2 patients. Limited chronic GvHD developed in 2 patients. Parainfluenza type 3 sinusitis and pneumonitis caused significant morbidity in 5 patients. Day 100 treatment-related mortality occurred in 4 patients (30%) due to; infection (2), hemorrhage (2). Relapse occurred in 5 patients (36%). The estimated one year overall and disease-free survival is 25% and 17%, respectively. T-cell recovery was slow. The median CD4 count/ul for engrafted patients was 44 (range 4–516) and 61(range 2–237) at 3 and 6 months following transplantation, respectively. The median CD8 count/ul was 7 (range 0–359) and 108 (range 0–728) at 3 and 6 months following transplantation, respectively. A comparison of results from the two cohorts is presented in the table. The addition of 200cGy and increasing the cell dose facilitated by dual cord blood transplantation doubled the chance for sustained donor engraftment. Improved engraftment was accompanied by increased treatment-related morbidity and mortality, erasing the potential for improved disease-free survival. Disease relapse, in part due to slow immune recovery resulting in impaired anti-tumor response, was the other major impediment to successful outcome. Techniques focused on enhancing immune recovery would significantly improve outcomes of adult cord blood transplantation. Comparison of Cohort 1 vs Cohort 2 Evaluable Patients Med. Nuc Cell Dose/kg D100 TRM(%) Sustained Donor Engraftment (%)† Disease-Free Survival(%)† †estimated (1yr) *P=0.08 **P=NS Flu / Cy / ATG (Cohort 1) 13 2.1 × 107 15 41 15 Flu/Cy/ATG/200cGy(Cohort 2) 12 3.5 × 107 30 83* 17**

An International Multi-Institutional Study of Double Cord Blood Transplantation in a Racially Diverse Population.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2017-2017
Author(s):  
Karen Ballen ◽  
Brian Wang ◽  
Joseph Rosenthal ◽  
Auayporn Nademanee ◽  
Chatchada Karanes ◽  
...  
Keyword(s):  
Cord Blood ◽  
Multivariate Analyses ◽  
Cord Blood Transplantation ◽  
Disease Free Survival ◽  
Racially Diverse ◽  
P Values ◽  
Free Survival ◽  
Cell Dose ◽  
Blood Transplantation ◽  
Disease Free

Abstract Cord blood (CB) is an alternative stem cell source for patients, but single CB products may not contain sufficient cell dose for cord blood transplantation (CBT) of adults. Double cord blood transplantation (DCBT) has been used to increase the cell dose, but the majority of reported patients have been Caucasian. We conducted a retrospective analysis of 89 consecutive DCBT recipients who received at least one CB product from the StemCyte CB banks. The median age was 20 years (range 1–63), with 58% over age 18, and the median weight was 60 kg (range 11–137), with 70% ≥ 50 kg. Diagnoses were: 29 ALL, 23 AML, 10 Thalassemia, 6 CML, 5 MDS, 4 AA, 3 lymphoma, and 9 others. 33% had IBMTR advanced disease status, 28% intermediate, 18% early, and 21% unknown status for the leukemia/lymphoma/MDS cases. 70% of the recipients with known race were non-Caucasian (NC) with 35 Asians (A), 24 Caucasians (C), 9 African Americans, 8 Hispanics, 3 Native Americans, 10 others. Patients were treated with a variety of conditioning regimens (33% reduced intensity) at 39 U.S. and international centers on 4 continents with 37% at non-US centers. Thirty-seven patients (42%) received both units as plasma depleted cord blood products. CB product characteristics were as follows: median pre-freeze TNC dose 3.8×107/kg, median pre-freeze CD34+ dose 1.4×105/kg. The median time to neutrophil (ANC500) engraftment was 21.5 days and the median time to platelet (Plt) 20K and 50K engraftment were 42 and 59 days respectively. Kaplan-Meier (KM) estimates of 100-day transplant related mortality (TRM), 1-year overall (OS) and disease free survival (DFS) were 37±6%, 50±6%, and 37±6% respectively. Causes of death include infection (26%), relapse (23%), multi-organ failure (16%), GvHD (2%), and other (33%). Engraftment correlated with cell dose and disease risk status in univariate analysis. Survival correlated with higher pre-freeze TNC dose (p=.03), higher pre-freeze CD34+ dose (p=.04), and non-washed CB (p=.01). Survival, disease-free survival, ANC 500, plt 20K, and 50K engraftment, and TRM were not different between C and NC or between A and Non-Asians (NA) in multivariate analyses. 1-year OS for C and NC patients were 48% and 54% respectively (p=.24), with DFS of 35% and 40% (p=.32), respectively. In conclusion, this multi-centered international study shows that 1) DCBT can be performed effectively on a racially diverse patient population, 2) Survival and other outcome measures were similar between C and NC or between A and NA patients in multivariate analyses, 3) Cell dose remains important for engraftment even with DCBT. ANC500 Plt 20K 1 Yr Relapse 100-Day & 1-Yr TRM 1-Yr OS 1-Yr DFS * W = Washed CB, NW = Unwashed, CI = Cumulative Incidence; P-values from multivariate Cox Regression model adjusting for recipient weight, malignancy, and # of StemCyte units involved in DCBT. % & Median Days to Engraftment CI 83±7 KM 90±4 21.5 days CI 57±7 KM 78±7 42days 31±7 21±4 37±6 50±6 37±6 P-values* C vs. NC (W) .34 .86 .86 .87 .92 .86 C vs. NC (NW) .06 .59 .90 .35 .72 .92 A vs. NA (W) .43 .15 .80 .33 .13 .66 A vs. NA (NW) .69 .37 .75 .70 .30 .30

The Use of Double-Unit Umbilical Cord Blood Transplantation In Adults with Hematologic Disease.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4579-4579
Author(s):  
Xiao Ma ◽  
Wu Depei ◽  
Aining Sun
Keyword(s):  
Survival Rate ◽  
Cord Blood ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Disease Free Survival ◽  
Umbilical Cord Blood Transplantation ◽  
Hematologic Disease ◽  
Free Survival ◽  
Blood Transplantation ◽  
Disease Free

Abstract Abstract 4579 Objective: In this study, we explored the efficiency and toxicity of 38 cases of double-unit umbilical cord blood transplantation (CBT) in adults with hematologic disease. Methods: The tolerance; transplant related complications; survival rate and disease free survival rate were observed and analyzed. A nonmyeloablative conditioning regimen included cyclophosphamide, fludarabine and 2Gy TBI. Cyclosporine combined mycophenolate mofetil and ATG were used to prevent graft versus host disease (GVHD). Results: All these 38 patients tolerated the therapy well while two patients had graft failure. Severe acute GVHD was presented in 6 patients. Chronic GVHD was occurred in 16 patients. Fatal infection complications were occurred in 5 patients (including CMV idiopathic pneumonia in 2 patients) and 4 patients relapsed after transplantation. Neutrophil engraftment obtained on day +17 and platelet reconstitution occurred on day +42 on median. In the follow-up duration of 17 months on median, the expected 2-year relapse mortality was 17.95%; non-relapse mortality was 25.90%; overall survival was 60.80%, and disease free survival was 52.11%. Compare with 39 cases of haplo-identical HSCT in our department, significant delays in engraftment and lower severe GVHD occurred after CBT. There was no apparent difference between the risk of relapse and DFS in both groups. Conclusion: The use of double-unit CBT after reduced intensive conditioning therapy in adults with hematologic disease is an effective and safe treatment. Fatal infection and relapse are the main reasons of failure. Disclosures: No relevant conflicts of interest to declare.

Early NK Cell Proliferation After Umbilical Cord Blood Transplantation Is Associated With Superior Disease-Free Survival Due To Reduced Leukemia Relapse

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4610-4610
Author(s):  
Rachel Joy Bergerson ◽  
Sarah Cooley ◽  
Julie Curtsinger ◽  
Ryan Shanley ◽  
Claudio Brunstein ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cord Blood ◽  
Nk Cells ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Nk Cell ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free

Compared to traditional chemotherapy, allogeneic hematopoietic cell transplantation (allo-HCT) has the potential of triggering graft vs. leukemia (GVL) reactions that make this procedure uniquely curative. Despite this, relapse remains the most common cause of treatment failure. Early after allo-HCT the donor immune system reconstitutes within the host and natural killer (NK) cells are the earliest lymphocyte population to recover. Previous studies by us and other investigators have linked rapid lymphocyte recovery and/or high NK cell numbers early after transplant with less relapse. Mechanistically, the reasons for this are unknown. We hypothesized that NK cell proliferation would be associated with allo-HCT outcomes. In a large data set with short-term follow-up we compared stem cell source to NK cell proliferation at Day 28 after transplantation (using Ki67+ staining). In patients undergoing autologous (n=117), sibling (n=57), single umbilical cord blood (sUCB) (n=62) or double umbilical cord blood (dUCB) (n=50) transplantation there were significant differences in the median NK cell proliferation (2.1%, 3.3%, 3.8%, and 19.2%, respectively, p<0.0001). These results suggest that NK cell proliferation is increased when patients are transplanted with stem cell sources that have an increased number of HLA mismatches (dUCB). We next examined factors extrinsic to the NK cells to determine whether differences in the four patient groups were due to these factors. Regulatory T cells (Tregs) are known to negatively regulate the proliferation and activation of a variety of cell types, including NK cells. We utilized the percentage and absolute number of Tregs (defined as CD4+CD25highFoxP3+CD127low) at Day 28 (available for a subset of the above patient samples) and correlated it with the percentage of proliferating NK cells at Day 28 after allogeneic transplant (n=212). The median percentage of Tregs within the lymphocyte fraction was 1.49%. In patients with higher than 1.49% Tregs, the mean NK cell proliferation was 10.8% +/-16.4. In contrast, patients with lower than 1.49% Tregs had a mean NK cell proliferation of 21.2% +/-24.3 (p=0.0004). A nearly identical trend was observed for the absolute numbers of Tregs, suggesting that Tregs may play an extrinsic role in NK cell proliferation after allo-HCT. To further address differences in lymphocyte proliferation and clinical outcomes, we used Ki67 staining to assess T cell (CD4+ and CD8+) and NK cell (CD3-CD56+) proliferation at Day 28 in a different subset of patients undergoing dUCB transplant with acute leukemia or MDS (80%) or other malignant disorders using either myeloablative (42%) or reduced intensity conditioning (58%) and a median of one year follow-up (n=53). There was no association of transplant outcomes with T cell (CD4 or CD8) proliferation. In the NK cell compartment there was a wide range in the percentage of proliferating NK cells (0-86%), with a median of 20%. Patients were segregated into high (>20%) and low (<20%) NK cell proliferating groups and assessed for cytokine levels and transplant outcomes. At Day 28 soluble IL15 levels were not different between high and low NK cell proliferating patients. There was no significant association between NK cell proliferation and the probability or time to neutrophil recovery (p=0.15) or treatment related mortality (p=0.88). Excluding the 14 patients who developed aGVHD prior to day of NK cell assessment (Day 28), the high NK proliferating group had a trend toward a higher cumulative incidence of aGVHD (46% vs. 25%, p=0.17). Using multivariable analysis to control for a variety of patient and disease-associated variables, patients with high NK cell proliferation had significantly better disease-free survival (HR=0.29, 95%CI=0.12-0.71, p=0.01) (Figure 1). Strikingly, patients with high NK cell proliferation were 4-times less likely to relapse (HR=0.24, 95%CI=0.08-0.77, p=0.02). Collectively, these studies show that early NK cell proliferation is associated with superior outcomes after dUCB transplantation, due to reduced relapse, and that this is partly modulated by Tregs. Prospective strategies to increase NK cell proliferation may be of therapeutic benefit to improve transplant outcomes.Figure 1Disease Free Survival for patients undergoing dUCB transplant (n=53) based on low (blue) vs high (red) NK cell proliferation at Day 28 post transplant.Figure 1. Disease Free Survival for patients undergoing dUCB transplant (n=53) based on low (blue) vs high (red) NK cell proliferation at Day 28 post transplant. Disclosures: Wagner: Novartis: Research Funding. Miller:Coronado Biosciences: Scientific Advisory Board Other.

Outcome Of Unrelated Umbilical Cord Blood Transplantation For Children With Osteopetrosis: An Eurocord and Inborn Errors Working Party (IEWP)-EBMT Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2100-2100 ◽  
Author(s):  
Robert Chiesa ◽  
Annalisa Ruggeri ◽  
Marco Zecca ◽  
Franco Locatelli ◽  
Marta Gonzalez-Vincent ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Conditioning Regimen ◽  
Cell Dose ◽  
Blood Transplantation

Abstract Osteopetrosis (OP) is a genetic disease characterized by increased bone density due to osteoclast dysfunction, leading to life-threatening multi-systemic complications in early childhood. Haematopoietic stem cell transplantation (HSCT) is the only curative approach for most children with OP and can effectively prevent serious complications such as blindness, bone fractures, hydrocephalus and cranial nerve compression. Since timing of transplant is critical in OP, umbilical cord blood is an attractive stem cell source, due to its prompt availability. We analysed the outcomes of unrelated umbilical cord blood transplantation (UCBT) in 45 children with osteopetrosis transplanted in EBMT centers between 1996 and 2012, using data reported to Eurocord. Median age at UCBT was 6 months (1.1 month - 7.4 years). Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allelic level) in 14 or HLA mismatched at 1 (n= 23) or 2 (n= 7) loci. Information on conditioning regimen was available for 42 patients; it was myeloablative (mostly busulfan-based) in 40 children and reduced intensity in 2 patients. GvHD prophylaxis consisted mainly of cyclosporine combined with either prednisolone (n= 20), or methotrexate (n=6), or mycophenolate mofetil (n=3). Anti thymocyte globulin (ATG) or alemtuzumab was given to 37/40 patients. Median number of infused total nucleated cell (TNC) and CD34+ was 13x107/kg and 3.4x105/kg, respectively. Median follow-up for survivors was 44 (range 4-144) months. Neutrophil recovery with donor chimerism was documented in 27/45 patients; 19/25 evaluable patients presented full donor engraftment, while 6 children presented mixed donor chimerism. Median time to neutrophil recovery was 20 (range 10-60) days. Eighteen patients experienced graft failure and 3/18 are alive at last follow up. Information on treatment post-graft failure was available 7/18 children: 6 patients underwent a second HSCT and 3 of them survived. Stem cell dose was associated with a trend for a better probability of donor engraftment: the cumulative incidence of donor engraftment was 46% in patients who received a CD34+ cell dose<2 x 105/kg, versus 71% in children receiving a CD34+ cell dose ≥2x105/kg (p = 0.09). Eleven patients developed grade II-IV acute graft-versus-host disease (aGvHD: n=6 grade II, n=4 grade III, n=1 grade IV) and 5 patients chronic GVHD (cGvHD: n=3 limited, n=2 extensive). Overall survival (OS) at 3 years was 45+8%. Twenty-four patients died after UCBT due to: infections (n=13), acute respiratory distress syndrome (n=2), veno occlusive disease (VOD), (n=2) hemorrhage (n=2), or other causes (n=5). VOD was observed in 7/26 evaluable patients. Stem cell dose and HLA disparity were the only predictors of superior outcome in univariate analysis. The 3-year probability of OS was 50% in patients who received grafts with a CD34+ cell dose >2x105/kg versus 0% in children receiving grafts with a CD34+ cell dose < 2x105/kg (p=0.001). According to HLA disparities, 3-year probability OS was 54% versus 58% versus 0% in patients receiving a 6/6, 5/6 and 4/6 HLA-mismatched graft, respectively (p=0.01). Interestingly, 4/4 children receiving a treosulfan-based myeloablative regimen achieved donor engraftment and 3 children are alive at last follow up. These data suggest that transplantation of unrelated UCB is a valid alternative for children with OP without a matched sibling or a suitable matched unrelated adult donor. The use of CB units mismatched at >1 HLA locus should be avoided due to worse survival. The incidence of primary graft failure was high and therefore the optimization of the conditioning regimen and/or the use of CB units containing a high TNC and CD34+ cell dose must be considered in this setting. The use of treosulfan-based conditioning regimens is worth further investigation, as well as the use of defibrotide prophylaxis to reduce the risk of VOD in this population of high risk patients. Disclosures: No relevant conflicts of interest to declare.

Kinetics of Chimerism and Unit Predominance After Double Umbilical Cord Blood Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 225-225 ◽  
Author(s):  
Pablo A. Ramirez ◽  
John E. Wagner ◽  
Todd Defor ◽  
Bruce R. Blazar ◽  
Michael Verneris ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Hematologic Malignancies ◽  
Cell Dose ◽  
Blood Transplantation ◽  
Reduced Intensity

Abstract Abstract 225 Double umbilical cord blood (dUCB) transplantation (dUCBT) is a strategy to overcome dose limitation in adult recipients. It is established that after dUCBT, one unit will predominate by day +100 after transplant in >95%. While in some studies order of infusion has been associated with unit predominance, this has not been reproduced in an analysis at our center. However, significant differences in UCB infusion between these two analysis were present. In particular, at our center, unit order of infusion is random and the second infusion is within minutes of the first, while this prior study separated infusion time by 6 hours. Between 2001 and 2009, 262 patients with hematologic malignancies underwent a dUCBT and engrafted. Of these, 233 were >18 years of age with 39% conditioned with cyclophosphamide (CY) 60 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320–1375 cGy and 61% with CY 50 mg/kg, FLU 200 mg/m2 and TBI 200 cGy with 1/3 also receiving antithymocyte globulin (ATG); 100% received cyclosporine and mycophenolate mofetil posttransplant immunosuppression. Median recipient weight was 78 kg and median follow-up was 2.7 years (0.5-7.2). The following factors were considered in the logistic regression model: total nucleated cell (TNC), CD34+ and CD3+ cell and colony forming units-granulocyte macrophage (CFU-GM) doses, HLA match, sex and ABO-match, CXCR4 expression on CD34+ cells, order of infusion and cell viability. Cell viability, infused TNC, CD34+ and CD3+ cell and CFU-GM doses were remarkably similar between the predominating and non-predominating unit. By day 21, the predominating unit (i.e., representing >70% of hematopoiesis) was achieved in 73 of 90 (81%) patients after MA conditioning and in 88 of 145 (61%) patients after reduced dose conditioning (p<0.01). Subsequently, predominant unit chimerism in the bone marrow between MA and NMA was similar by day 100 (95% vs. 97%, p=0.35), day 180 (97% vs. 100%, p=0.3), day 365 (97% vs. 98%, p=0.84) and day 730 (94% vs. 93%, p=0.81). Notably, CD3+ cell dose and HLA were strongly associated with unit predominance. In the MA setting, CD3+ cell dose was the most significant factor that predicted unit predominance [OR 4.4 (95% CI, 1.8–10.6, p<0.01)]; while CD3+ cell dose [OR 2.1 (95%CI, 1.0–4.2, p=0.05)] and HLA-match [OR 3.4 (95%CI 1.0–11.4, p=0.05)] were independent predictors in the reduced intensity setting. In summary, immunological graft-graft interactions are likely responsible for unit predominance. While the combined CD34 dose and CFU-GM dose from the two UCB units are critical for rate of neutrophil recovery (data previously reported), CD3 dose and HLA match after reduced intensity conditioning are important in determining which unit will ultimately predominate. These findings have potential implications in the algorithm of graft selection. Disclosures: No relevant conflicts of interest to declare.

Total Body Irradiation 1350cGy/Fludarabine (TBI/FLU) vs Myeloablative Busulfan/Fludarabine (Bu/Flu) Preparation in Adult Recipients of Dual Umbilical Cord Blood (UCB) Transplantation: Superior Engraftment with Low Treatment-Related Mortality

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4403-4403
Author(s):  
Mitchell Horwitz ◽  
John Chute ◽  
Cristina Gasparetto ◽  
Gwynn Long ◽  
David Rizzieri ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Umbilical Cord Blood Transplantation ◽  
Cell Dose ◽  
Blood Transplantation ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract A high graft failure rate due to low stem cell dose and high treatment-related mortality have historically been the major pitfalls of myeloablative adult umbilical cord blood transplantation. The goal of this phase II clinical trial was to identify an approach that addresses both of these problems. There is compelling evidence that increasing the cell dose with the use of two partially matched UCB grafts reduces the graft failure rate. While non-myeloablative preparative regimens reduce treatment-related mortality, many patients with high-risk hematologic malignancies may be at increased risk for disease relapse following transplantation. Recently, myeloablative Bu/Flu has gained acceptance as an alternative to standard myeloablative regimens due to published treatment related mortality (TRM) rates as low as 3%. We recently reported an 80% graft failure rate when Bu 130mg/m2 daily × 4 and Flu 160mg/m2 is followed by dual UCB transplantation in adult recipients (Horwitz et al. BBMT 2008). We now report early results of a concurrent cohort of patients, treated on the same prospective clinical trial, who were prepared with myeloablative TBI (1350cGy)/Flu (160mg/m2). Methods: 16 patients with a median age of 35 (range 21–55) signed consent for the trial. All patients had high risk hematologic malignancies including AML(CR2) 7, ALL(CR1 or CR2) 4, MDS 2, NHL 3. The UCB grafts were at least 4 of 6 matched (antigen level class I, allele level class II) with the recipient and 3 of 6 matched with each other. Each graft contained a minimum cell dose of 1.5 × 107/kg providing a minimum combined total nucleated cell dose of 3 × 107/kg. Tacrolimus and mycophenolate mofetil were used for GvHD prophylaxis and G-CSF was administered until the neutrophil count exceeded 1000/mm3. Voriconazole, acyclovir and ciprofloxacin were used as anti-infective prophylaxis for at least 3 months post transplantation. Results: With a median follow-up of 15 months, the Kaplan-Meier event-free and overall survival is 61% and 56%, respectively. Three patients experienced graft failure. Hematopoiesis was restored in all three patients with either autologous (2) or allogeneic (1) hematopoietic stem cells. The remainder of patients evaluable for engraftment (competing risk; relapse) achieved &gt;90% donor myeloid chimerism from a single dominant UCB graft. The cumulative incidence of neutrophil engraftment (ANC&gt;500) and platelet engraftment (&gt;50K) is 79% and 75%, respectively. The median time to neutrophil and platelet engraftment was 27 days and 47 days, respectively. Toxic death occurred in 2 patients, resulting in a treatment-related mortality at 6 months of only 9%. In summary, the combination of myeloablative TBI and fludarabine is superior to Bu/Flu in the setting of umbilical cord blood transplantation. This is likely attributable to more effective host immunosuppression provided by the TBI. Acute GvHD occurred in 4 of 9 patients at risk for this complication (Grade II-3, Grade III-1). Chronic GvHD occurred in 2 patients (limited-1, extensive-1). Like the Bu/Flu regimen, we find the TBI/Flu regimen to be well tolerated, resulting in a notably low treatment-related mortality rate compared to more conventional myeloablative drug combinations. Conclusion: We find the approach consisting of myeloablative TBI/Flu preparation followed by dual umbilical cord blood transplantation in adult patients to be promising and worthy of further investigation.

Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1343-1347 ◽  
Author(s):  
Juliet N. Barker ◽  
Daniel J. Weisdorf ◽  
Todd E. DeFor ◽  
Bruce R. Blazar ◽  
Philip B. McGlave ◽  
...  
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Hematologic Malignancy ◽  
Disease Free Survival ◽  
Human Leukocyte ◽  
Free Survival ◽  
Leukocyte Antigen ◽  
Cell Dose ◽  
Single Donor

AbstractLimited umbilical cord blood (UCB) cell dose compromises the outcome of adult UCB transplantation. Therefore, to augment graft cell dose, we evaluated the safety of the combined transplantation of 2 partially human leukocyte antigen (HLA)–matched UCB units. Twenty-three patients with high-risk hematologic malignancy (median age, 24 years; range, 13-53 years) received 2 UCB units (median infused dose, 3.5 × 107 nucleated cell [NC]/kg; range, 1.1-6.3 × 107 NC/kg) after myeloablative conditioning. All evaluable patients (n = 21) engrafted at a median of 23 days (range, 15-41 days). At day 21, engraftment was derived from both donors in 24% of patients and a single donor in 76% of patients, with 1 unit predominating in all patients by day 100. Although neither nucleated or CD34+ cell doses nor HLA-match predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (P &lt; .01). Incidences of grades II-IV and III-IV acute GVHD were 65% (95% confidence interval [CI], 42%-88%) and 13% (95% CI, 0%-26%), respectively. Disease-free survival was 57% (95% CI, 35%-79%) at 1 year, with 72% (95% CI, 49%-95%) of patients alive if they received transplants while in remission. Therefore, transplantation of 2 partially HLA-matched UCB units is safe, and may overcome the cell-dose barrier that limits the use of UCB in many adults and adolescents.

Unrelated Donor Umbilical Cord Blood Transplantation in Children with Acquired Aplastic Anemia. Korean Experience of 12 Cases.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5402-5402
Author(s):  
Hoon Kook ◽  
Hee-Jo Baek ◽  
Tai-Ju Hwang ◽  
Hong-Hoe Koo ◽  
Keon-Hee Yoo ◽  
...  
Keyword(s):  
Cord Blood ◽  
Aplastic Anemia ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Mixed Chimerism ◽  
Unrelated Donor ◽  
Cell Dose ◽  
Blood Transplantation

Abstract Matched unrelated donor transplants have been reserved for patients with severe aplastic anemia (SAA) who fail a round of immunosuppressive therapy (IST). Despite the general acceptance of cord blood as an alternative stem cell source, unrelated donor cord blood transplantation (CBT) has not yet been recommended for SAA because of the high risk of graft failure and infectious complications. Only a few cases of successful CBT in SAA have been reported in the literature. From July, 2003 to Dec., 2005, twelve cases of unrelated donor CBTs in Korean children with acquired SAA were performed, and enrolled in this retrospective study. Two of them received double unit CBT. One patient who rejected a CBT received the second transplant with double unit CBT. All patients had no matched family donors. The median age and weight at the time of transplant were 7.0 years (2.8–18.8 years) and 23.3 kg (12.1–49.4 kg), respectively. Seven patients received previous IST including ATG/ALG plus cyclosporine (CyA). The median interval from the diagnosis to transplant was 20.5 months. The HLA discrepancy between the single unit umbilical cord blood and the patient was 0/6 in 1, 1/6 in 8, and 3/6 in 1. The conditioning regimen was heterogeneous, but included radiation in 3, and fludarabine in 3. The median infused nucleated cell dose was 3.3 × 107/kg (0.3–9.4 × 107/kg), and median CD34+ cell dose was 1.7 × 105/kg (0.4–6.6 × 105/kg) of recipient weight. Graft-versus-host disease (GvHD) prophylaxis was CyA plus methylprednisolone in 9 cases. Primary engraft failure was encountered in 3. The absolute neutrophil count ≥500/μL was achieved at 17.0 days (15–34 days), and platelet count ≥20,000/μL at 57.0 days (32–122 days), respectively. Complete donor chimerism was promptly observed in 8, with transient mixed chimerism in another patient. Acute GvHD ≥ II was observed in 5 cases, and extensive chronic GvHD was found in 2 among 8 evaluable cases. The 3-year overall survival was 74.1%, and 3-year estimated failure-free survival was 58.3%. The causes of death were sepsis, cytomegloviral pneumonitis, and chronic GvHD with intracranial hemorrhage in each patient. Cytomegaloviral disease was found in 3 cases. These results are comparable with those from unrelated donor BMT in refractory SAA. Considering the better tolerability of HLA mismatching, CBT should be considered as an alternative source of transplants. A randomized, prospective study comparing the 2nd-line IST, unrelated bone marrow transplants, or CBT is warranted to answer the best option for those who fail to 1st line IST without matched siblings.

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