Double Umbilical Cord Blood Research Articles

Allele Matching At HLA-C or DRB1 Is Associated with Improved Survival After Reduced Intensity Double Umbilical Cord Blood Transplantation

Abstract 2010▪▪This icon denotes a clinically relevant abstractMismatch at HLA-C has been associated with increased transplant-related mortality in unrelated bone marrow and peripheral blood stem cell transplantation as well as single myeloablative umbilical cord blood transplantation (UCBT) in children, but the impact of HLA-C mismatch in adult double reduced-intensity conditioning (RIC) UCBT is unknown. Matching at HLA-C is not routinely considered in cord unit selection. We studied the effect of HLA-C matching in 125 patients who underwent double UCBT for hematologic malignancy at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2003 through 2010. The median age was 49 years (range 16–69), and the diagnoses included acute leukemia (45%), MDS (12%), lymphoma (27%), myeloproliferative neoplasms (2%), and others (13%). Data on HLA-C match were recorded but not used in the UCB unit selection strategy. UCB unit selection criteria were a 4/6 allele level A, B, DR match with the patient and other UCB unit. 82% of patients received a fludarabine/melphalan/antithymocyte globulin RIC, and 62% received sirolimus-based graft vs host disease (GVHD) prophylaxis. The median follow-up time among survivors was 32 months (range 6–73). The degree of allele matching at HLA-C (donor to both cords) was 0/4 in 14 patients (11%), 1/4 in 21 patients (17%), 2/4 in 62 patients (50%), 3/4 in 20 patients (16%), and 4/4 in 8 patients(6.4%). Patients who received 2 UCB units both with > 6/8 match at HLA-A,-B,-C, and -DRB1 had improved survival (3 year overall survival (OS) 56% vs 29%, p= 0.01). There was a significant correlation between degree of matching at HLA-C and the frequency of neutrophil engraftment (ANC > 500 by day 42) (0/4=79%, 1/4=76%, 2/4=71%, 3/4=80%, 4/4=100%; p=0.004). Similarly, matching at HLA-C was significantly correlated with platelet engraftment (plt>20,000 by day 100) (0/4=50%, 1/4=52%, 2/4=57%, 3/4=70%, 4/4=100%; p=0.0004). Matching at HLA-A,-B, or –DRB1 did not correlate with engraftment. There was no effect of matching at HLA-C on relapse, acute GVHD, or chronic GVHD. A full match at HLA-C (4 alleles) was associated with improved survival (3-year OS 67% vs 33% with less than full match, p=0.05) but there only 8 patients who received 2 HLA-C matched UCB units. Degree of match individually at HLA-A,-B, or DRB1 was not alone associated with survival. When various combinations of match were examined, full matching at either HLA-C or full matching at HLA-DRB1 (with less than full matching at HLA-C), compared to full matching at neither locus, was associated with improved 3-year OS (67% vs. 42% vs. 24%, p=0.03). HLA-C match did not predict the dominant UCB unit. In summary, (1) patients who received closer HLA allele-level matched UCB units had improved survival after RIC double UCBT; (2) matching at HLA-C in RIC double UCBT may be associated with earlier neutrophil and platelet engraftment; (3) survival may be improved when patients received UCB units fully matched at HLA-C or fully matched at HLA-DRB1 (if less than fully matched at HLA-C) compared to recipients of units fully matched at neither locus; and (4) matching at HLA-A,-B, or DRB1 alone did not correlate with differences in engraftment or survival. These data are limited by the small number of patients that were compatible at HLA-C but warrant examination in a larger cohort to determine the role of matching at HLA-C in UCB unit selection algorithms. Disclosures:Soiffer:Genzyme: Consultancy; Fresenius biotech: Research Funding; Miltenyi Biotech: Consultancy.

Allogeneic Hematopoietic Stem Cell Transplant Reverses the Phenotype of GATA2 Deficiency.

AbstractAbstract 3091 Background:Recently, sporadic and heritable mutations in the zinc finger transcription factor GATA2 were shown to be responsible for four different syndromes in young adults coupling opportunistic infection with a predilection to develop myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). These four syndromes are: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome, lymphedema and MDS with monosomy 7; and familial MDS/AML. Life-threatening infections, and the transformation to AML, either alone or together, constitute a rationale for allogeneic hematopoietic stem cell transplant (HSCT) for GATA2 deficiency. Methods:We evaluated matched related, unrelated, and umbilical cord blood as donor sources for nonmyeloablative conditioning for HSCT in GATA2 deficiency. Twelve patients with GATA2 deficiency underwent allogeneic transplant: 4 received peripheral blood stem cells (PBSCs) from matched related-donors (MRD), 4 received PBSC from matched unrelated-donors (MUD), and 4 received umbilical cord blood (UCB) units. Recipients of MRD and MUD transplant received fludarabine and 200cGy of total body irradiation (TBI), while UCB recipients received cyclophosphamide 50 mg/kg, fludarabine, and 200cGy of TBI. All patients received tacrolimus and sirolimus for GVHD prophylaxis.This cohort of patients had considerable pre-transplant morbidity: two patients required baseline oxygen for pulmonary alveolar proteinosis, one of whom was on a ventilator at the time of transplant; one patient had active hepatitis C that was not responding to therapy; one patient had RAEB-2; two patients were platelet transfusion-dependent; one patient had recurrent strokes and culture negative endocarditis two months before transplant. Results:Median follow-up for patients was 14.4 months (range 0.2–38.2 months). Ten of 11 patients engrafted at a median of 10 days (range 0–76); engraftment was not evaluable in a recipient of an UCB transplant due to death early in the post-transplant period. One rejection occurred in a recipient of a double UCB transplant who had been heavily transfused pre-transplant. All patients who engrafted had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of NTM infection and extensive human papilloma virus infections regressed starting around 6 months post transplant. Two patients required a single cycle of pre-transplant chemotherapy for RAEB-1 and RAEB-2, respectively. In both patients the monosomy 6 and monosomy 7 clones have not recurred, now 2.5 years and 9 months following single UCB and MUD transplant, respectively.Three patients died, two early after transplant. One recipient of UCB, who had pre-transplant hepatitis C, died on day+7 of fulminant liver failure and sepsis. A second patient, who was intubated at the time of transplant because of severe pulmonary alveolar proteinosis and pulmonary hypertension, died on day + 88 of grade IV GVHD after MRD transplant. The third patient died 9 months after transplant of sepsis. One recipient of a MRD relapsed from her MDS at 1 year following transplant and was retransplanted using a myeloablative conditioning regimen. She is alive with no evidence of MDS at 3 months. Acute GVHD developed in 6 patients, five of which were steroid-responsive. One patient developed chronic GVHD. Other complications included immune mediated cytopenias that responded to rituximab and eltrombopag. Conclusions:Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B and NK cell populations and reversal of the infection susceptibility phenotype. The TRM in this cohort of patients with severe comorbidities was 25%. Now that genetic testing for GATA2 mutations is available, we anticipate that earlier diagnosis will enable patients to be transplanted earlier in the course of disease, before significant organ damage or clonal evolution of MDS to AML. Disclosures:No relevant conflicts of interest to declare.

Outcomes of Unrelated Umbilical Cord Blood Transplantation Using a Conditioning Regimen of TBI/Ara-c/CY without ATG for Adolescent and Adults Patients with High-Risk Hematologic Malignancies

AbstractAbstract 4525To retrospectively analyze the curative efficacy of umbilical cord blood transplantation (UCBT) using total body irradiation (TBI)-based myeloablative conditioning regimen without antithymocyte globulin (TBI/Ara-c/CY w/o ATG) in adolescent and adult patients with high-risk hematological malignancies.Outcomes of forty-five consecutive adolescent and adult patients with high-risk hematological malignancies treated with TBI-based myeloablative UCBT without ATG in a single center between September 2006 and February 2012 were retrospectively analyzed. The conditioning regimen included TBI/Ara-c/CY:TBI 12GY (four fractionated) + Ara-C 8g/m2 (two days fractionated) + CY 120mg/kg (two days fractionated), and rhG-CSF was administered for myeloid leukemia by continuous infusion at a dose of 5μg·kg−1·d−1. Infusion of G-CSF was started 24 hours before the first dose of Ara-C and stopped at the completion of the last dose. The patients included 31 males and 14 females, with a median age of 21 years (range: 14–40) and a median weight of 58 kg (range: 42–76). Of those, 17 patients (37.8%) had advanced disease. Double UCB grafts were used for 16 patients, while single UCB graft was used for 29 patients. The median number of nucleated cells infused was 3.57 (1.94∼6.76)×107/kg and the median CD34+cells infused was 2.11 (0.71∼4.95)×105/kg. All patients received a combination of cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis.All patients successfully engrafted. The median times to neutrophil (ANC≥0.5×109/L) and platelet (PLT PLT≥20×109/L) recovery were 19 days (range: 13–35 days) and 36 days (range: 24–90 days) respectively after transplantation in 40 evaluable patients. Acute GVHD occurred in 21 patients and the cumulative incidences of gradeII-‡W and grade III-‡W acute GVHD were 24.4% and 11.1%, respectively. Chronic GVHD occurred in five of 40 evaluable patients (12.5%). Of the 45 patients, 9 (20%) had relapse. After a median follow-up of 25.1 months (range: 6–65.1) among survivors, treatment-related mortality (TRM) within 100 days and within one year was 8.9% and 24.4%, respectively. The main causes of death were pneumonia and severe acute GVHD. The probability of three-year disease-free survival and overall survival (OS) was 53.3% and 57.8%, respectively.The TBI/Ara-c/CY myeloablative conditioning regimen has been well tolerated by patients at our institution and seems to be able to establish sustained donor cell engraftment and decrease the risk of transplant-related death. For high risk patients and patients with advanced disease, this conditioning regimen could reduce relapse and chronic GVHD, indicating the feasibility of TBI/Ara-c/CY as a conditioning regimen for CBT in adolescent and adult patients with hematologic malignancies. Disclosures:Sun:Key Scientific and Technological Project of Anhui province “Twelfth Five-Year Plan” (11010402164): Research Funding; the Fund of the Key Medical Project of Anhui Provincial Healthy Department (2010A005): Research Funding; Anhui Provincial “115” Industrial Innovation Program (2009): Research Funding.

Treatment of relapsed myelodysplastic syndrome following double umbilical cord blood transplantation with interferon alpha and 5‐azacytidine

Treatment of relapsed myelodysplastic syndrome following double umbilical cord blood transplantation with interferon alpha and 5‐azacytidine

Double Umbilical Cord Blood Transplantation: A Study of Early Engraftment Kinetics in Leukocyte Subsets using HLA-Specific Monoclonal Antibodies

Single cord blood unit (CBU) predominance is usually established within the first month after double umbilical cord blood transplantation (UCBT). However, the kinetics of engraftment of the different leukocyte subsets and the mechanism of graft predominance is largely unknown. To investigate whether a differential engraftment might reveal a specific subset that could play a key role in the mechanism of graft predominance, we studied early engraftment kinetics of different leukocyte subpopulations by flow cytometry using human monoclonal antigen–specific human leukocyte antigen antibodies, directed against mismatched human leukocyte antigen-A or –B antigens between recipient and CBUs. Twenty-two patients, who had received a double UCBT preceded by a reduced-intensity conditioning regimen, were evaluated at days +11, +18, +25, and +32 posttransplantation. Single CBU predominance in the various leukocyte subsets was established within 18 days posttransplantation. CD4+ T cells of the dominant CBU showed early peripheral blood expansion. Moreover, chimerism in CD4+ and CD8+ T cell and natural killer cell subsets at day +11 was predictive of ultimate graft predominance. These findings show that engraftment kinetics of the various leukocyte subsets vary considerably after double UCBT and may suggest an important role for CD4+ T cells in a presumed alloreactive graft-versus-graft rejection.

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Aim Chimerism testing is routinely performed post-hematopoietic cell transplant (HCT) to evaluate donor engraftment. In most cases, absent rejection, complete donor chimerism is observed in all lineages. If long-term mixed chimerism occurs, it is usually found in all cell subsets. Here we report an unusual case of stable, long-term, mixed chimerism in the CD3+ lineage only in a patient who underwent two HCT. Methods Chimerism analysis was performed on peripheral blood (PB) sorted CD3+, CD56+, CD33+ cells and whole bone marrow (BM). STR testing was performed with Qiagen QIAmp DNA Micro Kit extracted DNA using Promega PowerPlex16 and the ABI 3130xl genetic analyzer. Results A 22-year-old woman diagnosed with pre-B ALL Ph+ underwent a myeloablative matched family donor (MFD) HCT in 2006. The patient was 100% donor in all lineages but relapsed in 2009 and underwent a double umbilical cord blood transplant (dCBT) in 2010. Chimerism testing following the dCBT revealed that PB CD3+ cells were predominantly derived from the previous MFD (Range 89-100%) while the CD33+ and CD56+ fractions were derived from one of the two cord blood (CB) units. Of 2 unsorted BM tested, d82 was 100% dominant CB unit, while at d361 the MFD could also be detected (3%). In contrast to the ANC which was normal, absolute T-cell counts lagged well below normal throughout the 2 year post-2nd HCT period (Range: 0.01-0.5; Normal = 0.8-2.7). Conclusions To our knowledge this is the first report of prolonged compartmental mixed chimerism in the T-cell lineage in a patient who underwent a MFD HCT followed by a dUCBT 3 years later to treat post-transplant relapse. To date, the patient remains in remission with a T-cell compartment predominantly derived from the MFD and the myeloid cell compartment of CB origin. While the mechanism underlying this phenomenon is unknown, the lag in recovery of the CD3+ count, as well as evidence of MFD cells in the d361 BM, points to some degree of ongoing competition between the MFD and the dominant CB donor.

Phase II Trial of Parathyroid Hormone after Double Umbilical Cord Blood Transplantation

Transplantation of 1 or 2 umbilical cord blood products is a useful alternative stem cell source. However, the limited number of stem cells in each infusion results in slow engraftment. In mouse models, administration of parathyroid hormone (PTH) is an effective way to enhance the ability of limited numbers of hematopoietic stem cells to support hematopoiesis. In this study, patients received either a myeloablative or a reduced-intensity double umbilical cord blood transplantation, followed by PTH at 100 μg/day for 28 days. Thirteen patients (median age, 42 years) were enrolled. All patients engrafted; the median time to neutrophil and platelet engraftment of >20 × 10(9) cells/L was 30 days and 61 days, respectively. The incidence of grade II-IV acute GVHD was 38.5% at day 100. Four deaths occurred before day 100, prompting early study closure. No patient who received a myeloablative regimen relapsed. Overall survival at 6 months after transplantation was 62%, and disease-free survival at 2 years was 39%. At the dose and schedule studied, there was no evidence that PTH influenced blood count recovery.

An unusual case of donor‐derived myelodysplastic syndrome following double‐unit umbilical cord blood transplantation in acute lymphoblastic leukemia

Umbilical cord-blood transplantation is considered an effective treatment strategy for acute lymphoblastic leukemia (ALL) when a human leukocyte antigen (HLA)-matched donor is unavailable. The use of a second unit helps ensure engraftment in larger adults and those with comorbidities, even though only one unit engrafts in most patients. Herein, we present the clinical and laboratory characteristics of a patient who developed donor-derived myelodysplastic syndrome (ddMDS) after double umbilical cord-blood transplantation (dUCB HSCT). To our knowledge, no cases of ddMDS have been described in a patient with a history of ALL in molecular remission after receiving a dUCB HSCT. Current molecular techniques, including analysis of short tandem repeats (STR) and fluorescence in situ hybridization (FISH) allowed us to firmly establish donor origin.

Acute leukemia in adults: novel allogeneic transplant strategies

Acute myeloid leukemia (AML) is the most common indication for hematopoietic cell transplantation (HCT). Significant improvements in histocompatibility testing have resulted in identifying better alternative donors to provide grafts; coupled with expanding use of reduced-intensity conditioning (RIC) regimens, patient outcomes have improved. Most AML patients in complete remission now can undergo allogeneic HCT procedures with an anticipated result that approaches that obtained with sibling donors and myeloablative conditioning (MAC). Treatment-related mortality (TRM), relapse, GVHD and, for umbilical cord blood (UCB) grafts, slow engraftment/engraftment failures, however, continue to plague HCT. Newer strategies include the use of double unit UCB HCT and ex vivo expansion of UCB units using: multipotent mesenchymal stromal cells (MSCs); polyamine copper chelator tetraethylenepentamine (TEPA); and Notch ligand. Haploidentical bone marrow and blood HCT are increasing in numbers given the improved outcome with post-HCT cyclophosphamide therapy. Novel chemotherapeutic preparative regimens incorporating agents such as clofarabine and treosulfan, and novel radiation preparative regimens utilizing selective radiation approaches (helical tomotherapy) and targeted myeloablative radioimmunotherapy appear to enhance the anti-AML effect. Immunological approaches with chimeric antigen receptor-redirected T lymphocytes have been added to the armamentarium. Other novel maneuvers include more sophisticated T-cell depletion of the donor graft and post-transplant immunotherapy with regulatory T cell (Treg) therapy and MSCs for GVHD prevention. These and other strategies are improving the outlook of AML HCT recipients.

Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation

AbstractUsing a uniform detection method for donor-specific anti-HLA antibodies (DSAs), we sought to determine the effect of preformed DSAs on outcomes in double umbilical cord blood transplantation. DSAs were associated with an increased incidence of graft failure (5.5% vs 18.2% vs 57.1% for none, single, or dual DSA positivity; P = .0001), prolongation of the time to neutrophil engraftment (21 vs 29 days for none vs any DSA; P = .04), and excess 100-day mortality or relapse (23.6% vs 36.4% vs 71.4% for none, single, or dual DSA positivity; P = .01). The intensity of DSA reactivity was correlated with graft failure (median of mean fluorescent intensity 17 650 vs 1 850; P = .039). There was inferior long-term progression-free and overall survival when comparing patients with DSAs against both umbilical cord blood units to those without DSAs (3-year progression-free survival, 0% vs 33.5%, P = .004; 3-year overall survival 0% vs 45.0%, P = .04). We conclude that identification of preformed DSAs in umbilical cord blood recipients should be performed and that the use of umbilical cord blood units where preformed host DSAs exist should be avoided.

Humoral HLA sensitization matters in CBT outcome

In this issue of Blood, Cutler and colleagues present evidence that donor-specific anti-HLA antibodies are associated with graft failure in double umbilical cord blood transplantation (CBT).1 Engraftment of donor cells is the first important step in successful transplantation and, until recently, the causes of engraftment failure remained elusive.

KIR-Ligand Incompatibility Is Not Associated with Relapse Reduction After Double Umbilical Cord Blood Transplantation,

Abstract 4150Natural killer (NK) cell alloreactivity has been implicated in graft-versus-host (GVH), graft-versus-leukemia (GVL), and host-versus-graft reactions following hematopoietic stem cell transplantation (HSCT). Though the basic mechanisms of NK cell alloreactivity are well described, comparatively little is known about its clinical effects. In umbilical cord blood (UCB) transplantation, both stem cells and donor-derived T-cell numbers are limited compared to other transplant modalities, so NK cell effects may be more pronounced. NK cell-mediated cytotoxicity is mediated by a balance of activating and inhibitory cell-cell contacts, the most important of which entails engagement of MHC-I on target cells by inhibitory killer immunoglobulin-like receptors (KIR) on NK cells. This interaction inhibits NK cell cytotoxicity, whereas the absence of MHC-I on target cells stimulates cytotoxicity, thus providing a mechanism for immune surveillance against pathologic states in which MHC-I is down-regulated such as cancer and viral infection. Applied to the scenario of HSCT, based on the specificity of various KIR for MHC-I encoded by particular HLA-B and HLA-C alleles, GVH NK cell alloreactivity can be predicted from the HLA genotypes of donors and recipients. The clinical impact of predicted GVH NK cell alloreactivity, termed KIR ligand incompatibility, has been investigated retrospectively in various transplant settings (Verheyden 2008), including UCB transplantation (Brunstein 2009, Willemze 2010), with inconsistent results regarding its association with relapse, GVH disease incidence, and survival. Methods: We stratified a cohort of 80 patients who underwent double umbilical cord blood (UCB) transplantation according to the presence or absence of KIR ligand incompatibility in the graft-versus-host direction. The median age was 48 years. Patients had a mix of myeloid and lymphoid malignancies, the most common of which were AML (31%) and non-Hodgkin lymphoma (18%). 59% of patients received non-myeloablative conditioning. Results: We found no association between KIR ligand incompatibility and neutrophil (p=0.30) or platelet (p=0.95) engraftment, incidence of acute (p=0.70) or chronic (p=0.44) GVHD, relapse (p=0.67), or progression-free (p=0.73) and overall (p=0.71) survival. Graft rejection, defined as neutrophil engraftment with donor-predominant chimerism followed by loss of donor chimerism, occurred in six patients in the cohort, all but one of whom received KIR-ligand-incompatible UCB units (p=0.08). Of these six patients, the only one who received a KIR-ligand-compatible transplant received a far less immunosuppressive conditioning regimen than the rest of the cohort due to comorbidities. When this patient was retrospectively excluded from the analysis, the association between graft rejection and KIR ligand incompatibility was statistically significant (p=0.01). An analysis accounting for the dominance of one cord unit and its associated KIR incompatibility was not performed due to the concordance of KIR ligand compatibility/incompatibility among transplanted cord unit pairs. Conclusions: These results suggest a role for NK cell alloreactivity in mediating graft rejection in double UCB transplantation but no effect on relapse or survival. These findings warrant further evaluation in larger cohorts. Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for FA Patients with Acute Leukemia or Advanced MDS,

Abstract 4146Fanconi anemia (FA) patients with acute leukemia or advanced myelodysplastic syndrome (MDS with ≥ 5% blasts) have a poor prognosis and hematopoietic cell transplantation (HCT) experience is limited. We report on the outcomes of 21 patients with FA and acute myeloid leukemia (AML, n=16), acute lymphocytic leukemia (ALL, n=2) or advanced MDS (n=3) who underwent allogeneic HCT at the University of Minnesota from 1988–2009. Five patients had biallelic BRCA2 mutations. Only 2 of 7 patients who received chemotherapy before HCT achieved remission both of whom had biallelic BRCA-2 mutations and T-cell ALL. Median age was 15.5 (range 1.1–48.5) years. Median age for BRCA2 patients was substantially lower at 1.9 (range 1.4–6.6) years. Patients received cyclophosphamide, antithymocyte globulin and either single fraction total body irradiation (n=15) or busulfan (n=6), with (n=11) or without (n=10) fludarabine (FLU) followed by HLA-matched sibling (n=3) or alternative (n=18) donor stem cells consisting of bone marrow (BM, n=14), single (n=4) or double (n=3) umbilical cord blood (UCB). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and methylprednisolone. Probability of neutrophil engraftment was 75% without FLU and 100% with FLU based regimens. Probability of acute GVHD was 19%. For the entire cohort, probability of survival at 1 year was 43%. A higher rate of survival was observed in the 11 patients who received a FLU based regimens (50%; figure) and in the 5 patients with BRCA2 mutations (60%). Probability of relapse was 21% in these 11 patients. [Display omitted] These data suggest that HCT with a FLU based preparative regimen offers potential curative therapy for FA patients with acute leukemia or advanced MDS. Except perhaps for BRCA-2 patients with T cell ALL, there is no clear role for chemotherapy prior to HCT in FA patients with AML or MDS. Disclosures:No relevant conflicts of interest to declare.

Immune Reconstitution After Cord Blood Transplantation in Adults Depends on Activity of Thymic Epithelial Cells and Vascular Endothelial Elements,

Abstract 4075Umbilical cord blood (UCB) grafts are increasingly used as sources of hematopoietic stem cells. UCBT in adults results in delayed and insufficient immune reconstitution leading to high infection-related morbidity and mortality. We recently determined that thymic regeneration as identified by T-cell receptor rearrangement excision circles (TREC) is a strong predictive factor for clearance of CMV viremia and for overall survival in adult UCBT recipients. We were able to detect TRECs by 100 days that was faster than in other adult UCBT studies reported previously, in which TRECs remained undetectable during the first year. A significant difference between our study and previous reports was the use of 2 UCB units in all our patients whereas only a single unit was used in the previous trials. Human UCB is enriched in endothelial precursors that sustain thymopoiesis in SCID mice transplanted with human thymic grafts where they engraft and promote neovascularization and wound healing. The loss of thymopoietic capacity after allogeneic stem cell transplantation results from injury of the thymic microenvironment, particularly of thymic epithelial cells (TEC). We hypothesized that thymic neovascularization induced by UCB-derived endothelial progenitors might be a critical factor promoting early recovery of TEC, which support T cell development and expansion via production of interelukin-7 (IL-7) and stem cell factor (SCF; a kit ligand). In the present study we examined whether thymic regeneration and immune reconstitution in adult recipients of double UCBT was associated with IL-7 and SCF levels and with activity of endothelial progenitors. Thirty-two patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by infusion with two sequential UCB units. GvHD prophylaxis was with tacrolimus and sirolimus. Results are based on 27 evaluable patients. Assessments were done prior to and at 1, 2, 3, 6 and 12 months after UCBT. Serum levels of IL-7 displayed a 3-fold increase at 1 month after UCBT and gradually declined to the pre-transplant levels at 12 months. SCF peaked at 2 months after UCBT and gradually decreased to the pre-transplant levels by 12 months. Strikingly, IL-7 and SCF levels displayed a strong inverse correlation (p<0.001) with TREC, CD4, CD8 and Treg cell numbers at various time intervals after UCBT suggesting that uptake of these cytokines by cognate IL-7R and Kit receptors expressed on the surface of immature T cell progenitors resulted in differentiation and expansion of these T cell populations. Moreover, there was a strong inverse correlation (p<0.001) of IL-7 and SCF levels with the ability of T cells to differentiate into pathogen-specific effectors as determined by CMV-specific, IFN-γ ELISpot, underlying the potential clinical implications of these findings. To determine whether TEC activity correlated with endothelial lineage engraftment and neovascularization, we assessed levels of serum thrombomodulin (TM), which is expressed by metabolically active vascular endothelial cells. Serum TM at 1, 2, 3 and 6 months strongly correlated (p<0.005) with the levels of IL-7 and SCF at various time points after UCBT. Thus, quantitative and qualitative T cell immune reconstitution after UCBT depends on IL-7 and SCF and is associated with activity of vascular elements. These results support the intriguing hypothesis that infusion of 2 UCB units might have a cell dosage effect on thymic regeneration and immune reconstitution similar to that seen with improved rates of hematologic engraftment in double versus single UCB recipients. Disclosures:No relevant conflicts of interest to declare.

Double Umbilical Cord Blood Transplantation Preceded by a Reduced-Intensity Conditioning Regimen: Rapid Induction of Single Donor Chimerism and Highly Predictive Value of Early CD4+ T Cell and NK Cell Predominance

Abstract 3026 BackgroundDouble umbilical cord blood transplantation (UCBT) results in higher engraftment rates as compared to single UCBT in adult patients. Sustained hematopoiesis is usually derived from a single cord blood unit (CBU) after double UCBT. So far, the mechanism of predominance of a particular CBU is unresolved. In a prospective single-arm phase II study (HOVON-106) we monitored early engraftment kinetics to determine whether graft predominance after double UCBT is driven by specific leukocyte subpopulations. Methods 36 consecutive patients (pts) from 5 Dutch centers with high-risk hematological diseases received a double UCBT, preceded by a reduced-intensity conditioning regimen (Cy 60 mg/kg/ Flu 160 mg/m2/ TBI 2×2 Gy). CBUs were selected by intermediate resolution typing for HLA-A and -B loci and by high-resolution typing for HLA-DRB1. The minimal required HLA-match grade was 4/6. Chimerism analysis (STR-PCR) of unseparated peripheral blood (PB) and bone marrow (BM) cells was performed as from day +32 onwards. In addition, chimerism analysis in PB leukocyte subpopulations by flowcytometry using lineage-specific (CD45, CD3, CD4, CD8, CD19, CD16/56, CD14 and CD33) monoclonal antibodies (mAbs) in combination with human HLA-antigen specific mAbs (HLA-mAbs) was performed at day +11, +18, +25 and +32 if discriminating HLA-mismatches between recipient and CBUs were present. Day +32 flowcytometry results were compared to day +32 PB STR-PCR results. Results The median number of prefreeze total nucleated cells (TNC) per CBU was 2.3×107/kg (range: 1.5–5.5). Median numbers of post-thaw viable CD34+ cells, T-, B- and NK cells were 0.32 (range: 0–1.7), 4.4 (range: 0.4–36), 9.7 (range: 0.7–79) and 7.2 (range: 0.24–45) x105/kg, respectively. One pt was non-evaluable for engraftment due to insufficient follow up after early relapse. The cumulative incidence of neutrophil recovery (≥0.5×109/l) was 91% with a median time to neutrophil recovery of 33 days (range: 15–82). Primary graft failure occurred in 1 pt. Chimerism analysis, performed at day +32 by STR-PCR revealed single CBU predominance in all pts whereas residual non-engrafting CBU and recipient cells were detectable in only 3 and 7 pts, respectively. Simultaneous 3-donor-origin detection of leukocyte subpopulations by flowcytometry based on HLA disparities was possible in 12 pts. Flowcytometry using HLA-mAbs demonstrated single CBU predominance in various leukocyte subsets as from day +11 onwards in the majority of pts. Moreover, ultimate engraftment of a particular CBU was reliably predicted for by chimerism within the CD4+ (in 90% of pts) and NK cell (in 90% of pts) subsets at this early time point. In contrast, predominance of the engrafting CBU in monocytic en myeloid subsets was observed in only 70% and 33% of pts, respectively, at day +11. The numbers of CD8+ and B-cells were too low for analysis in the majority of pts. Predominance of the ultimate engrafting CBU was established in all subpopulations at day +18. Furthermore, the contribution of the non-engrafting CBU to the different leukocyte subsets was negligible or even absent as from day +18 onwards. Recipient hematopoiesis did not contribute to PB cell recovery either. The results of day +32 flowcytometry (CD45+ population) were similar to results of day +32 PB STR-PCR. The number of prefreeze TNC did not predict for the ultimately engrafting CBU, nor did the number of post-thaw CD34+, T, B or NK cells. Engraftment was not associated with the degree of HLA mismatches or presence of KIR ligand mismatches among recipient and CBUs. Conclusions These results show that single donor chimerism is rapidly established after double UCBT, preceded by a 4 Gy TBI-based conditioning regimen without ATG. In addition, our flowcytometry data suggest the occurrence of CBU predominance within 2 weeks post transplant, in the course of which both CD4+ and NK cell predominance at day +11 are highly predictive for ultimate single donor chimerism. That early engraftment pattern of leukocyte subsets might suggest a key role for either CD4+ T cells or NK cells in CBU predominance. Disclosures:Janssen:Novartis: Consultancy.

Clinicohistologic Assessment of Bone Marrow Engraftment In Patients with Hematologic Malignancies Received Double Umbilical Cord Blood Transplantation – A Single Institutional Observation

Abstract 4578 Background:Double umbilical cord blood transplantation (dUCBT) has been gradually accepted as an alternative for the treatment of patients with hematologic malignancy requiring allogeneic hematopoietic stem cell transplant but who lack suitable adult donors. The therapeutic strategy has achieved success with either reduced intensity conditioning (RIC) or myeloablative regimens (MAC). According to large series, the 3-year event free survival (EFS) and median overall survival (OS) for RIC-dUCBT approaches 39% and 45%, respectively. Nevertheless, early mortality and development of graft-versus host disease (GVHD) exist. In addition, since UCB contains 10-fold fewer hematopoietic stem cells (HSCs) than adult donor HSC sources, engraftment takes longer even with protracted or double dosage hematopoietic growth factor administration. The relationship between bone marrow (BM) status and delayed engraftment and survival in UCBT patients is not well illustrated. This study aims to retrospectively evaluate our institutional UCBT cases and correlate the bone marrow findings with the clinical outcome. Design:Clinical and pathologic data from patients with hematopoietic malignancies receiving dUCBT between 11/2009 and 05/2011 were reviewed. Sequential BM biopsies from each patient pre- and post- dUCBT were reviewed by two hematopathologists. BM cellularity and peripheral blood counts about day 21, 30, and 90 were correlated with CBCs, chimerism and the clinical outcomes as well as survival. Results:Thirty-one patients with hematologic malignancies (AML = 13, ALL = 6, CLL = 3, FL = 2, DLBCL = 2, HL = 1, MCL = 1, PTCL =1, Myeloma =1, and MDS = 1) received conditioning with chemotherapy and total body irradiation (MAC = 12; RIC = 19) followed by dUCBT. The median age was 45.7 years (range, 18–68 years) with a male to female ratio of 1.1:1. All patients received GvHD prophylaxis with cyclosporine and MMF and G-CSF from day +1 until engraftment. The median time to neutrophil engraftment was 22 days (range, 15 – 59) following MAC and 22 days (range 6 – 43) following RIC. Bone marrow cellularity, the corresponding WBC, and chimerism data are shown (Table 1). On the day 21 BM assessment, 80% (8/10) of patients receiving MAC achieved a marrow cellularity at or above the median and 87.5% (7/8) were alive at last follow-up. Following RIC, 59% (10/17) of patients achieved at least the median cellularity (10%) and 70% (7/10) survived. For patients below the median cellularity at day 21, survival was only 50% (1/2) and 43% (3/7) following MAC and RIC, respectively. With a median follow-up for survivors of 264 days (range 72 – 613) (MAC 286 days; RIC 239 days), the estimated overall survival at 1 year was 47% (28 – 68%). Thirteen patients died due to infection (n = 6), relapse (n = 3), GvHD (n = 2), or hemorrhage (n = 2).Table 1Post UCBT bone marrow status in correlation with clinical and laboratory parametersVariableMyeloablative Conditioning (n = 10)Reduced Intensity Conditioning (n = 17)Myeloablative Conditioning (n=7) (nReduced Intensity Conditioning (n=11) (nDay 21Number alive at last follow-up with value ≥ medianDay 21Number alive at last follow-up with value ≥ medianDay 28Number alive at last follow-up with value ≥ medianDay 28Number alive at last follow-up with value ≥ medianBM % cellularity Median (range)5% (4-20)8/1010% (4-35)10/1128% (25-45)4/720% (5-50)5/11% Blast count (%) Median (range)4% (0.5-10.5)5/71.85% (0-17)4/81.5% (0-8)1/31% (0-1.5)4/6WBC ( x 109/L) Median (range)0.85 (0.04-2.5)6/60.4 (0-1.4)5/105 (0-7.6)4/62 (1-4)2/5≥90% donor Number (%)7/10 (70%)5/85/17 (29.4%)4/94/6 (66.7%)3/66/11 (54.5%)3/5 Conclusion:Our results demonstrate that the bone marrow cellularity early post-transplant may serve as a predictor of survival following transplant. Since 6 of 13 patients (46%) died due to infection, this may indicate further impaired immune recovery regardless of total WBC. Larger case series are needed to elucidate a correlation between the bone marrow environment and the long term survival following dUBCT. Disclosures:No relevant conflicts of interest to declare.

FT1050 (16,16-dimethyl Prostaglandin E2)-Enhanced Umbilical Cord Blood Accelerates Hematopoietic Engraftment After Reduced Intensity Conditioning and Double Umbilical Cord Blood Transplantation

Abstract 653▪▪This icon denotes a clinically relevant abstractUmbilical cord blood (UCB) transplantation relies on a small number of hematopoietic stem cells (HSCs) to restore hematopoiesis. Even with double umbilical cord blood transplantation, engraftment times are prolonged and immune reconstitution delayed. Preclinical studies have suggested that ex vivo treatment of HSCs with FT1050 (16,16-dimethyl PGE2) can enhance engraftment of HSCs without stem cell expansion or differentiation of HSCs to committed progenitors. Using both murine and human-xenograft model systems, the mechanisms of action of FT1050 treatment of HSCs have been demonstrated to involve improved homing via CXCR4-SDF-1, increased proliferation and entry into the cell cycle, and decreased rates of apoptosis (North 2007; Goessling 2009; Hoggatt 2009; Goessling 2011). A Phase Ib trial was designed to evaluate the safety of FT1050-treated HSCs and whether this ex vivo treatment can enhance engraftment after double UCB transplantation in adults. The competitive engraftment dynamic of double UCB transplantation also permits determination of whether FT1050-HSCs are able to out-compete untreated HSCs. Methods: Patients without a matched sibling or matched-unrelated donor were conditioned with fludarabine (30 mg/m2/day IV Day −8 to −3), melphalan (100 mg/m2/day IV Day −2), and rabbit ATG (1 mg/kg/day Days −7, −5, −3 and −1). GvHD prophylaxis was with sirolimus (target 3–12 ng/mL) and tacrolimus (target 5–10 ng/mL). Patients received 2 UCB units: the first UCB unit (FT1050-UCB) was thawed, washed and treated with FT1050 for 2 hours at 37°C. After an additional wash to remove residual FT1050, the FT1050-UCB was infused without further manipulation. The second untreated UCB was thawed, washed and infused 2–6 hours later. The primary objective of the study was to determine the safety of FT1050-UCB based upon engraftment by Day 42 with > 5% chimerism of the FT1050-UCB unit. Secondary objectives included time to engraftment, the rates of non-hematologic toxicity, graft failure, acute and chronic GvHD, relapse, treatment related mortality (TRM), fractional chimerism, and relapse-free and overall survival. Results: A total of 12 subjects received FT1050-UCB in this fashion, of which 11 are currently evaluable. The median age was 57.5 years (range 19–66) and 67% were male. Diagnoses included: AML(5), MDS(4) and NHL/CLL(3). The median precryopreservation UCB sizes were FT1050-UCB: 2.7×107 TNC/kg (range 2.0–5.1) with 1.3×105 CD34/kg (range 0.3–6.3); untreated UCB: 2.0×107 TNC/kg (range 1.8–5.0) with 1.1 × 105 CD34/kg (range 0.5–3.4). The median combined cell dose was 4.7×107 TNC/kg (range 3.9–10.1) with 2.1×105 CD34/kg (range 1.4–9.7). The FT1050 incubation did not result in significant cell loss, with a mean viable CD34 cell recovery of 90%. The adverse events attributed to FT1050-UCB consisted of five Grade 1/2 infusion-related events in 4 subjects, consisting of chills, flushing, abdominal pain, and cough. One additional subject with known coronary artery disease experienced transient Grade 4 ST-elevation following infusion and evidence of myocardial ischemia by cardiac troponin assay. The median time to neutrophil recovery (> 500 cells/μL) was 17 days (range 15–27 days), which compares favorably to a median of 21 days for a historic control group of similarly treated patients at our institution (n=53; p= 0.025). The median time to an unsupported platelet count of 20,000/μL was 42 days (n=9 evaluable). There were no instances of primary or secondary graft failure. The FT1050-UCB was the dominant source of hematopoiesis in 9 of the 11 evaluable subjects, and the median total chimerism of FT1050-UCB at day 14 was 90%, with long-term dominance again by the FT1050-UCB unit. To date, 2 cases of Grade 2 acute GvHD have been observed and one patient developed NIH mild chronic GvHD. No cases of EBV-lymphoproliferative disease were noted. TRM was 9% (1 subject) and 1 patient has relapsed; 9 subjects remain alive without relapse with a median follow-up of 5.0 months (range 1.6–9.4). Conclusions: These data support the potential benefit of a novel ex vivo modulation approach to improving engraftment in patients undergoing UCB transplantation. Additional studies exploring the potential use of FT1050-HSCs in other low cell dose settings are planned, including whether FT1050-UCB can enable single UCB transplant in adults. Disclosures:Shoemaker:Fate Therapeutics: Employment, Equity Ownership. Robbins:Fate Therapeutics: Employment. Desponts:Fate Therapeutics: Employment. Goessling:Fate Therapeutics: Consultancy. North:Fate Therapeutics: Consultancy. Mendlein:Fate Therapeutics: Employment, Equity Ownership. Multani:Fate Therapeutics: Employment, Equity Ownership.

Cytomegalovirus-Specific T Cells Are Elicited Early After Umbilical Cord Blood Transplant but Fail to Expand In Vivo and Control Virus Replication

Abstract 1974Cytomegalovirus (CMV) is a major infectious complication in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and has been linked to deficiencies of virus-specific T cell immunity. Compared to bone marrow or peripheral blood stem cell transplants, recipients of single or double umbilical cord blood transplants (UCBT) receive lower numbers of donor T cells that have not previously been primed to CMV and are at increased risk for early and recurrent CMV infections. At our institution, the rate of CMV reactivation in CMV seropositive patients undergoing CBT is close to 100% with standard dose Acyclovir as prophylaxis [Delaney unpublished data]. Here, we systematically analyzed the kinetics of recovery, durability, and specificity of CMV-specific CD8+ and CD4+ T cell responses in UCBT recipients. CD8 T cell responses to CMV were analyzed by interferon γ (IFN-γ) intracellular cytokine staining after stimulating recipient peripheral blood mononuclear cells (PBMC) obtained at various time points after CBT with autologous patient fibroblasts infected with the RV798 virus, which is a mutant CMV strain that lacks the viral US genes that downregulate class I MHC and can present all potentially immunogenic epitopes of the virus. The mean absolute CD8 T cell counts were 59, 93 and 213 cells/μl and the mean CD4 T cell counts were 154, 223 and 397 cells/μl in PBMC at day 56, 180 and 365 respectively. Direct assays of PBMC after a 4–6 hour stimulation with RV798-infected fibroblasts did not detect a significant frequency of IFN-γ+ CD8+ T cells in CBT recipients, in contrast to normal CMV+ donors that exhibited frequencies of CD8+ T cells of 2–10%. However, IFN-γ+ CMV specific CD8 T cells were readily detectable in PBMC obtained as early as day 42 after UCBT from 8 out of 8 CMV positive CBT recipients after a 10 day stimulation with RV798 infected fibroblasts. These responses were sustained at multiple time points through day 365 post transplant. This result was not a consequence of in vitro priming of CD8 T cells by prolonged stimulation with RV798 since we did not detect a CMV-specific T cell response in 3 out of 3 CMV seronegative recipients at any time through day 365 with the same assay. To assess CD4+ T cell responses, we performed lymphoproliferative assays (LPA) by stimulating patient PBMC obtained at the same time points with whole CMV antigen. The proportion of patients with a positive response at day 56, 80, 180 and 365 was 0.38, 0.50, 0.88, and 1.0 respectively. All of the CMV positive CBT recipients in our study had multiple occurrences of CMV reactivation throughout the first year post CBT requiring antiviral drug therapy.The CMV-specific CD8 T cell response in normal CMV+ individuals recognizes a large number of distinct dominant and subdominant antigens and a potential explanation for the failure to control CMV after CBT is that the T cell response may not be sufficiently diverse. We analyzed the specificity of CMV specific CD8+ T cells that developed after CBT in 4 recipients by assessing recognition of COS cells transfected with the class I HLA restricting alleles and with a CMV plasmid library consisting of 142 ORFs, subdivided into pools. A response was seen in 3 out of 4 patients to at least 3 different CMV antigens by day 80 post CBT, including previously defined dominant epitopes in pp65 and this diversity was maintained through 6–12 months post transplant. One patient had a less diverse response early post CBT and the response changed over time to include recognition of new epitopes.Collectively, our results demonstrate that CD8+ and CD4+ T cells are primed to CMV antigens very early after CBT despite the infusion of limited numbers of naïve T cells and the administration of post transplant immunosuppression. The inability to control CMV infection may be due to a quantitative deficiency of CMV-specific T cells resulting from the inability of CMV-specific T cells to expand in vivo to numbers sufficient to eliminate virus replication. Disclosures:No relevant conflicts of interest to declare.

Unrelated Cord Blood Transplantation (UCBT) in Adult and Pediatric Acute Lymphoblastic Leukemia: Impact of Minimal Residual Disease on Relapse and Survival,

Abstract 4114 Background:Umbilical cord blood (UCB) has become a valuable alternative source of stem cells for patients with high risk acute lymphoblastic leukemia (ALL) lacking a matched sibling donor. Data on the efficacy of transplant outcomes after UCB in ALL are limited, particularly for the adult population. Methods:We report the outcomes of 143 patients (74 children <18 years and 68 adults) with ALL who received UCBT at University of Minnesota between 1999–2010. Most had precursor-B ALL (n=87 [61%]), Philadelphia positive ALL (Ph+; n=41 [29%] and T cell ALL (n=15 [10%]). All except 7 patients were in complete remission (CR1: n=59 [41%] or CR2/CR3: n=77 [54%]). Most adults received double UCB grafts (adult =90% vs. children =27%, p=0.01) with HLA locus matching of 4/6 and 5/6 in 65% and 28% of adults vs. 29% and 53% of children (p=0.01). 86 had an assessment of Minimal Residual Disease (MRD) prior to UCBT using 4 to 6 color flow-cytometric analysis and MRD was based on prior (diagnostic) immunophenotype and according to published standards. Ten patients had MRD detected immediately prior to UCBT (2 patients were in CR1, 7 in CR2, 1 in CR3) and 76 patients were MRD-negative.Most patients (82%) received myeloablative conditioning (cyclophosphamide 120 mg/kg, fludarabine 75mg/m2 and total body irradiation (TBI) 1200–1320cGy). Non-myeloablative conditioning (cyclophosphamide 50mg/kg, fludarabine 200mg/m2 and TBI 200cGy was given to patients above 45 years (n=18 [13%]) and in those with poor fitness (n=8 [5%]). All patients received cyclosporine (day −3 to day +180) and mycophenolate mofetil ( day −3 to day +45) post-HCT. Results:The cumulative incidence of neutrophil engraftment by day 42 was 97% (95%CI 92–99%). Six months platelet engraftment was 71% (95%CI 67–85%), 48% (95% CI 32–64%) and 84% (95%CI 58–100%); p<0.01) for patients ≤18 years, 19–45 and >45 years of age, respectively. With a median follow-up of 3.9 years (0.5–11.8 years), the 3-year leukemia-free survival (LFS) and overall survival (OS) was 47% (95%CI 38–55%) and 49% (95%CI 40–57%) with trend to better OS in children (Table). Cumulative incidence of relapse at 1 year was 17% (95%CI 11–23%) and the relative risk tended to lower rates in adults following MA vs NMA conditioning (7% [95%CI 0–14% vs 21% [95%CI 5–37%]; p=0.19). In univariate analysis age, disease status (CR1 vs CR2/CR3 vs. non CR), disease group (pre-B ALL, Ph+ALL, T-ALL) or time to transplant had no impact on relapse rate. Treatment-related mortality at 1 year was higher in adult patients aged 18–45 years (46% [95%CI 31–61%]) compared to children (19% [95%CI 10–28%]) or older patients who received NMA conditioning regimen (TRM 5% [95%CI 0–15%]; p<0.01). Patients with MRD detected immediately prior to UCBT had a higher relative risk of relapse at 2 years (30% [95%CI 4–56%]) and lower LFS (30% [95%CI 7–58%]) compared to MRD- group (16% [95%CI 8–25%]; p=0.05 and 61% [95%CI 49–70%]; p=0.05); respectively. Conclusion:UCBT expands the options for patients with ALL and offers potent protection from post-transplant relapse. Our results indicate that novel strategies in UCB HCT for ALL should focus on decreasing TRM in adult patients receiving myeloablative conditioning and improving leukemia control to induce a MRD- state pre- transplant.Post HCT outcomes @ 3 yearsAge <=18 years (n=74)19–45 years (n=50)>45 years (n=19)p-valueDFS51% (95%CI 38–62%)42% (95%CI 28–55%)44% (95%CI 19–67%)0.20OS52% (95%CI 39–63%)41% (95%CI 27–54%)55% (95% CI 27–76)0.06Relapse @1yr22% (95%CI 12–32%)6% (95%CI 0– 13%)26% (95%CI 7– 46%)0.21TRM @1yr19% (95%CI 10–28%)46% (95%CI 31–61%)5% (95%CI 0–15%)<0.01 Disclosures:No relevant conflicts of interest to declare.

Reduced-Intensity Conditioning Stem Cell Transplantation: Comparison of Double Umbilical Cord Blood and Unrelated Donor Grafts

There are little data comparing umbilical cord blood (UBC) and conventional stem cell sources for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis of RIC HCST using double UCB (dUCB) grafts and RIC HSCT using unrelated donor (URD) grafts. The study included 64 dUCB transplantations and 221 URD transplantations performed at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2004 and 2008. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 14.1% for dUCB and 20.3% for URD (P = .32). The 2-year cumulative incidence of chronic GVHD was significantly lower in dUCB compared with URD (21.9% versus 53.9%; P < .0001). The 2-year cumulative incidence of nonrelapse mortality was significantly higher in dUCB (26.9% versus 10.4%; P = .0009). In our analysis, dUCB HSCT and URD HSCT had comparable 3-year overall survival (46% in dUCB and 50% in URD; P = .49) and progression-free survival (30% in dUCB and 40% in URD; P = .47). dUCBT was associated with greater nonrelapse mortality despite less chronic GVHD. Our findings suggest that the use of 2 partially matched UCB units appears to be a suitable alternative for patients undergoing RIC HSCT without an HLA-matched donor.