Cord Blood Transplantation In Adults Research Articles

Outcomes After Unrelated Cord Blood Transplantation For Adults With Primary Or Secondary Myelofibrosis: A Retrospective Study On Behalf Of Eurocord and Chronic Malignancy Working Party-EBMT

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative option for patients (pts) with myelofibrosis (MF). Patients with MF transformed to Acute Myeloid Leukemia (AML) have a very short life expectancy without transplantation (< 4 months). Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative to conventional allogeneic HSCT for pts with hematologic malignancies who do not have an HLA matched donor. Delayed engraftment and graft failure are the limitations of this procedure and represent a major issue for MF. Patients and MethodsWe analyzed 42 adults (28 males and 14 females) who underwent a single (n=15) or double (n=27) HLA mismatched UCBT between 2005 and 2012 in 26 EBMT centers reported to Eurocord. At diagnosis, 21 had primary MF (PMF), 5 polycythemia vera (PV), and 16 essential thrombocytemia (ET). Twelve patients transformed to acute myeloid leukemia (AML) before UCBT. Among pts with pre-transplant information available, 13/25 had severe marrow fibrosis; 8/16 had a high Lille score at diagnosis and 13/27 had JAK2 V617F mutation; 13/35 underwent splenectomy and 16/30 had an abnormal karyotype. The median time from diagnosis to transplant was 80 months (range 5-316), while in the subgroup of pts with transformation to AML, it was 119 months (range 5-246). Five pts had a prior transplant (1 autologous, 3 allogeneic and 1 had 2 consecutive allogeneic transplants). The median age at UCBT was 54 years (range 28-69). Conditioning regimens were reduced intensity (RIC) (n= 29) or myeloablative (MAC) (n=13). The most common conditioning in both MAC (n=5) and RIC (n=16) was Cyclophosphamide and Fludarabine associated with total body irradiation (TBI). Overall, 27 pts received TBI with a dose of 12-14 Gy in MAC (n=6) and 2-4 Gy in RIC (n=21); 20 pts received anti-thymoglobulin (ATG) in the conditioning regimen. The median infused total nucleated and CD34+ cells were 3,4x107/Kg (range 0,3-6,8) and 1,3x105/Kg (range 0,04-3,8),respectively. ResultsMedian follow-up for survivors was 25 months (range 6 -72). The cumulative incidence (CI) of neutrophil engraftment was 64% (28 pts) with a median time of 29 days, and among the 12 pts transformed to AML, 10 engrafted in a median time of 30 days, while 18 of 30 pts without transformation engrafted in a median time of 28 days. Of the 14 pts who did not reach neutrophil engraftment, 7 had no hematological recovery, 6 of them died after a median of 3 months and 1 pt is alive at 14 months post UCBT. The remaining 7 pts had an autologous reconstitution, and 4 of them are alive with progressive disease at a median time of 42 months. Pts who received RIC conditioning had better engraftment (79% versus 36%, p=0.02).Twelve pts developed acute GvHD of grades II-IV; 7 pts had limited chronic GvHD with a median time of onset of 144 days.Overall, 17 pts relapsed (6 had transformed into AML before transplantation) at a median time of 5 months. The CI of relapse at 2 years was 29%±2%. The CI of transplant-related mortality at 1 year was 33%±2%. Causes of death were relapse (n=9), post-transplant lymphoproliferative disease (n=3), GvHD (n=3), multiorgan failure (n=1), bacterial infection (n=3), acute respiratory distress syndrome (n=2), infection of unknown origin (n=3), cardiac toxicity (n=1) and fungal infection (n=1). OS at 2 years was 44±8%: 80%, 21% and 52% for pts transplanted respectively for MF secondary to PV, ET and PMF (p=0.07). No difference in OS was seen in the subgroup of pts with JAK2 mutation. OS was 51% versus 29% for pts receiving double or single UCBT (p=0.15), and it was 37% for AML-transformed pts. Pts who did not receive ATG, had an OS of 59% versus 24% for those who received ATG (p=0.01). Among pts who underwent RIC (n=29), 13 had a TBI based conditioning without ATG, and 7 are alive. Failure-engraftment free survival at 2 years was 29±7%, better in pts receiving double UCBT as compared with single (40% versus 8% , p=0,01), and in pts receiving TBI (43% versus 7%, p=0,03). ConclusionGraft failure was a major concern for these pts. Despite a limited number of patients, our results indicate that life expectancy can be increased with UCBT particularly for patients with advanced stage MF. Furthermore, the use of RIC TBI based regimen without ATG and double CB might improve outcomes. Disclosures:Gluckman:Cord use: Honoraria; gamida: Honoraria.

Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.

Myeloablative Cord Blood Transplantation in Adults with Acute Leukemia: Comparison of Two Different Transplant Platforms

We compared the clinical outcomes of adults with acute leukemia that received single-unit umbilical cord blood transplantation (sUCBT) after conditioning with a busulfan/antithymocyte globulin (BU-ATG)–based regimen at University Hospital La Fe (n = 102) or double-unit UCBT (dUCBT) after conditioning with a total body irradiation (TBI)–based regimen at the University of Minnesota (n = 91). Nonrelapse mortality, relapse and disease-free survival were similar in the 2 groups. Multivariate analyses, showed more rapid neutrophil (hazard ratio [HR], .6; 95% confidence interval [CI], .45 to .80; P = .0006) and platelet recovery (HR, .59; 95% CI, .43 to.83; P = .002) after the BU-ATG-based conditioning and sUCBT. Although there was a lower risk of acute graft-versus-host disease (GVHD) grade II to IV (HR, 2.81; 95% CI, 1.75 to 4.35; P < .001) after BU-ATG and sUCBT, the incidences of grade III to IV acute and chronic GVHD were similar between the 2 groups. Regarding disease-specific outcomes, disease-free survival in both acute myeloid leukemia and acute lymphoblastic leukemia (ALL) patients were not significantly different; however, a significantly lower relapse rate was found in patients with ALL treated with TBI and dUCBT (HR, .3; 95% CI, .12 to .84; P = .02). In the context of these specific treatment platforms, our study demonstrates that sUCB and dUCBT offer similar outcomes.

Comparison of outcomes after single or double cord blood transplantation in adults with acute leukemia using different types of myeloablative conditioning regimen, a retrospective study on behalf of Eurocord and the Acute Leukemia Working Party of EBMT

We report outcomes after single (s) and double (d) umbilical cord blood transplantation (UCBT) after myeloablative conditioning (MAC) regimen for 239 patients transplanted for acute leukemia in first complete remission (CR1). All sUCBT patients received a total nucleated cell dose >2.5 × 10(7)/kg. Conditioning regimen for sUCBT was total body irradiation (TBI)12 Gy- or busulfan (BU)-based ± fludarabine (Flu) (n=68, group 1), thiotepa+BU+Flu (TBF) (n=88, group 2), and for dUCBT it was TBI12 Gy+cyclophosphamide ± Flu (n=83, group 3). dUCBT recipients were younger, received higher cell dose and less frequently antithymocyte globulin. In multivariate analysis, we found similar neutrophil recovery among the three groups; however, acute graft-versus-host disease II-IV was higher in dUCBT compared with others. Non-relapse mortality and relapse incidence were not statistically different among the three groups. Leukemia-free survival was 30% for sUCBT using TBI- or BU-based MAC compared with 48% for sUCBT TBF and 48% for dUCBT (P=0.02 and P=0.03, respectively), and it was not statistically different between sUCBT with TBF and dUCBT. In conclusion, use of sUCBT with adequate cell dose (>2.5 × 10(7)/kg) and a specific conditioning regimen in the MAC setting results in similar outcomes as dUCBT. The choice of TBF conditioning regimen for sUCBT may improve results, and whether this regimen may be effective in dUCBT should be further analyzed.

Importance of factors influencing the decision to proceed with cord blood transplantation in adults: results of a web-based survey of the Canadian transplant community

Importance of factors influencing the decision to proceed with cord blood transplantation in adults: results of a web-based survey of the Canadian transplant community

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.

Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia

AbstractCell dose is a major limitation for umbilical cord blood (UCB) transplantation because units containing a minimum of 2.5 × 107 total nucleated cells (TNC)/kilogram patient body weight are frequently not available. The transplantation of 2 partially HLA-matched UCB units has been adopted as a simple approach for increasing the TNC. We sought to determine whether the relative safety and efficacy of this approach was comparable with a single UCB transplantation. Included are adults with acute leukemia who received transplants with 1 (n = 106) or 2 (n = 303) UCB units. All UCB units for single UCB transplantations contained TNC ≥ 2.5 × 107/kg. For double UCB transplantations, the total TNC for units 1 and 2 were > 2.5 × 107/kg but in approximately half of these transplantations, 1 of the 2 units contained < 2.5 × 107 TNC/kg. Adjusting for factors associated with outcomes, risks of neutrophil recovery (odds ratio 0.83, P = .59), transplantation-related mortality (hazard ratio [HR] 0.91, P = .63), relapse (HR 0.90, P = .64), and overall mortality (HR 0.93, P = .62) was similar after double UCB and adequate dose single UCB transplantations. These data support double UCB unit transplantation for acute leukemia when an adequately dosed single UCB unit is not available thereby extending access to nearly all patients.

Impact of Myeloablative and Reduced Intensity Conditioning on Outcomes After Unrelated Cord Blood Transplantation for Adults with Acute Lymphoblastic Leukemia

Abstract Abstract 3117 Allogeneic hematopoietic stem cell transplantation is the only curative option for high risk or relapsed acute lymphoblastic leukemia (ALL) in adults. In the absence of an HLA identical sibling donor, HLA matched adult donor or HLA mismatched cord blood are alternative sources of stem cell to treat those patients. However, very few data on the outcomes after umbilical cord blood transplantation (UCBT) for adult ALL using myeloablative or reduced intensity conditioning regimens have been reported. With this aim, we conducted a retrospective survey on the outcomes after UCBT for adult ALL and a more specific analysis for patients with cytogenetic data transplanted in remission with either a myeloablative (MAC) or reduced intensity conditioning regimen (RIC). From 1996 to 2011, 433 adult patients (pts) received a UCBT for ALL. Overall 2-year LFS was 37% for pts in first complete remission (CR1) (n=199), 32% for CR2 (n=138) and 9% for advanced disease (n=96). Complete cytogenetic information at diagnosis was available for 316 pts, of those 251 pts were transplanted in CR1 (63%, n=157) or in CR2 (37%, n=132). Median age at UCBT was 33 years (18 to 66 years) and 76% of the pts (n=191) had an abnormal karyotype at diagnosis. Pts were analyzed according to the presence of t(9;22) as Ph+ (n=115) and Ph- (n=136). Double CBT was performed in 109 pts (43%) and the median total nucleated cell dose at freezing was 4.02×107/kg. Most pts received CBU with one (30%, n=74) or two (56%, n=136) HLA disparities. A myeloablative (MAC) conditioning was given to 177 pts (70%) and 73 (30%) received a reduced intensity conditioning (RIC). Overall 2-year leukemia- free survival (LFS) was 36±3%; 37% for Ph- and 35% for Ph+ pts (p=0.74). On multivariate analysis, 3 factors were associated with improved LFS: age Table 1 . In pts transplanted with MAC (n=177), most frequent conditioning regimens were Cy-TBI (27%) and Bu+Flu+Thio (25%). Median follow-up (FU) was 26 and 35 months for those in CR1 (n=107) and CR2 (n=70), respectively. Cumulative incidence (CI) of 60-day neutrophil recovery was 87% for pts in CR1 and 83% for those in CR2; acute GVHD was 43% and 37%, respectively. Two-year CI of NRM was 41% for CR1 and 49% for CR2 and 2-year RI was 24% for CR1 and 22% for CR2. Two-year LFS was 35% for CR1 and 30% for CR2. No factor was found to be associated with LFS, relapse nor NRM. One-hundred and four pts died, 81 of transplant-related causes (79%, n=46 for CR1 and 74% n=35, for CR2), mainly due to infections (53% n=24 for CR1 and 38% n=12 for CR2). In pts transplanted with RIC (n=94), Cy+Flu+TBI regimen was used in 74% (n=54). Median FU was 31 and 34 months and median age was 50 and 39 years for those in CR1 (n=49) and CR2 (n=24), respectively. At 2 years, CI of NRM was 22% for CR1 and 17% for CR2. Two-year RI was 30% and 47%, respectively. Two-year LFS was 49% for CR1 and 36% for CR2. For pts in CR1, univariate analysis showed that younger age ( UCBT is an option to treat high risk and relapsed adult ALL. Pts transplanted with MAC had an LFS comparable with that reported with other stem cell sources, but strategies to reduce toxicity are still needed, especially for pts in CR2. Results with RIC are encouraging and may be considered in younger pts. Importantly, in this large series outcomes after UCBT for Ph+ ALL were not statistically different from those compared to Ph-. Table 1 . Outcomes according to disease status at UCBT and conditioning regimen MAC RIC CR1 (n=107) CR2 (n=70) CR1 (n=49) CR2 (n=24) LFS (2y) 35 ± 5% 30 ± 6% 49 ± 7% 36 ± 10% Relapse (2y) 24 ± 4% 22 ± 5% 30 ± 7% 47 ± 11% NRM (2y) 41 ± 5% 49 ± 6% 22 ± 6% 17 ± 8% Disclosures: No relevant conflicts of interest to declare.

Outcomes After Double Cord Blood Transplantation Compared to Single Cord Blood Transplantation in Adults with Acute Leukemia Given a Reduced Intensity Conditioning Regimen

Abstract Abstract 232 Unrelated cord blood (UCB) is an alternative source of allogeneic hematopoietic stem cell transplantation (HSCT) for adults with acute leukemia lacking a HLA matched donor. Double cord blood unit (dUCBT) has been increasingly used over single CB unit (sUCBT) after reduced intensity conditioning regimen (RIC). Since there is an increased relapse incidence (RI) using RIC-HSCT compared to myeloablative conditioning regimen, we have driven the hypothesis that RI may be decreased and leukemia-free survival (LFS) rate increased after dUCBT compared to sUCBT, due to probably increased graft-versus leukemia (GVL) effect. With this aim, we analyzed 360 adults (>18 years) with ALL (n= 77) or AML (n=238) in CR1 (n=212) and in CR2 (n=148) transplanted with a sUCBT (n=131) or a dUCBT (n=229) after a RIC. Only patients transplanted with a single unit containing more than 2.5×107/kg total nucleated cells (TNC) were included. Patients were transplanted from 2005–2011 in EBMT centers. Comparing the two groups of patients receiving a sUCBT or a dUCBT in CR1, there were no statistical differences according to age, diagnosis (AML or ALL), weight, CMV serostatus, cytogenetics risk, number of HLA incompatibilities. However, dUCBT were performed more recently (2009 vs 2008), the time from CR1 to transplantation was longer (142 days vs 121 days), more frequently transplanted with CY+FLU+TBI2Gy (87% vs 68%), lower frequency of ATG use (21% vs 35%) and finally, dUCBT recipients received higher number of TNC collected (5×107/kg vs 3.9×107/kg) or infused (4×107/kg vs 3.1×107/kg). Median follow-up was 23 months in both groups. Cumulative incidence (CI) of 60 days neutrophil recovery was 82±3% after dUCBT and 76±2% after sUCBT (p=0.86) and frequency of full donor chimerism at day 100, was not statistically different between dUCBT (81%) and sUCBT (86%). At day 100, CI of acute GVHD (grade II-IV) was 35% in both groups, however there was a trend of increased incidence of grade III-IV after sUCBT (19%) compared to dUCBT (10%, p=0.06) but increased incidence of grade II aGVHD after dUCBT (28%) compared to 17% after sUCBT (p=0.05). CI of chronic GvHD at 2 years was 21±4% after dUCBT and it was 12±5% after sUCBT (p=0.15). At 2 years, CI of non relapse mortality (NRM) after dUCBT was 28±4% and it was 30±6% after sUCBT (p=0.87). However, CI of 2y relapse was 21±4% after dUCBT whereas it was 38±2% after sUCBT (p=0.03). In a multivariate analysis adjusting for the differences between the 2 groups, dUCBT was associated with lower incidence of relapse compared to sUCBT (HR=0.74, p=0.01). Therefore, there was an improved 2-y LFS after dUCBT (51±5%) compared to sUCBT (32±3%; p=0.03). This was confirmed in a multivariate analysis (HR=0.64, p=0.04). Concerning patients transplanted in CR2 (n=148), there were no statistically differences of outcomes after dUCBT (n=93) or sUCBT (n=55). At 2y, LFS was 40±6% after dUCBT and 48±3% after sUCBT (p=0.32). In a subgroup analysis of dUCBT (n=118) and sUCBT (n=51) recipients using the same conditioning regimen (CY+FLU+TBI2Gy), 2 y LFS were 54±5% and 33±7% respectively (p=0.05). Conclusion: In this retrospective comparative based registry analysis, in AL patients transplanted in CR1, neutrophil recovery, GVHD and NRM were not statistically different after RIC-dUCBT or RIC-sUCBT, however, dUCBT recipients had decreased relapse incidence and improved LFS. For AL patients transplanted in CR2, there was no benefit of using dUCBT when compared to sUCBT recipients. Disclosures: No relevant conflicts of interest to declare.

Markers of Angiogenesis and Neovascularization Correlate with Functional Recovery of Thymic Epithelial Cells and T Cell Immune Reconstitution After Cord Blood Transplantation in Adults

Markers of Angiogenesis and Neovascularization Correlate with Functional Recovery of Thymic Epithelial Cells and T Cell Immune Reconstitution After Cord Blood Transplantation in Adults

Umbilical cord blood transplantation in adults:

Umbilical cord blood transplantation in adults:

Acute kidney injury after myeloablative cord blood transplantation in adults: the efficacy of strict monitoring of vancomycin serum trough concentrations

Acute kidney injury (AKI) is a common medical complication after myeloablative allogeneic stem cell transplantation (SCT). We have previously performed a retrospective analysis of AKI after cord blood transplantation (CBT) in adults, and found that the maximum of vancomycin (VCM) trough levels were significantly higher in patients with AKI. Following these results, we have monitored VCM serum trough concentrations more strictly, to not exceed 10.0mg/L, since 2008. In this report, we performed an analysis of AKI in a new group of 38 adult patients with hematological malignancies treated with unrelated CBT after myeloablative conditioning between January 2008 and July 2011. Cumulative incidence of AKI at day 100 after CBT was 34% (95% confidence interval 19-50). The median of the maximum value of VCM trough was 8.8 (4.5-12.2) mg/L. In multivariate analysis, no factor was associated with the incidence of AKI. No transplant-related mortality was observed. The probability of disease-free survival at 2years was 83%. These findings suggest that strict monitoring of VCM serum trough concentrations has a beneficial effect on outcomes of CBT.

BK Virus Reactivation After Double Umbilical Cord Blood Transplantation in Adults Correlates with Tregs and Delayed Reconstitution of CD4+ and CD8+ T Effector Cells

Abstract 4174Umbilical cord blood transplantation (UCBT) in adults is associated with impaired immune function and increased infection-related morbidity and mortality due to lack of antigen experienced cells and delayed immune reconstitution. BK virus (BKV) is a human polyomavirus that remains latent in renal epithelial cells and can be reactivated after hematopoietic stem cell transplantation (HSCT), leading to hemorrhagic cystitis. Data regarding BKV reactivation and its association with immune reconstitution after UCBT is lacking. We evaluated the status, cellular mechanisms, and clinical implications of immune reconstitution on BK viremia in adults with hematologic malignancies undergoing double unit cord blood transplantation. 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 of two sequential UCB grafts and GvHD prophylaxis with tacrolimus and sirolimus. The grafts were at least a 4/6 match with each other and the recipient. The results are based on 27 evaluable patients. Assessments were done prior to transplant and at 1, 2, 3, 6 and 12 months after UCBT. After UCBT, 15 patients had detectable serum BKV DNA, median 2.6×104 copies/ml (range, 2.5×102–7.9×106) with a median time to viremia of 40 days (range, 26–733). The cumulative probability of developing BK viremia by day 100 was 0.52 (95% CI, 0.33–0.71). In 9 of the 15 patients with detectable serum BKV DNA, urinary BKV PCR was also performed. All 9 tested patients had detectable urinary BKV and developed clinical symptoms ranging from dysuria to hemorrhagic cystitis. To determine whether development of BK viremia was related to the immunological status, we analyzed detection of serum BKV DNA in conjunction with parameters of immune reconstitution. At 6 and 12 months after transplantation development of BK viremia displayed a statistically significant inverse correlation with CD4+ and CD8+ T cells (p<0.05). Development of BK viremia at these time intervals also inversely correlated with CD4+CD45RO+ and CD8+CD45RO+ T cells (p<0.05), consistent with a potentially significant role of these effector populations in preventing and/or clearing BKV. Conversely, simultaneoulsy, there was a significant positive correlation of BK viremia with T regulatory cell numbers (p<0.05) suggesting that cellular mechanisms of Treg-mediated immune suppression were directly involved in regulating this clinical outcome. At 3 months after UCBT there was a significant positive correlation (p<0.05) between BK viremia and T cell receptor excision circles (TRECs), which are expressed in recent thymic emigrant T cells. BK viremia was not dependent on any other immune cell populations including CD20+ B cells, CD16+CD56+ NK cells and CD14+ monocytes. Furthermore, prevention and/or clearance of BK viremia was not dependent on naïve cell numbers as determined by lack of correlation between BK viremia -or absence thereof- with CD4+CD45RA+ T cells and CD8+CD45RA+ T cells. These observations were in complete contrast to our previous findings regarding CMV-specific immunity, which revealed that prevention and/or clearance of CMV viremia depend on reconstitution of thymopoiesis and increase of TRECs and naïve CD4+CD45RA+ cells. In addition, we found no correlation between development of CMV viremia and BK viremia in UCBT recipients. Our results indicate that reactivation of BK virus occurs with high frequency in adult UCBT recipients and is related to the inability of TREC positive cells to control BK viremia, the impaired and delayed reconstitution of CD4+ and CD8+ T effector cells, and the suppressive function of Treg. Furthermore, our results indicate that distinct immunological mechanisms govern CMV-specific and BK-specific anti-viral responses after UCBT. Disclosures:No relevant conflicts of interest to declare.

Recovery of Thymic Epithelial Cells and T Cell Immune Reconstitution After Cord Blood Transplantation in Adults Depends On Angiogenesis and Neovascularization

Abstract 4175Umbilical cord blood transplantation (UCBT) is increasingly used as alternative source for allogeneic hematopoietic stem cell transplantation. UCBT in adults results in delayed and insufficient immune reconstitution leading to high infection-related morbidity and mortality. A significant component of immune reconstitution after UCBT involves the thymic regeneration, which can be measured by T-cell receptor rearrangement excision circles (TRECs). TREC levels are a strong predictive factor for overall survival in adult recipients of UCBT. HSCT compromises thymopoiesis due to injury of the thymic microenvironment, particularly thymic epithelial cells (TEC). Human UCB is enriched in endothelial precursors that can sustain thymopoiesis in immunodeficient mice transplanted with human thymic grafts, where they engraft and promote neovascularization and wound healing. We hypothesized that thymic neovascularization induced by the UCB-derived endothelial progenitors might be a critical factor involved in the recovery of TEC, which subsequently 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 markers of angiogenesis and neovascularization ANG1 and VEGF were associated with TEC function as determined by assessment of IL-7 and SCF levels and with thymic regeneration as determined by TREC values and recovery of T cell subsets. 27 evaluable 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 grafts and GvHD prophylaxis with tacrolimus and sirolimus. Results are based on 27 evaluable patients. Assessments were done prior to transplantation and at 1, 2, 3, 6 and 12 months after UCBT. At various time points after UCBT, serum levels of IL-7 and SCF displayed a strong correlation (p<0.005) with the levels of ANG1 and VEGF indicating that functional recovery of TEC is associated and coincides with angiogenesis and neovascularization. In contrast, serum levels of IL-7 and SCF displayed a strong inverse correlation (p<0.001) with TREC, CD4+, CD8+ and Treg numbers suggesting that uptake of these cytokines by cognate IL-7R and Kit receptors expressed on immature T cell progenitors resulted in differentiation and expansion of these immature T cells. Similarly, IL-7 and SCF levels displayed a strong inverse correlation (p<0.001) 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. Conversely, VEGF and ANG1 levels positively correlated (p<0.001) with CD4+, CD4+CD25+ and CD4+CD45RA+ numbers at various time points after UCBT. Our results are consistent with a model of TEC recovery supported by VEGF and ANG1, leading to production of SCF and IL-7 by TEC, and uptake of these cytokines by T cell progenitors resulting in their differentiation and expansion. Thus, T cell immune reconstitution after UCBT depends on TEC and is associated with indicators of angiogenesis. These sequential steps in the process of thymic regeneration might represent novel therapeutic targets for improvement of immune reconstitution after UCBT. Disclosures:No relevant conflicts of interest to declare.

Impact of Myeloablative and Reduced Intensity Conditioning On Outcomes After Unrelated Cord Blood Transplantation for Adults with Acute Lymphoblastic Leukemia.

AbstractAbstract 3117▪▪This icon denotes a clinically relevant abstractAllogeneic hematopoietic stem cell transplantation is the only curative option for high risk or relapsed acute lymphoblastic leukemia (ALL) in adults. In the absence of an HLA identical sibling donor, HLA matched adult donor or HLA mismatched cord blood are alternative sources of stem cell to treat those patients. However, very few data on the outcomes after umbilical cord blood transplantation (UCBT) for adult ALL using myeloablative or reduced intensity conditioning regimens have been reported. With this aim, we conducted a retrospective survey on the outcomes after UCBT for adult ALL and a more specific analysis for patients with cytogenetic data transplanted in remission with either a myeloablative (MAC) or reduced intensity conditioning regimen (RIC). From 1996 to 2011, 433 adult patients (pts) received a UCBT for ALL. Overall 2-year LFS was 37% for pts in first complete remission (CR1) (n=199), 32% for CR2 (n=138) and 9% for advanced disease (n=96). Complete cytogenetic information at diagnosis was available for 316 pts, of those 251 pts were transplanted in CR1 (63%, n=157) or in CR2 (37%, n=132). Median age at UCBT was 33 years (18 to 66 years) and 76% of the pts (n=191) had an abnormal karyotype at diagnosis. Pts were analyzed according to the presence of t(9;22) as Ph+ (n=115) and Ph- (n=136). Double CBT was performed in 109 pts (43%) and the median total nucleated cell dose at freezing was 4.02×107/kg. Most pts received CBU with one (30%, n=74) or two (56%, n=136) HLA disparities. A myeloablative (MAC) conditioning was given to 177 pts (70%) and 73 (30%) received a reduced intensity conditioning (RIC). Overall 2-year leukemia- free survival (LFS) was 36±3%; 37% for Ph- and 35% for Ph+ pts (p=0.74). On multivariate analysis, 3 factors were associated with improved LFS: age <44 years (HR: 0.6, p=0.004), CR1 at transplant (HR: 0.6, p=0.005) and use of RIC (HR: 0.6, p=0.015). Since the outcomes were different according to disease status and conditioning intensity, a subgroup analysis was performed. Results are shown in Table 1.In pts transplanted with MAC (n=177), most frequent conditioning regimens were Cy-TBI (27%) and Bu+Flu+Thio (25%). Median follow-up (FU) was 26 and 35 months for those in CR1 (n=107) and CR2 (n=70), respectively. Cumulative incidence (CI) of 60-day neutrophil recovery was 87% for pts in CR1 and 83% for those in CR2; acute GVHD was 43% and 37%, respectively. Two-year CI of NRM was 41% for CR1 and 49% for CR2 and 2-year RI was 24% for CR1 and 22% for CR2. Two-year LFS was 35% for CR1 and 30% for CR2. No factor was found to be associated with LFS, relapse nor NRM. One-hundred and four pts died, 81 of transplant-related causes (79%, n=46 for CR1 and 74% n=35, for CR2), mainly due to infections (53% n=24 for CR1 and 38% n=12 for CR2).In pts transplanted with RIC (n=94), Cy+Flu+TBI regimen was used in 74% (n=54). Median FU was 31 and 34 months and median age was 50 and 39 years for those in CR1 (n=49) and CR2 (n=24), respectively. At 2 years, CI of NRM was 22% for CR1 and 17% for CR2. Two-year RI was 30% and 47%, respectively. Two-year LFS was 49% for CR1 and 36% for CR2. For pts in CR1, univariate analysis showed that younger age (< 50 years) was associated with improved LFS (62% × 36%, p=0.042) and lower NRM. Eighteen patients died, 6 of relapse and 12 of transplant-related causes. All patients who died from NRM were 50 years or older.UCBT is an option to treat high risk and relapsed adult ALL. Pts transplanted with MAC had an LFS comparable with that reported with other stem cell sources, but strategies to reduce toxicity are still needed, especially for pts in CR2. Results with RIC are encouraging and may be considered in younger pts. Importantly, in this large series outcomes after UCBT for Ph+ ALL were not statistically different from those compared to Ph-.Table 1Outcomes according to disease status at UCBT and conditioning regimenMACRICCR1 (n=107)CR2 (n=70)CR1 (n=49)CR2 (n=24)LFS (2y)35 ± 5%30 ± 6%49 ± 7%36 ± 10%Relapse (2y)24 ± 4%22 ± 5%30 ± 7%47 ± 11%NRM (2y)41 ± 5%49 ± 6%22 ± 6%17 ± 8% Disclosures:No relevant conflicts of interest to declare.

Outcomes After Double Cord Blood Transplantation Compared to Single Cord Blood Transplantation in Adults with Acute Leukemia Given a Reduced Intensity Conditioning Regimen

AbstractAbstract 232▪▪This icon denotes a clinically relevant abstractUnrelated cord blood (UCB) is an alternative source of allogeneic hematopoietic stem cell transplantation (HSCT) for adults with acute leukemia lacking a HLA matched donor. Double cord blood unit (dUCBT) has been increasingly used over single CB unit (sUCBT) after reduced intensity conditioning regimen (RIC). Since there is an increased relapse incidence (RI) using RIC-HSCT compared to myeloablative conditioning regimen, we have driven the hypothesis that RI may be decreased and leukemia-free survival (LFS) rate increased after dUCBT compared to sUCBT, due to probably increased graft-versus leukemia (GVL) effect. With this aim, we analyzed 360 adults (>18 years) with ALL (n= 77) or AML (n=238) in CR1 (n=212) and in CR2 (n=148) transplanted with a sUCBT (n=131) or a dUCBT (n=229) after a RIC. Only patients transplanted with a single unit containing more than 2.5×107/kg total nucleated cells (TNC) were included. Patients were transplanted from 2005–2011 in EBMT centers. Comparing the two groups of patients receiving a sUCBT or a dUCBT in CR1, there were no statistical differences according to age, diagnosis (AML or ALL), weight, CMV serostatus, cytogenetics risk, number of HLA incompatibilities. However, dUCBT were performed more recently (2009 vs 2008), the time from CR1 to transplantation was longer (142 days vs 121 days), more frequently transplanted with CY+FLU+TBI2Gy (87% vs 68%), lower frequency of ATG use (21% vs 35%) and finally, dUCBT recipients received higher number of TNC collected (5×107/kg vs 3.9×107/kg) or infused (4×107/kg vs 3.1×107/kg). Median follow-up was 23 months in both groups.Cumulative incidence (CI) of 60 days neutrophil recovery was 82±3% after dUCBT and 76±2% after sUCBT (p=0.86) and frequency of full donor chimerism at day 100, was not statistically different between dUCBT (81%) and sUCBT (86%). At day 100, CI of acute GVHD (grade II-IV) was 35% in both groups, however there was a trend of increased incidence of grade III-IV after sUCBT (19%) compared to dUCBT (10%, p=0.06) but increased incidence of grade II aGVHD after dUCBT (28%) compared to 17% after sUCBT (p=0.05). CI of chronic GvHD at 2 years was 21±4% after dUCBT and it was 12±5% after sUCBT (p=0.15). At 2 years, CI of non relapse mortality (NRM) after dUCBT was 28±4% and it was 30±6% after sUCBT (p=0.87). However, CI of 2y relapse was 21±4% after dUCBT whereas it was 38±2% after sUCBT (p=0.03). In a multivariate analysis adjusting for the differences between the 2 groups, dUCBT was associated with lower incidence of relapse compared to sUCBT (HR=0.74, p=0.01). Therefore, there was an improved 2-y LFS after dUCBT (51±5%) compared to sUCBT (32±3%; p=0.03). This was confirmed in a multivariate analysis (HR=0.64, p=0.04).Concerning patients transplanted in CR2 (n=148), there were no statistically differences of outcomes after dUCBT (n=93) or sUCBT (n=55). At 2y, LFS was 40±6% after dUCBT and 48±3% after sUCBT (p=0.32). In a subgroup analysis of dUCBT (n=118) and sUCBT (n=51) recipients using the same conditioning regimen (CY+FLU+TBI2Gy), 2 y LFS were 54±5% and 33±7% respectively (p=0.05). Conclusion:In this retrospective comparative based registry analysis, in AL patients transplanted in CR1, neutrophil recovery, GVHD and NRM were not statistically different after RIC-dUCBT or RIC-sUCBT, however, dUCBT recipients had decreased relapse incidence and improved LFS. For AL patients transplanted in CR2, there was no benefit of using dUCBT when compared to sUCBT recipients. Disclosures:No relevant conflicts of interest to declare.

Higher HHV-6 Reactivation After Cord Blood Allo-SCT Is Not Related to HHV-6 Cell Receptor CD46 Expression

AbstractAbstract 1931 Introduction:Cord Blood (CB) are increasingly used as an alternative stem cells source in adults for allogeneic Stem Cell Transplantation (allo-SCT). The risk of human herpes virus (HHV-6) reactivation is significantly higher after CB transplant vs unrelated peripheral blood stem cells (PBSC) allo-SCT (Chevallier et al, BMT 2010). Higher HHV-6 cell receptor CD46 expression on progenitor cells in CB may explain this difference (Thulke et al, Virol J 2006). Patients and Methods:We have prospectively compared the HHV-6 cell receptor CD46 expression on various cell subsets of three freshly harvested blood sources on one hand and of three graft sources on the other hand. 52 samples were used for the purpose of this study. They were issued from peripheral blood (PB, n=10), G-CSF mobilised PB (GCSF-PB, n=10), cord blood (CB, n=10), unmanipulated bone marrow (uBM, n=5), leukapheresis product (LP, n=10) and thawed CB graft (n=7). CD46 expression was assessed by FACS analysis using a FACS CANTO II (BD Biosciences, San Jose, CA, USA) on total lymphocytes, monocytes, NK cells, T and B cells subsets, plasmacytoid (pDCs) dendritic cells and stem cells. Results:As all cell subsets were found CD46 positive, CD46 mean fluorescence intensity (MFI) was then considered for comparison. When considering the three blood sources, CD46 MFI were found similar on T cells, CD4-/CD8+ and CD4-/CD8- T cells, NKT cells, Tregs, memory B lymphocytes, pDCs and CD34+ stem cells. CD46 MFI was significantly lower on CD4+/CD8- and CD4+/CD8+ T cells, transitional B cells, total and naïve B lymphocytes, and NK cells in CB while higher on monocytes. The highest CD46 MFI was observed on monocytes in CB and on CD4+/CD8+ T cells in GCSF-PB and PB. Also, highest CD46 MFI was detected on T cells compared to B lymphocytes and NK cells in all blood sources while CD46 MFI was higher on CD4+/CD8- T cells compared to CD8+/CD4- T cells.When considering the three graft sources, CD46 MFI was similar on CD4-/CD8- T cells and NKT cells. CD46 MFI was found significantly lower on all other sub-populations in thawed CB graft, except monocytes. The highest CD46 MFI was observed on monocytes in CB graft, on CD4+/CD8+ T cells in LP and on monocytes and on CD4+/CD8- T cells in uBM. Also, highest CD46 MFI was detected on T cells compared to B lymphocytes and NK cells in all graft sources while CD46 MFI was higher on CD4+/CD8- T cells compared to CD8+/CD4- T cells. Conclusion:This original study shows strong differences in term of quantitative CD46 expression between several blood and grafts samples. Our results suggest that other factors (such as another HHV-6 cell surface receptor) than the qualitative CD46 expression play a role in the higher HHV-6 reactivation observed after CB transplant in adults. Disclosures:No relevant conflicts of interest to declare.

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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.

A Clinical Study on Double-Unit Umbilical Cord Blood Transplantation in Adults with Hematologic Disease

Abstract 4486 Objective:In this study, we explored the efficiency and toxicity of 46 cases of double-unit 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 46 patients tolerated the therapy well while four patients had graft failure. Severe acute GVHD was presented in 6 patients. Chronic GVHD was occurred in 18 patients. Fatal infection complications were occurred in 7 patients (including CMV idiopathic pneumonia in 2 patients) and 5 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 29 months on median, the expected 3-year relapse mortality was 16.7%; non-relapse mortality was 26.1%; overall survival was 57.7%, and disease free survival was 48.2%. 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.