Double Cord Blood Transplantation Research Articles

Second Allogeneic Transplant with Cord Blood for Treatment of Failed First Allogeneic Transplant Due to Primary Graft Failure or Disease Recurrence

▪Background: For patients with graft failure or disease relapse following allogeneic hematopoietic cell transplant (HCT), a second HCT may be lifesaving. Prior studies have shown a survival advantage of this approach over non-HCT treatment options, although data remains limited. In the setting of a failed first allogeneic transplant, cord blood (CB) as the donor source for the second HCT provides the important advantage of prompt availability of donor cells without risk to the donor during cell procurement. In the event of second HCT to treat disease relapse, CB offers the ability to use highly mismatched grafts with the potential of enhancing the graft versus leukemia effect. Herein, we report the outcomes of patients undergoing second HCT with CB grafts after relapse or graft failure following their first allogeneic HCT.Methods: Twenty-three patients median age 33 yrs (range 4-69 yrs) received a CB transplant (CBT) as a second allogeneic HCT at the Fred Hutchinson Cancer Research Center between 2006 – 2013 for MDS/AML (n = 12), ALL (n =8), Hodgkin Lymphoma (n = 2) and DLBCL (n = 1). Eight patients received their initial transplant from an HLA-matched sibling, 6 from a matched and 2 from a mismatched unrelated donor, 4 from a haploidentical donor and 3 patients had a prior double CBT (dCBT). Primary indications for a second allograft were relapse (n = 19), graft failure (n = 3) and donor derived MDS (n = 1). Conditioning regimens for the first HCT were myeloablative (MAC) in 15 patients and nonmyeloablative (NMA) in 8 patients. Median time between first and second transplant was 505 days (range, 55 - 3515). At the time of second HCT, 19 patients were in CR (5 with minimal residual disease) and 4 patients had persistent disease. For their second transplant, patients were conditioned with NMA or MAC regimens based on their age, history of prior TBI and clinically determined comorbidity score. Ten patients received NMA conditioning with fludarabine (Flu) 200mg/m2, cyclophosphamide (Cy) 50 mg/kg and 200-400 cGy TBI and 13 patients received MAC conditioning with either treosulfan 42mg/kg, Flu 150-200mg/m2 and TBI 200 cGy (n = 11) or Flu 75mg/m2, Cy 120mg/kg and 1200 - 1320cGy TBI (n = 2). All patients received GVHD prophylaxis with cyclosporine and mycophenolate mofeteil. Twenty of the 23 patients received a dCBT with a median TNC of 4.8 x 107 cells/kg and a post-thaw median CD34+ of 2.2 x 105 cells/kg. 91% of UCB grafts were 1-2 HLA antigen mismatched with the recipient.Results: Median time to engraftment was 22 days (range day 6 - 49) among 21 evaluable patients; 2 patients died prior to engraftment. Median time to platelet engraftment was 55 days (range 23 - 83). Death prior to day 100 was seen in 5 patients (infection/organ failure (n=3), encephalopathy (n =1), and relapse (n =1). Acute grade II-IV and III-IV GVHD was diagnosed in 18 of 21 and 6 of 21 evaluable patients respectively, and 9 of 16 evaluable patients developed chronic GVHD (6 mild, 2 moderate, 1 severe). At a median follow-up of 356 days (range among survivors 176 - 1876), the cumulative incidence of 1-year disease free survival (DFS) for all patients was 65% (CI 95%: 42-84) with patients receiving MAC vs NMA demonstrating significantly different results: 84% (51-95) vs 40% (12-79) (p=0.011), respectively. Overall one-yearnon-relapse mortality (NRM) was 22% (95% CI: 8-40): 15% (3-39) in the MAC group vs. 30% (7-58) in the NMA group (p=0.32). Relapse at 1 yearwas 21% (95% CI: 8-40), with no relapses in the MAC group compared to 30% in the NMA group (7-57) (p =0.034).Conclusions: Our results demonstrate quite favorable outcomes in patients undergoing CBT as a second allogeneic HCT, with a one year DFS of 65%. The outcomes were particularly good for patients undergoing MAC CBT in which there were no relapses and the one-year DFS was 84%. This small study supports the use of CB as a donor source for second allogeneic HCT in the treatment of primary graft failure or disease recurrence after a first HCT. The use of CB as the stem cell source is particularly attractive in this setting as it eliminates the need to put a conventional donor at risk. While MAC may be preferable based on this limited data set, one must weigh the risk of the added toxicity of this approach and select conditioning regimens based on each patient’s pre-transplant disease and comorbidities. DisclosuresNo relevant conflicts of interest to declare.

Comorbidity Index in the Context of Cord Blood Transplantation: An Accurate Predictor of Treatment Related Mortality?

Background: The hematopoietic cell transplantation comorbidity index (HCT-CI) has been demonstrated to be a useful tool for evaluating the risk of treatment related mortality (TRM) in HLA-matched sibling (MRD) and matched unrelated donor (URD) bone marrow (BM) and peripheral blood stem cell transplant (PBSCT) patients (Sorror et al 2005). In recent years, umbilical cord blood transplant (CBT) has emerged as a common treatment for hematologic malignancy patients without a suitably matched conventional BM or PBSCT donor and patients who require a rapidly available donor. However, the initial analysis evaluating the use of the HCT-CI did not include CBT patients. Therefore, the value of this risk assessment tool as it applies to risk of TRM in the CBT setting is not known. Reduced intensity conditioning (RIC) CBT is often reserved for older adults and those with high comorbidities due to concern for excessive TRM with myeloablative regimens. In this retrospective analysis, we sought to evaluate the association of HCT-CI scores with TRM in patients undergoing RIC UCBT.Methods: Charts were reviewed and HCT-CI scores tabulated for 143 patients (80 male, 63 female), median age 54 years (5-73), who were sequentially enrolled on two multicenter CBT studies coordinated by the Fred Hutchinson Cancer Research Center (FHCRC) between 2006 - 2013. Patients were transplanted for high risk (n = 68) and standard risk (n = 75) AML/MDS (n =91), ALL (n = 22), Non-Hodgkin Lymphomas (n = 12), CML (n = 3), Hodgkin Lymphoma (n =3), and other hematologic malignancies (n = 12). 77 patients received RIC with cyclophosphamide 50mg/kg, fludarabine 200mg/m2, and either 200 or 300 cGy TBI, while the remaining 66 received a “midi” regimen of treosulfan 42g/m2, fludarabine 150-200mg/m2, and 200 cGy TBI. All patients received cyclosporine and mycophenolate mofeteil for GVHD prophylaxis. Only seven patients received a single CBT, and the remaining 136 received a double CBT. The incidence of TRM was estimated by using cumulative incidence methods, with relapse considered a competing risk.Results: Median HCT-CI for the whole group (n =143) was 2 (range 0 - 8) with distribution as follows: (HCT-CI = 0 (n = 25), HCT-CI = 1 (n = 15), HCT-CI = 2 (n = 34), HCT-CI = 3 (n = 34), HCT-CI = 4 (n = 16), HCT-CI = 5 (n = 9), HCT-CI = 6 (n = 8), HCT-CI = 7 (n = 2), and HCT-CI = 8 (n = 1). TRM for the group as a whole was 7% (95% CI: 3-12) at Day 100 and 32% (95% CI: 24-42) at 1 year. When divided into 2 groups by HCT-CI score ≤ 3 (n = 107) and >3 (n = 36), demographics were similar with the exception of younger age in the HCT-CI ≤ 3 group (52 vs. 57 years; p = 0.02) and more CMV seropositive patients in the HCT-CI ≤ 3 group (73 vs. 50%; p = 0.01). The incidence of TRM at 1-year was 25% (CI 95%: 16-35) vs. 58% (CI 95%: 35-75) in the HCT-CI ≤ 3 vs > 3 groups respectively (p=0.001). The hazard of TRM in the HCT-CI > 3 group was higher than that in the HCT-CI ≤ 3 group after adjusting for age, CMV serostatus, gender, disease risk, and conditioning regimen (HR=2.31; 95% CI 1.13-4.7; p=0.021). At Day 100 there was a trend for higher incidence of TRM in patients with HCT-CI > 3 = 14% (CI 95%: 5-27) vs HCT-CI ≤ 3 = 5% (CI 95%: 2-9) (p=0.08). Successful engraftment occurred in 92% of patients (n = 131) at a median of 19 (6-89) days. Of the 126 patients evaluable, 17 developed grade III-IV acute GVHD. OS for the whole group at 1 year was 55% (CI 95%: 45-63): patients with HCT-CI ≤ 3 = 62% (52-72) vs. > 3 = 32% (16-48) (p = 0.0016).Conclusions: This analysis demonstrates that higher HCT-CI score is associated with increased risk of TRM at 1 year post-transplant in a series of patients undergoing RIC UCBT. Due to the significant risk of TRM in patients with HCT-CI > 3 compared to those with HCT-CI ≤ 3, patients with a HCT-CI score >3 should be counseled regarding their heightened risk of TRM prior to undergoing CBT. DisclosuresNo relevant conflicts of interest to declare.

OR32: GETTING OUT OF THE PANIC MODE: MATERNAL BLOOD CONTAMINATION IN A CORD BLOOD UNIT FOR DOUBLE CORD HEMATOPOIETIC CELL TRANSPLANTATION

Aim A patient with severe aplastic anemia was scheduled for double cord blood transplant. However the confirmatory typing results revealed the detection of extra class II alleles for one of the cord blood unit (CBU). The aim of our study was to determine if a typing error had occurred or if there was maternal blood contamination. If there was maternal contamination, would there be a risk of GVHD? Should the transplant physicians cancel the scheduled transplant and identify a different CBU?. Method Reverse SSO at HLA-A, B, C, DRB1 and DQB1 loci, SSP and sequencing based typing (SBT) at HLA-DRB1 locus were performed. Chimerism testing was also performed using multiplexed short tandem repeat (STR) to determine the percentage of maternal blood contamination. Results Confirmatory typing at DRB1 by SBT for one of the CBUs was found to be discrepant with NMDP consensus results: DRB1∗04:03, 04:07; our results: DRB1∗01:01, 04:03, 04:07, with HLA-A and B results by SSO being concordant with NMDP. Further allele specific DRB1∗04 SSP testing confirmed the presence of DRB1∗04:03, 04:07. Class II SSO typing indicated the presence of DRB1∗01and DQB1∗05, consistent with DRB1∗01:01 by SBT. Due to the identification of an extra antigen for one of the CBUs, the hematopoietic cell transplant physician canceled the pretransplant work-up and requested further investigation. The back-up segment of this problematic cord, maternal sample and HLA typing were requested through NMDP coordinators. Maternal HLA typing was found to be DRB1∗ 01:01, 04:07. No extra antigens were detected for this CBU at HLA-A and B loci by SSO method, possibly due to the decreased sensitivity of this method. STR test was performed on maternal blood and CBU. The STR results indicated approximately 5% maternal blood contamination in the CBU. The NMDP physician was consulted and indicated that maternal contamination adds no additional GVHD risk because the maternal cells should be all dead. The transplant was performed. The patient is currently doing well with 90 day posttransplant follow up indicating 99.5% engraftment. Conclusion NMDP sources estimate approximately 1% of cord units have maternal blood contamination, and expect a 1–5% chimerism result by STR analysis. The contamination from maternal blood does not appear to increase the risk for GVHD.

Clinical study of unrelated umbilical cord blood transplantation for 25 patients with hematological diseases

This study was purposed to investigate the engraftment, graft-versus-host disease (GVHD), transplantation related mortality (TRM), relapse and survival in hematologic patients received unrelated umbilical cord blood transplantation (UCBT). A total of 25 patients with hematological disease underwent UCBT, including 8 pediatric and 17 young adult patients. Among them 3 cases received single unit of UCBT and 22 cases received double units of UCBT. For donor/recipients human leukocyte antigen (HLA) matching: HLA 6/6 loci matched in 9 cases, HLA 4-5/6 loci matched in 16 cases. There were 19 patients with hematologic malignancies, including 3 cases in the period of disease progression and 6 cases of non-hematologic malignancies. Conditioning regimens were TBI/Cy ± Flu ± ATG or BuCy ± Flu ± ATG for 21 patients and Cy+Flu+ATG for 4 patients. For prophylaxis of acute graft-versus-host disease (aGVHD) the regimen of cyclosporine (CsA) as dominant drug was used. The results showed that among 16 patients (80.0%) achieved engraftment, 20 patients survived for more than 42 d after transplantation. The cumulative neutrophil recovery rate on day 42 after transplant was 64.0%, with a median time of 17.0 d;the cumulative platelet recovery rate on day 100 after transplant was 60.0 %, with a median time of 35.0 d. The cumulative rate of grade II-IV and III-IV aGVHD after transplantation 100 d was 44.0% and 30.7%, respectively. Until the end of the follow-up, the cumulative rate of TRM was 54.3%. For all the patients, overall survival rate was 42.7%. Out of 17 evaluable patients with hematologic malignancies 7 cases (41.2%) survived to date, and only 1 case relapsed, so event-free survival rate was 35.3%. Out of 5 evaluable patients with non-hematologic malignancies, 4 patients survived and 2 patients were in stable engraftment state, 2 cases with autologous hematopoietic recovery. Among 3 cases of hematologic malignancies at advanced stage, only 1 case survived to date. It is concluded that HLA-4-6/6 loci matched UCBT is an effective option to treat hematological diseases. Double cord blood transplantation (dUCBT) can overcome the disadvantage of insufficient cells of single cord blood UCBT to treat overweight children and adult.

Low rate of infusional toxicity after expanded cord blood transplantation

Background aimsUmbilical cord blood (CB) is used with increasing frequency to restore hematopoiesis in patients with bone marrow transplant who lack a suitable human leukocyte antigen–matched donor. CB transplantation is limited by low cell doses and delays in neutrophil and platelet engraftment. CB progenitors expanded ex vivo before transplantation provide more rapid hematopoietic and immune reconstitution as well as less engraftment failure compared with unmanipulated CB. However, the safety of infusing double and ex vivo–expanded CB has not been systematically examined. MethodsWe reviewed the immediate adverse events (AE) associated with the infusion of CB occurring within 24 hours in 137 patients enrolled in clinical CB transplant trials at the MD Anderson Cancer Center from February 2004 to May 2010. All patients received an unmanipulated CB unit followed by infusion of a second unmanipulated CB unit or a second CB unit expanded ex vivo with the use of cytokines in a liquid culture system or in mesenchymal stromal cell co-cultures. ResultsA total of three grade 2 and two grade 3 infusion reactions occurred within 24 hours of CB transplantation. This resulted in an AE rate of 3.7%. The majority of AEs manifested as signs of hypertension. No association with patient age, sex, disease status, premedication, ABO compatibility or total infusion volume was observed. In summary, the incidence of infusion-related toxicities in patients who receive unmanipulated and ex vivo–expanded double CB transplantation is low. ConclusionsWe conclude that the infusion of unmanipulated followed by expanded CB products is a safe procedure associated with a low probability of inducing severe reactions.

Maintenance of Naïve T Cells and a Diverse TCR Repertoire Are Critical for Reconstitution of EBV-Specific Immunity after Double Cord Blood Transplantation

Maintenance of Naïve T Cells and a Diverse TCR Repertoire Are Critical for Reconstitution of EBV-Specific Immunity after Double Cord Blood Transplantation

Outcomes of Double Unit Umbilical Cord Blood Transplantation Using Fludarabine/Busulfan Based Reduced Intensity Conditioning Regimen

Outcomes of Double Unit Umbilical Cord Blood Transplantation Using Fludarabine/Busulfan Based Reduced Intensity Conditioning Regimen

Double Unit Umbilical Cord Blood Transplant for Adults with Acute Leukemia and Myelodysplastic Syndrome Results in Comparable Outcome As Matched Sibling or Unrelated Donor Transplant Only after Myeloablative Conditioning but Not Reduced Intensity Conditio

Double Unit Umbilical Cord Blood Transplant for Adults with Acute Leukemia and Myelodysplastic Syndrome Results in Comparable Outcome As Matched Sibling or Unrelated Donor Transplant Only after Myeloablative Conditioning but Not Reduced Intensity Conditio

Hemophagocytic Lymphohistiocytosis in Infants: A Single Center Experience from India

There is paucity of outcome data for hemophagocytic lymphohistiocytosis (HLH) in infants from India, especially post stem cell transplant (SCT). We report outcome data of eight infants diagnosed with HLH. Mean age was 7.1 months (range 2–11). Mutation analysis was possible in seven patients. One patient had Griscelli syndrome. In three patients, no known mutation could be identified, while in remaining three homozygous mutations in Perforin, Munc and STX11 gene were identified. All were treated as per HLH 2004 protocol. Four died during induction phase. One patient abandoned therapy. Two underwent SCT, while one is awaiting SCT. First patient is alive and disease-free at 22 months postmatched sibling donor SCT. Second underwent unrelated double cord blood transplant, but died 5 months posttransplant due to renal failure. It is feasible to offer SCT for infants with familial HLH in the developing world although barriers like sepsis and disease refractoriness remain.

Factors Affecting Unit Predominance In Double Umbilical Cord Blood Transplantation

BackgroundUmbilical cord blood transplantation is seen as an alternative source of hematopoietic support for patients who lack suitable HLA-matched donors. Disadvantages of this method include the relatively low cellularity, late engraftment and consequently restrictive use to pediatric patients, due to the low number of hematopoietic progenitors. Transplantation of two cord blood units has been seen as a strategy to overcome the low yield, often leading to the long-term establishment of hematopoiesis supported by a single cord blood unit. Predictive factors of the predominant unit are still unclear. Total nucleated cell count, CD34+, CD3+ dose were independent factors associated with unit predominance, although this is still a controversial issue. MethodsThis retrospective study included 21 patients with hematologic malignancies and immunodeficiencies who underwent double unit cord blood transplantation. We analysed HLA mismatch, ABO group, total nucleated cell count (TNC), CD34+ dose and post-thaw viability and their correlation with the prevalent unit. Transplantations were performed from 2007 to 2013. Six patients were excluded due to incomplete information and another three died before engraftment. ResultsMedian NC and CD34+ doses were similar between engrafted and non-engrafted units. Nine transplantations (60%) resulted in engraftment of the higher TNC unit. TNC dose in the predominant units varied between 2.02-3.05x107/kg (median dose: 2.651x107/kg), and in the non-engrafted units between 1.69x107/kg-4.39x107/kg (median dose: 2.44x107/kg), which was not statistically significant (p= 0.65). Sixty percent of the transplantations (9 patients) also resulted in engraftment of the unit with higher CD 34+ (median dose: 2.05x106/kg), compared to 40% (6 patients) in which the lower dose unit prevailed (median dose: 1.95 x106), also not statistically significant (p= 0.861). As for ABO, 26% of the units were ABO matched with the recipient, while the majority was HLA mismatched (93%). ConclusionMultiple factors related to the unit and patient influence UCB predominance. In the sample studied, no particular variant played a specific role, probably due to the limited sample size. Current evidence suggests that immunologic-related mechanisms (CD34+ and CD3+ dose) are involved, yet further studies are necessary for a better understanding of which factors lead to unit engraftment. Disclosures:No relevant conflicts of interest to declare.

Early Multilineage Chimerism Predicts The ‘Winning' Unit In Double Cord Blood Transplantation

BackgroundUmbilical cord blood (UCB) is an established alternative haemopoietic cell source for use in clinical transplantation for life-threatening malignant and non-malignant disorders. One challenge in using UCB in adolescents and adults has been delayed engraftment due to the finite and limited cell dose of a single unit, which has been shown to be a key determinant of engraftment, transplant related mortality and survival. The use of double unit transplantation, pioneered at the University of Minnesota, has become one of the most successful approaches to overcome this limitation to date. This group have also developed a reduced intensity conditioning (RIC) regimen, successfully broadening access to UCB transplant to older patients and those with co-morbidities. The kinetics of granulocyte, T cell and B cell chimerism in this setting require detailed study. MethodsSince 2009, the British Society of Blood and Marrow Transplantation have conducted a prospective, phase II study of UCB transplantation using the Minnesota RIC conditioning regimen (Fludarabine 200mg/m2, Cyclophosphamide 50mg/kg and TBI 2Gy), with Ciclosporin and Mycophenolate Mofetil graft versus host disease prophylaxis. Lineage specific chimerism was performed at days 7, 14, 21, 28, 35, 60, 100, 180, 360 and 720 post transplant and analysed at laboratories associated with participating centres. Results28 consecutive adult trial patients who have received a double unit transplant, have engrafted and have chimerism data up to at least day 35 are included in this analysis. The ‘winning' unit had a median unit:recipient match of 4/6 (range 4-6/6), with a median pre freeze total nucleated cell (TNC) count of 189x107 (range 83-250) and CD34 of 84x105 (range 23-169). The ‘losing' unit had a median unit:recipient match of 5/6 (range 4-6/6), with a median pre freeze total nucleated cell (TNC) count of 183x107 (range 127-303) and CD34 of 55x105 (range 42-95). Despite the low white count early post transplant, peripheral blood (PB) lineage specific chimerism for mononuclear cells (PBMC), T cells and granulocytes was feasible in nearly all patients. B cell chimerism was unsuccessful or not available in 55% of time points. The pattern of early T cell and granulocyte chimerism is summarised in the table.From day 60 onwards, the median granulocyte and T cell chimerism remained 100% winning unit. However, T cell chimerism at day 14 identified the winning unit in all patients with a result at this time point (n=25). Contribution to the B cell compartment was 100% winning unit by day 35, with 83% recipient at day 7 and 24% at day 14 and 4% losing unit at day 7 and 14. ConclusionsLineage specific chimerism is technically feasible in the immediate post transplant period and gives important insights into the kinetics of double cord blood unit engraftment. Although the ‘losing' unit may contribute to the B and T cell compartments in the first 2 weeks, it contributes little after day 21. The winning unit is clearly identifiable by day 14 in all lineages. Early granulocyte recovery (driven by G-CSF) in the RIC setting is seen to be primarily due to autologous recovery until around day 21 after which the winning unit predominates. These data provide an insight into the biology of engraftment that may also inform additional novel strategies such as ex vivo CD34 expansion and adding in haploidentical stem cells. Disclosures:No relevant conflicts of interest to declare.Table% Median contribution (range)Day post transplantRecipientWinning unitLosing unitT CELLS770 (22-94)23 (0-73)5 (0-41)144 (0-30)87 (29-100)0 (0-38)210 (0-35)100 (52-100)0 (0-34)280 (0-24)100 (32-100)0 (0-44)350 (0-3)100 (58-100)0 (0-42)600 (0-4)100 (91-100)0 (0-8)GRANULOCYTES7100 (84-100)0 (0-16)0 (0-10)1455 (1-100)28 (0-99)0 (0-20)210 (0-99)80 (0-100)0 (0-25)280 (0-54)99 (15-100)0 (0-6)350 (0-27)99 (21-100)0 (0-16)600 (0-8)100 (40-100)0 (0-52)

Compare The Outcome Of Patients With Hematological Malignancies Treated With Allogeneic Stem Cell Transplant In Patients Age Over 50 Conditioned With Reduce Intensity Regimens With Those Under 50 Conditioned With Standard Intensity Regimen In a Rural University Hospital – A Single Institution Experience

BackgroundMajority of hematological malignancies occurs in older individuals and most can only be cured with high dose chemotherapy followed by stem cell transplantation. Unfortunately these patients who need transplantation the most cannot tolerate chemotherapy well. Development of reduced-intensity transplant regimens has allowed older patients be treated with allogeneic transplantation. AimsTo compare the outcome of allogeneic hematopoietic stem cell transplantation in patients age over 50 conditioned with reduce dose intensity regimens with those under 50 conditioned with standard dose intensity regimen MethodsWe analyzed retrospectively the data in a cohort of 50 consecutive patients with hematological malignancies treated with allogeneic stem cell transplant. We divided the patients into two groups, those under 50 years and those over 50 years. Those under 50 years received standard dose conditioning regimen, while those over 50 years received reduced dose regimen except for one patient. Cyclosporine and standard dose methotrexate was used as GVHD prophylaxis in patients under 50yrs while Cyclosporine and low dose methotrexate was used in patients over 50. Type of hematological malignancies, disease condition at transplant, type of transplant, conditioning regimen, dose of CD34+ stem cell and nucleated cell infused, day to myeloid and platelet engraftment and day 90 mortality is shown in the table. Patients who received unrelated donor transplant received ATG. Five high risk patients received peri-transplant Keratinocyte Growth Factor. All patients received G-CSF beginning day-0.Patients < 50 years oldPatients > 50 years oldNumber of Patients3020Age18 to 46 years (Median 31 yrs)50 to 69 years (Median 57.5 yrs)Indication for transplantAcute Leukemia & MDS (18), Aplastic Anemia (3), Chronic Leukemia (4), Lymphoma (5)Acute Leukemia & MDS (14), Myelofibrosis (1), Chronic Leukemia (1), Lymphoma (4)Type of transplanta) Sibling - 13b) MUD – 13 (43%)c) Cord Blood/Double Cord- 2/2a) Sibling - 13b) MUD – 6 (30%)c) Double Cord blood - 1Disease Status at Transplanta) Remission - 14b) Active – 15 (50%)c) Unknown - 1a) Remission - 5b) Active – 14 (70%)c) Unknown - 1Conditioning RegimenBu/CTX (11), Bu/Flu (9), CTX/TBI (2), ATG/CTX (2) Melphalan Containing Regimen (6).Mel/Flu (9), Bu/Flu (8), CTX/TBI (1), Bu/CTX (I), Mel/Thio (1).Dose of CD34+ hematopoietic stem cell infusedRange 0.12 x106 to 15.83 x 106 cells/kg (median 3.15 x 106 cells/kg).Range 1.51 x106 to 9.08 x 106 cells/kg (median 4.21 x 106 cells/kg).Dose of Nucleated cell infusedRange 0.22 x 108to 41.46 x 108 cells/kg (median 9.37 x 108nucleated cells/kg).Range 5.19 x 108to 18.32 x 108 cells/kg (median 9.08 108nucleated cells/kg).Day of Myeloid EngraftmentRange 10-30 days. Median 14 daysRange 9 to 21 days. Median 14 daysDay of Platelet Engraftment Range (Median day)Range 10 -42 days. (Median 16 days)Range 10-68 days. (Median 18 days)Engraftment Failure2 Patients (both received cord blood)0 PatientsEarly mortality (day 90)9/30 Patients (30%)9/20 Patients (45%) Results43% of patient < 50 years of age underwent match unrelated donor transplant vs. 30% in those over 50. Four underwent cord blood transplant in patient < 50 yrs. old vs. one in those over 50. 50% of patients had active disease in < 50 years group vs. 70% in those over 50. All but two patients (underwent cord blood transplantation <50 years of age) engrafted. Four patients died prior to engraftment in each group. Myeloid engraftment occurred at a median day 14 in each group. Platelet engraftment occurred at median day 16 in patients age under 50 years vs. day 18 in patients over 50. One patient with double cord blood transplant had platelet engraftment on day +68 (age >50). Two patients who received cord blood under 50 years group had engraftment failure. Ninety day mortality was 30% in those under 50 vs. 45% in those over 50. ConclusionsReduced intensity allogeneic stem cell transplantation is feasible and well tolerated in older patients with hematological malignancies with good engraftment however with high early (day 90) mortality. 70% of the patients had active disease at the time of transplant which could account for their high mortality. To prevent early peri-transplant mortality patients with active disease should not go to transplant or should be treated with newer chemotherapy or targeted agents to bring them into remission prior to transplantation Disclosures:No relevant conflicts of interest to declare.

Prostaglandin E2 enhances long-term repopulation but does not permanently alter inherent stem cell competitiveness

AbstractHematopoietic stem cell (HSC) transplantation is a lifesaving therapy for malignant and nonmalignant hematologic diseases and metabolic disorders. Although successful, hematopoietic transplantation can be hindered by inadequate stem cell number or poor engrafting efficiency. To overcome these deficits, we and others have previously reported the HSC-enhancing ability of a short-term exposure of prostaglandin E2 (PGE2); this strategy has now progressed to phase 1 clinical trials in double cord blood transplantation. To further analyze the short- and long-term effects of HSC exposure to PGE2, we followed the repopulation kinetics of PGE2-treated hematopoietic grafts through 5 serial transplantations and compared inherent long-term competitiveness in a HSC head-to-head secondary transplantation model. Treatment with PGE2 did not result in a long-term increase in HSC competitiveness, lineage bias, or enhanced proliferative potential, demonstrating that pulse exposure to PGE2 results in transient increases in HSC homing and engraftment potential.

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.

Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors

Allogeneic hematopoietic cell transplantation has an established role in the treatment of adults with acute lymphoblastic leukemia whose survival when recipients of grafts from adult unrelated donors approaches that of recipients of grafts from sibling donors. Our aim was to determine the role of mismatched unrelated cord blood grafts in transplantation for 802 adults with acute lymphoblastic leukemia in first or second complete remission. Using Cox regression we compared outcomes after 116 mismatched single or double cord blood transplants, 546 peripheral blood progenitor cell transplants and 140 bone marrow transplants. The characteristics of the recipients and their diseases were similar except cord blood recipients were younger, more likely to be non-Caucasians and more likely to have a low white blood cell count at diagnosis. There were differences in donor-recipient human leukocyte antigen-match depending on the source of the graft. Most adult donor transplants were matched at the allele-level considering human leukocyte antigens-A, -B, -C and -DRB1. In contrast, most cord blood transplants were mismatched and considered antigen-level matching; 57% were mismatched at two loci and 29% at one locus whereas only 29% of adult donor transplants were mismatched at one locus and none at two loci. There were no differences in the 3-year probabilities of survival between recipients of cord blood (44%), matched adult donor (44%) and mismatched adult donor (43%) transplants. Cord blood transplants engrafted slower and were associated with less grade 2-4 acute but similar chronic graft-versus-host disease, relapse, and transplant-related mortality. The survival of cord blood graft recipients was similar to that of recipients of matched or mismatched unrelated adult donor grafts and so cord blood should be considered a valid alternative source of stem cells for adults with acute lymphoblastic leukemia in the absence of a matched unrelated adult donor.

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.

Persistence of both cords nine months post double cord blood transplantation for juvenile myelomonocytic leukaemia

Persistence of both cords nine months post double cord blood transplantation for juvenile myelomonocytic leukaemia

Characteristics of chronic GVHD after cord blood transplantation

Most reports of chronic GVHD after cord blood transplantation (CBT) have utilized traditional diagnostic criteria. We used traditional criteria and National Institutes of Health (NIH) criteria prospectively to evaluate chronic GVHD in a cohort of 87 adult and pediatric recipients of single or double unrelated CBT for treatment of hematologic malignancies. Fifty-four patients developed traditionally defined chronic GVHD, for an estimated 2-year probability of 64%. Among 54 patients, 25 (46%) met the NIH criteria for persistent, recurrent or late acute GVHD at onset. Twenty-four (44%) had overlap chronic GVHD, including one who presented initially with late acute GVHD, and only seven (13%) had classic chronic GVHD, including one who also presented initially with late acute GVHD. Among patients who successfully discontinued all systemic immunosuppression (SI), the median time to discontinuation of corticosteroid treatment was 315 days (range 28-977), and the median time to discontinuation of all SI was 353 days (range 67-977). Chronic GVHD diagnosed by traditional criteria after CBT had a predominance of acute GVHD clinical features.

Graft-versus-Host-Disease after Double Cord Blood Transplantation: A New Look at Its Characteristics

Umbilical cord blood transplantation (UCBT) has become a widely available and accepted alternative stem cell source for pediatric and adult patients with malignant and nonmalignant hematologic diseases [1-4]. Over the last several years, multiple studies have reported lower rates of graft-versus-host disease (GVHD), both grade III-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD), in UCBT recipients compared with recipients of unrelated donor peripheral blood or bone marrow hematopoietic cell transplantation (HCT) [5-7]. However, the more recent decreased use of antithymocyte globulin as part of the conditioning regimen, the almost uniform use of combination cyclosporine and mycophenolate mofetil therapy for GVHD prophylaxis, and the increased use of 2 cord blood units (versus 1 unit) warrant a reevaluation of the incidence of aGVHD and cGVHD after UCBT. Furthermore, the rate of cGVHD reported after UCBT in the previous studies was determined using the traditional clinical diagnostic criteria (limited versus extensive), without taking in consideration the 2005 National Institutes of Health (NIH) consensus criteria [8]. Ponce et al. [9] conducted a single-center study in 115 pediatric and adult patients with hematologic malignancies who underwent double UCBT (dUCBT) to assess the incidence and manifestations of both aGVHD and cGVHD. The authors reported an incidence of grade II-IV acute GVHD of 53% at day þ180, which was similar to the rate previously reported by MacMillan et al. [5]. However, the data of Ponce et al. identify the gastrointestinal (GI) tract, not the skin, as the most commonly affected organ, with GI involvement in 80% of patients with grade II-IV aGVHD. This finding confirms previously reported results in a cohort of 79 pediatric UCBT recipients [10]. The propensity of isolated GI aGVHD reinforces the importance of using endoscopic biopsy for diagnosis when symptoms are limited to this single organ system.

Mesenchymal stromal cell supported umbilical cord blood ex vivo expansion enhances regulatory T cells and reduces graft versus host disease

Double cord blood transplantation (DCBT) may shorten neutrophil and platelet recovery times compared with standard umbilical cord blood transplantation. However, DCBT may be associated with a higher incidence of graft versus host disease (GVHD). In this study, we explored the effect of ex vivo expansion of a single cord blood unit (CBU) in a DCBT setting on GVHD and engraftment. Post-thaw cryopreserved CBUs from cord blood banks, hereinafter termed "banked" CBUs, were co-cultured with confluent bone marrow mesenchymal stromal cells (MSCs) supplemented with a cytokine cocktail comprising 100 ng/mL stem cell factor, 50 ng/mL flt3-ligand, 100 ng/mL thrombopoietin and 20 ng/mL insulin-like growth factor binding protein 2 for 12 days. When DCBT of one unexpanded and one expanded CBU was performed in non-obese diabetic/severe combined immunodeficient-IL2Rgamma(null) (NOD/SCID-IL2γ(-/-), NSG) mice, the expanded CBU significantly boosted in vivo hematopoiesis of the unexpanded CBU. The median survival of NSG mice was significantly improved from 63.4% (range, 60.0-66.7%) for mice receiving only unexpanded units to 86.5% (range, 80.0-92.9%) for mice receiving an expanded unit (P < 0.001). The difference in survival appeared to be due to a lower incidence of GVHD in the mice receiving expanded cells. This effect on GVHD was mediated by a significant increase in regulatory T cells seen in the presence of MSC co-culture. MSC-supported ex vivo expansion of "banked" CBU boosted unexpanded CBU hematopoiesis in vivo, increased regulatory T cell content and decreased the incidence of GVHD.