Unrelated Cord Blood Transplantation Recipients Research Articles

Unrelated cord blood transplantation vs. HLA-matched sibling transplantation for adults with B-cell acute lymphoblastic leukemia in complete remission: superior OS for patients with long-term survival

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for adult acute lymphoblastic leukemia (ALL). For patients who lack a human leukocyte antigen (HLA)-matched sibling donor, unrelated cord blood (UCB) is an alternative graft option. Previous studies have focused mainly on all T- and B-cell ALL (B-ALL) patients, while data related specifically to adult B-ALL patients after UCB transplantation (UCBT) are scarce.MethodsWe retrospectively compared the outcomes of UCBT and HLA-matched sibling transplantation (MST) in the treatment of adult B-ALL patients in complete remission (CR) at our center. From June 2006 to December 2020, 156 adult B-ALL patients who achieved CR before transplantation were enrolled. The main clinical outcomes of UCBT and MST were analyzed.ResultsHematopoietic recovery was significantly faster in MST recipients than in UCBT recipients. Higher incidences of grades II-IV and III-IV acute graft-versus host disease (aGVHD) were found in UCBT recipients (P < 0.001 and = 0.03), while a lower incidence of extensive chronic GVHD (cGVHD) was found in UCBT recipients (P < 0.001). The cumulative incidences of 2-year non-relapse mortality (NRM), 2-year relapse, 5-year disease-free survival (DFS) and 5-year GVHD-free relapse-free survival (GRFS) were comparable between MST and UCBT recipients. The overall survival (OS) during the first 700 days was similar between the MST and UCBT groups, while the OS of patients with a survival time of more than 700 days in the UCBT group was better than that in the MST group according to multivariate analysis (P = 0.03).ConclusionsOur study shows that when treating adult B-ALL patients in CR, UCBT can achieve comparable effects as MST, may provide superior OS for patients with long-term survival, and should be considered a good alternative.

Frequent Eczematous Dermatitis in Unrelated Cord Blood Hematopoietic Cell Transplant Recipients Compared With Other Donor Types

We have consistently noticed in our clinical practice eczematous dermatitis (EcD) without other pathologic findings of graft-versus-host disease (GVHD) in recipients of unrelated cord blood transplantation (CBT). We hypothesized that the incidence of EcD was higher in CBT compared with other donor types, and our objective in this study was to compare the frequency, clinical course, and response to therapy of EcD between CBT and non-CBT recipients. We conducted a retrospective study of 720 consecutive adult recipients of allogeneic hematopoietic cell transplants from 2010 to 2016 from any donor type and with follow-up for at least 1 year after transplantation. After using keyword-based automated scanning to identify "eczema," "dermatitis," or "spongiosis" terms in medical records, we retrieved 217 cases for manual record review. We identified 23 EcD cases (12 in CBT recipients and 11 in patients with other types of donors) with a median onset at 8 months after transplantation. The 2-year cumulative incidence of EcD was 20% (95% confidence interval [CI], 11.2% to 31.5%) after CBT and 1.7% (95% CI, .90% to 2.90%) with other types of donors (P < .0001). Fifteen cases had a skin biopsy without distinctive pathologic features of GVHD. The most common EcD-involved sites in CBT recipients were face (75%), neck (50%), and antecubital fossae (50%). Compared with patients with other types of donors, EcD after CBT was more likely to involve three or more sites (10 of 12 vs. 2 of 10; P=.008) and had a more protracted course (lasting >6 months in 6 of 58 vs. 1 of 661; P < .0001). In both groups, EcD responded to topical therapy, and only a few cases required systemic therapy. EcD is a relatively frequent skin condition among recipients of unrelated CBT. Irrespective of donor type, most cases of EcD can be successfully managed with only topical therapy. These findings will help providers recognize EcD, avoid potentially harmful systemic therapy, and better counsel transplant recipients.

Prognostic Value of Refined Disease Risk Index (rDRI) and Conditioning Regimen in Adult Patients Receiving Unrelated Cord Blood Transplantation (UCBT) for Haematological Malignancies - 15-Year Follow-up of Multicenter Study in Singapore

Introduction: Umbilical cord blood (UCB) is an established stem cell source for transplantation in patients with hematological diseases who lack suitable related or unrelated donors. Refined Disease Risk Index (rDRI) is a prognostic tool used in hematopoietic cell transplant (HCT), solely based on disease type and status. Its value in patients undergoing UCB transplants (UCBT) with different conditioning regime intensity is unclear. We sought to evaluate the predictive value of rDRI in patients undergoing UCBT. Methods: We performed a retrospective analysis of 107 adult patients with various hematological malignancies who underwent 4-6/6 HLA-matched UCBT using single unit UCB (n=14) or double unit UCB (n=93) between Aug 2006 and Nov 2019 at 2 academic tertiary hospitals in Singapore. Patients received pre-transplant conditioning with either myeloablative conditioning (MAC, n=63) regimen consisting of Fludarabine (Flu) 75mg/m2, Cyclophosphamide (Cy) 120mg/kg and total body irradiation (TBI) 12- 13.2Gy , intensified reduced intensity conditioning (i-RIC, N=22) regimen consisting of Flu 150 mg/m2, Cy 50mg/kg, thiotepa 10mg/kg and TBI 4 Gy, or nonmyeloablative conditioning (NM, n=22) regimen, consisting of Flu 200 mg/m2, Cy 50mg/kg and TBI 2 Gy. The median total nucleated cell dose infused was 5.07 x 107/kg (range, 2.61 to 11.5) Results: Median follow-up was 84 months (range, 6 to 167 months).. Kaplan-Meier estimates of overall (OS) and event-free (EFS) survival at 10 years were 40 % (95% CI, 31-50) and 37% (95% CI, 28-47) respectively. At 2 years, cumulative incidence (CI) of relapse-related mortality (RRM) and non-relapse mortality (NRM) were 27% (95% CI, 18-35) and 35 % (95% CI, 25-45), respectively. In multivariate analysis (MVA), rDRI showed significant correlation with OS (HR 2.41; 95% CI 1.41-4.11; p=0.001), EFS (HR 2.54; 95% CI 1.51-4.28; p=0.0004) and RRM (HR 2.71; 95% 1.36-5.41; p=0.005). Conditioning regimen intensity was found to have significant impact on NRM (p=0.047) and RRM (p=0.002) in MVA. When patients were further stratified into 4 risk groups incorporating both rDRI and conditioning regimen intensity, significant differences in OS (p=0.002) and EFS (p=0.001) were seen. 5-year OS (Figure 1) in patients receiving MAC/i-RIC and NM conditioning with low-intermediate risk rDRI were 52% and 36% respectively, compared with 24% and 13% in patients with high-very high risk rDRI (p=0.002). The corresponding ES were 50%, 29%, 20%, and 13%, respectively (Figure2). Conclusions: Our results confirm that rDRI has good predictive value for relapse and survival in UCBT recipients. Conditioning regime intensity was also found to have a significant impact on patient outcomes when evaluated together with rDRI. Prognostic scoring systems in HSCT are revised constantly with further studies needed to potentially incorporate the intensity of the conditioning regime into the rDRI. Outcomes in rDRI high risk patients remain poor and further studies are needed to define the best strategy that can induce sustained engraftment without increasing risk of relapse and toxicity death. Disclosures No relevant conflicts of interest to declare.

A longitudinal analysis of TCRβ repertoire diversity in immune tolerance of pediatric patients post-UCBT: T cell clonal deletion over clonal anergy

Abstract The mechanisms of long term immune tolerance after successful hematopoietic stem cell transplantation are not fully elucidated. We set up serial experiments to test central and peripheral mechanisms sustaining tolerance after HLA-mismatched unrelated cord blood transplant (UCBT) in the GvH direction. TCRβ ImmunoSEQ® (Adaptive Biotechnology®) was applied for tracking and characterizing host-reactive T cell clones from graft or patient samples. Seven UCBT recipients with non-malignant diseases were studied. All patients enrolled on the same reduced intensity conditioning trial (NCT01852370). Patients achieved tolerance if discontinued immunosuppression, exhibited immunocompetence without GvHD or graft rejection. Purified T cells responses to host APCs were measured by mixed lymphocyte reaction, cytokine bioplex, and micro CTL assays. T cells clones expanding &amp;gt;0.1% frequency in response to host APC were tracked and characterized with TCRβ ImmunoSEQ®. ImmunoSEQ® revealed the disappearance of host-reactive clones that expanded from an aliquot of the infused cord blood graft by 7 days of stimulation with purified host APC. Most of these allo-reactive T cell clones were not identifiable even in the presence of IL2 supplementation to break anergy. Serial experiments post-UCBT revealed novel host-reactive clones that were not identifiable within the alloreactive pool of the graft pre-UCBT. In summary, the acquisition of immune tolerance in the GvH direction post-UCBT is characterized by hypo-reactivity in all assays employed towards host APC. The disappearances of most host-specific clones in the graft indicate that deletion is a major mechanism of long term tolerance with possibly a small degree of anergy in contribution.

The Optimal Alternative Donor Transplant for Pediatric Patients with Acute Leukemia: A Comparison between Alfa-Beta T-Cell and B-Cell Depleted Haplo-SCT and UCBT

▪Children with acute leukemia (AL) in need of an allograft and lacking an HLA-identical sibling and an HLA-matched unrelated donor, could benefit either from unrelated cord blood transplantation (UCBT) or T-cell depleted haploidentical (haplo) stem cell transplantation (SCT).Different techniques of T-cell depletion have been developed for improving immune reconstitution and for enhancing the graft-versus-leukemia (GvL) effect. Locatelli et al. (Blood 2017) reported remarkable results for children with AL given haplo-SCT after a novel method of graft manipulation based on selective, negative depletion of alfa-beta T and B cells.On behalf of Eurocord, CTIWP, and PDWP of EBMT, we compared outcomes of patients < 18 years with AL undergoing either single-UCBT (n=444) or haplo-SCT after alfa-beta T-cell and B-cell-depletion (n=99) from 2012 to 2016 using a myeloablative conditioning regimen (MAC).Median age at SCT was 6 (range 0.3-18) and 8 (range 0.6-18) years, and median follow-up was 36 and 14 months (p<0.05) for UCBT and haplo-SCT recipients, respectively. Compared to UCBT, haplo-SCT were performed more recently (median year 2016 vs 2012, p<0.05). Acute lymphoblastic leukemia (ALL) was the most frequent diagnosis (62% versus 55%), while 38% and 45% of patients had acute myeloid leukemia (AML) in the UCBT and haplo-SCT group, respectively. Cytogenetics was mainly at intermediate risk for UCBT (54%) and haplo-SCT (73%, p<0.05); 49% and 54% of patients were in CR1 at time of the allograft in UCBT and haplo-SCT group, respectively (p=0.45). In vivo T-cell depletion with ATG was more frequently adopted in haplo-SCT recipients (90% versus 81%, p=0.05). For UCBT recipients, HLA compatibility was 6/6 matched for 19% of patients, 5/6 for 58% and 4/6 for 23%. Cord blood graft contained a median TNC count at cryopreservation of 7.02x10e7/Kg (range 2.63-43) and at infusion of 5.3x10e7/Kg (range 0.3-39).Conditioning regimen varied according to the type of transplant: for haplo-SCT recipients Fludarabine+TBI (28%) and Thiotepa+Busulfan+fludarabine (TBF) (24%) were the most frequent MAC. In UCBT, Busulfan+Cyclophosphamide (Cy), or Cy+Fludarabine+TBI or TBF were used in 19%, 15% and 13% of patients, respectively.Haplo-SCT recipients did not receive any additional pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis, while CyclosporineA (CSA)+ steroids and CSA+mycophenolate mofetil were used in 38% and 32% of UCBT recipients.The 60-day probability of neutrophil engraftment was 91% vs 93% (p<0.05) for UCBT and haplo-SCT. The cumulative incidence (CI) of grade II-IV and grade III-IV acute (a) GvHD was 38% vs 12% (p<0.05) and 17% vs 4% (p<0.05) in UCBT and haplo-SCT recipients, respectively. The 2-year CI of relapse (RI) was similar following from UCBT and haplo-SCT (22% vs 25%, p=0.75), as well as non-relapse mortality (NRM) (18% vs 10%, p=0.07), respectively. Disease recurrence was the most common causes of death in both groups, with infections and GvHD being the most frequent transplant-related fatalities.According to donor type, no differences were found in overall survival (OS) (65% vs 68%, p=0.17) and leukemia-free survival (LFS) (61% vs 65%, p=0.24), while a lower GvHD-free, relapse-free survival (GRFS) was observed in UCBT compared to haplo-SCT (49% vs 60%, p<0.05). OS was 67% and 58% for patients with AML and ALL respectively, p=0.11.In multivariate analysis, UCBT was associated with higher risk of NRM (HR 2.36, p<0.05), while RI was not associated with type of allograft. Higher risk of grade II-IV aGVHD was observed in UCBT (HR 2.81, p<0.05), with no difference for cGVHD among the two groups (HR 0.68, p=0.31). OS (HR 1.52, p=0.10) and LFS (HR 1.28, p=0.28) were comparable between UCBT and haplo-SCT, while GRFS resulted lower for UCBT (HR 1.58, p<0.05). No others factors were associated with outcomes.Our results showed that RI, LFS, OS and cGVHD were comparable between UCBT and haplo-SCT recipients, while better NRM, aGVHD and GRFS were observed in patients transplanted from a family donor. These data confirm that alfa-beta T-cell and B-cell depleted haplo-SCT is a valid alternative for patients in need of an urgent allograft. Costs of manipulation in the haplo-SCT setting and costs of cord blood procurement should be further investigated. Technical expertise with this refined approach of graft manipulation and center experience are important to optimize patient's outcome. DisclosuresLocatelli:Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Bader:Medac: Patents & Royalties, Research Funding; Cellgene: Consultancy; Neovii: Research Funding; Riemser: Research Funding; Novartis: Consultancy, Speakers Bureau.

Outcomes after Unrelated Cord Blood Transplantation (UCBT) in Patients with Chronic Myeloid Leukemia (CML): A Retrospective Study from the Cmwp-EBMT

The introduction of tyrosine kinase inhibitors (TKIs) to treat chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT continue to be recommended for patients progressing to a more advanced phase of the disease and those in first chronic phase (CP1) failing second and third generation TKIs. Although the role of allogeneic HSCT using matched related or unrelated donor remains well established in the post-TKI era, controversies exist in transplant using alternative donors, and data in this setting is scarce.Umbilical cord blood (UCB) can be used as an alternative stem cell source for patients in whom allogeneic HSCT is indicated, but lack an appropriate human leucocyte antigen (HLA)-matched adult donor. The advantages of UCBT include rapid availability, absence of donor risk, and the relatively lower risk of GVHD with preserved graft versus leukemia effect.Because of the lack of large studies on the outcome of UCBT for CML patients in the TKI era, we performed a retrospective analysis to identify risk factors for outcomes after unrelated cord blood transplants in adults with CML.Through the EBMT database, 150 CML patients were identified as UCBT recipients. Median year of UCBT was 2008 (range, 2000 to 2015) with a median follow up of 62.2 months (range, 3 to 203.1 months). Median age at the time of transplant was 40.4 years (range, 18.8 to 66.5) with a male to female ratio of 92/58. The median time from CML diagnosis to UCBT was 29.9 months (range, 3.4 to 273.6) with first (Q1) and third (Q3) quartile at 12.4 and 57.3 months respectively. Eleven patients received an UCBT as a second allogeneic HSCT. Conditioning regimen was of reduced intensity (RIC) in 44 patients while 92 received a myeloablative conditioning (MAC), and 61 out of 128 evaluable patients received T-cell depletion.Disease status at the time of transplant was first chronic phase (CP1, n=45), second or third chronic phase (CP2 and CP3, n=48) or advanced phase (accelerated phase or blastic phase, AP/BP, n=55).Overall survival (OS) at 12, 24 and 36 months were 52.1% (95% CI 44.0 to 60.1%), 44.5% (95% CI 36.3 to 52.6 %) and 41.2% (95% CI 33.0% to 49.4%) respectively. Median time to neutrophil and platelet engraftment were 23 and 47 days respectively in 119 patients who engrafted, while 24 and 7 patients experienced primary (16%) or secondary (4.6%) graft failure respectively.At 24 months, the cumulative incidence of non-relapse mortality (NRM) and relapse were 38.9% (95% CI 31.0 to 46.9%) and 25.3% (95% CI 18.2% to 32.3%), while cumulative incidence of grade 2-4 acute GvHD was 34.3% (95% CI 26.1 to 42.5%) and 24 months cumulative incidence of chronic GvHD was 24.8% (95% CI 15.6 to 34.0%).OS and disease-free survival (DFS) were significantly reduced for patients in AP/BP at the time of transplant compared to patients in CP1 or CP2/CP3 (24 months OS, 27.1% vs 55.3% and 53.7%, p=0.0026; 24 months DFS, 21.5% vs 39.4% and 47.1% respectively, p=0.0059, Figure 1). Cumulative incidence of relapse was significantly increased in patients in AP/BP at the time of HSCT compared to patient in CP1 or CP2/3 (24 months relapse incidence of 37.6% vs 20.6% and 17.1% respectively, p=0.0178).There was no significant difference in OS and DFS in patients receiving RIC compared to MAC (24 months OS 47.1 and 48.1% respectively, p=0.8; 24 months DFS 33% vs 40.6%, p=0.36). Cumulative incidence of relapse at 24 months was 34.7% in RIC and 24.6% in MAC, although this was not statistically significant (p=0.14).In conclusion, UCBT is more effective in CML patients who are in first CP but also in those who are in second or third CP at the time of transplant. NRM remains high, possibly related to differences in practices of UCBT over time and between centers. Comparison with alternative graft source such as haploidentical HSCT is needed, although little data is available in this setting.Patients who are in advanced phase disease at the time of transplant have a dismal prognosis comparable to those who receive an allogeneic HSCT from HLA-matched adult donors, although pre and post-transplant intervention with 3rd generation TKI may help improve outcome of these patients.Finally the use of RIC regimen for UCBT is an alternative for patients who cannot tolerate a MAC regimen; further analysis will help identify patients who would benefit from this approach. [Display omitted] DisclosuresDe Lavallade:Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Angelucci:Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

Comparison of unrelated cord blood transplantation and HLA-identical sibling peripheral blood stem cell transplantation for the treatment of adult hematological malignancies

目的比较单份清髓非血缘脐血移植（UCBT）与HLA相合同胞外周血干细胞移植（PBSCT）治疗成人恶性血液病的疗效。方法自2011年4月1日至2015年12月31日，共81例单份清髓UCBT与57例HLA相合同胞PBSCT患者入组进行比较。所有患者均采用清髓性预处理方案，环孢素A联合霉酚酸酯预防移植物抗宿主病（GVHD）。结果移植后42 d（+42 d）UCBT组中性粒细胞累积植入率为95.0%（95%CI 87.0%~98.1%），同胞PBSCT组为100%（P=0.863）。+100 d UCBT组血小板累积植入率低于同胞PBSCT组[87.3%（95%CI 76.8%~93.1%）对98.2%（95%CI 87.3%~99.7%），P=0.005]。+100 d UCBT组Ⅱ~Ⅳ度急性GVHD、Ⅲ/Ⅳ度急性GVHD的累积发生率分别为18.2%（95%CI 9.1%~26.4%）、10.4%（95%CI 3.3%~16.9%），同胞PBSCT组分别为8.9%（95%CI 1.1%~16.1%）、7.1%（95%CI 1.4%~13.7%），差异均无统计学意义（P=0.142，P=0.521）。UCBT组3年慢性GVHD、广泛型慢性GVHD累积发生率均低于同胞PBSCT组[14.9%（95%CI 5.2%~23.5%）对35.2%（95%CI 19.4%~47.8%），P=0.008；11.2%（95%CI 2.9%~18.7%）对31.4%（95%CI 16.2%~43.9%），P=0.009]。UCBT组、同胞PBSCT组3年移植相关死亡率（TRM）差异无统计学意义[30.1%（95%CI 19.2%~41.7%）对23.2%（95%CI 13.1%~35.0%），P=0.464]。UCBT组3年疾病复发率低于同胞PBSCT组[12.9%（95%CI 6.6%~21.5%）对24.3%（95%CI 13.5%~36.8%），P=0.039]。UCBT、同胞PBSCT组3年总生存率、无病生存率差异均无统计学意义[58.6%（95%CI 45.4%~69.7%）对54.8%（95%CI 39.9%~67.4%），P=0.634；57.0%（95%CI 44.0%~68.0%）对52.4%（95%CI 38.2%~64.9%），P=0.563]。UCBT组3年无GVHD及复发生存（GRFS）率高于同胞PBSCT组[55.7%（95%CI 44.1%~65.8%）对42.9%（95%CI 29.8%~55.3%），P=0.047]。结论对于成人恶性血液病，UCBT与HLA相合同胞PBSCT具有相似的急性GVHD发生率、TRM、总生存率和无病生存率，但UCBT组具有较低的慢性GVHD发生率及疾病复发率。

UCBT Using Myeloablative Conditioning Regimen without ATG Has Similar Survival but Better Life Quality Compared with Upbsct for Adults with Primary Acute Leukemia-a Multicenter Study in China

ObjectiveData regarding the outcome of unrelated cord-blood transplantation (UCBT) with myeloablative conditioning regimen without ATG comparing with unrelated peripheral blood stem cell transplantation (UPBSCT) for adults with primary acute leukemia.MethodsFrom Jan 2010 to Dec 2014, 175 consecutive adult patients with primary acute leukemia (AL), who had no HLA-compatible related donors who were eligible for a single UCBT (79 patients) or UPBSCT (96 patients). The two groups all received a TBI/CY2 and BU/CY2 based myeloablative conditioning regimen which plus fludarabine (FLU), etoposide (VP-16) or cytarabine (Ara-c). The GVHD prophylaxis regimens of UCBT were cyclosporine A (CsA) and mycophenolate mofetil (MMF) and UPBSCT were CsA, Methotrexate (MTX) and antithymocyte globulin (ATG).ResultsThere was no significant difference for the patients characteristics between the UCBT and UPBSCT group except for UCBT patients were younger. Although the UCBT patients received lower doses of nucleated and CD34 positive cells and more patients were HLA mismatched, the two groups acquired the similar percentage of hematopoiesis engraftment rate (97.4% vs 100%, p=0.497) but the granulocyte and platelet recovery was slower in UCBT group. The incidence of bacterial or invasive fungal infection in the UCBT group and the UPBSCT group had no significant difference (46.8% vs 52.6%, P=0.572) may be attributed to the omission of ATG in UCBT group. TRM by three years was 21.0% and 16.9% in the UCBT and UPBSCT cohorts (P=0.46). The 3-year cumulative incidence of relapse was similar between the UCBT group and the UPBSCT group (26.3% vs 27.1%, P=0.75). The grade II to IV acute graft-versus-host disease (aGVHD) and severe aGVHD (grades III and IV) incidence was similar between the two groups (24.7% vs 33.0%, P=0.40), (13.3% vs 8.7%, P=0.28)]. Compared with the UPBSCT cohort, the UCBT cohort had a significantly lower rate of chronic graft-versus-host disease (cGVHD) (20.7% vs 44.0%, p=0.003) or extensive cGVHD (5.6% versus 17.5%, P=0.04). The overall survival (63.2% vs 64.1%, P=0.996) and leukemia free survival (57.5% vs 59.8%, P=0.824) had no significant difference between the two groups. The performance status observed in patients surviving 3 years was measured using the Karnofsky performance score. The UCBT recipients had obviously higher activity scores than UPBSCT recipients (94.5% vs 83.5%, p=0.03).ConclusionWhen use intensive myeloablative conditioning regimen without ATG, UCBT can reach similar survival with UPBSCT and may have better life quality. Primary acute leukemia patients who lack an HLA-matched sibling donor can select UCBT or the UPBSCT of equal status. DisclosuresNo relevant conflicts of interest to declare.

The Impact of Donor Age on Outcome after Unrelated Bone Marrow Transplantation: Comparison with Unrelated Cord Blood Transplantation

Background: Donor selection is one of key factors for better outcomes after hematopoietic stem cell transplantation (HSCT). It is shown that increased donor age is associated with high mortality. In the era of high-resolution typing of HLA and various methodological options in HSCT (e.g. conditioning regimens or cell source), however, the significance of donor age in the selection of donor or cell source is unclear. Here we examined the impact of donor age on clinical outcome after unrelated bone marrow transplantation (UBMT) and compared to the outcome after unrelated cord blood transplantation (UCBT).Patients and methods: For this retrospective cohort study, clinical data of donors and recipients were obtained from the registry data of the Japan Society of Hematopoietic Cell Transplantation (JSHCT). This study included 6035 adult patients 16 years of age or older with AML, MDS, ALL, or CML who received the first HSCT between 2000 and 2010. Among them, 3304 recipients received UBMT from 8/8 HLA-matched or 7/8 HLA-matched for HLA-A, -B, -C, and -DRB1 allele-level donor and 2731 recipients received single-unit UCBT from maximum 2-antigen (HLA-A, -B, -DR antigen-level) mismatched donor. Risk factors for overall mortality and other endpoints were analyzed using Cox proportional hazards models and Fine and Gray's proportional hazards models, respectively.Results: The median ages of UBMT and UCBT recipients were 42 years (range, 16-77) and 50 years (range, 16-82), respectively. The median age of UBMT donor was 34 years (range, 20-55). Among 3304 UBMT recipients, older donor age (≥40 years) was a significant risk factor for overall mortality (adjusted HR, 1.14; 95% CI, 1.03-1.27, p=0.015) and grades II-IV acute graft-versus-host disease (aGVHD) (adjusted HR, 1.27; 95% CI, 1.13-1.43, p<0.001) after adjusting for other significant factors in the multivariable model. Similar results were obtained using donor age as a continuous variable (overall mortality: adjusted HR, 1.01; 95% CI, 1.00-1.02, p=0.007, aGVHD: adjusted HR, 1.02; 95% CI, 1.01-1.03, p<0.001). The effect of donor age on overall mortality was strongly detected in patients with the standard risk disease (interaction p=0.058) or recipients from 7/8 HLA-matched donor (interaction p=0.078). Therefore, we compared outcomes of the five groups including UCBT by donor types (8/8 matched younger donor, 8/8 matched older donor, 7/8 matched younger donor, 7/8 matched older donor and cord blood) only among the standard risk group (Figure). Survival in recipients from 8/8 matched older donor was similar to that in recipients from 7/8 matched younger donor (adjusted HR, 1.03; 95% CI, 0.83-1.28, p=0.790). In recipients from 7/8 matched older donor, the survival was comparable to that in recipients of cord blood (adjusted HR, 0.91; 95% CI, 0.73-1.13, p=0.398).Conclusions: The outcome of HSCT recipients with older donor (≥40 years) was worse compared with that of recipients with younger donor, especially in the standard risk group or HLA-mismatched donors. A 7/8 matched younger donor is a viable option as well as an 8/8 matched older donor in the absence of an 8/8 matched younger donor. In addition, UCBT is a reasonable option in the absence of these donors. Intensive GVHD prophylaxis in recipients with older donor might improve outcome, but further studies are needed to test this hypothesis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Unrelated Cord Blood Versus Non-T Cell Depleted Haploidentical Stem Cell Transplantation: Comparable Results in Adults with Acute Leukemia, a Eurocord and ALWP-EBMT Study

Unrelated cord blood transplantation (UCBT) and related Haploidentical non T-cell depleted stem cell transplantation (Haplo) are alternative options to treat patients with high risk acute leukemia. Both techniques have shown encouraging results.The current retrospective analysis aimed to compare the outcomes of both approaches in adults with ALL and AML receiving either UCBT (n=928) or Haplo (n=518) reported to EBMT centres between 2007 and 2011.Diagnosis was ALL for 716 patients (Haplo=158 and UCBT=558) and AML for 730 (Haplo=360, UCBT=370). Haplo grafts were not T-cell depleted, with 236 patients receiving unmanipulated bone marrow (BM), 253 receiving peripheral blood stem cells (PBSC) and 29 receiving BM+PBSC. For UCBT, 431 patients were treated with a single unit, while 497 received double unit UCBT.Compared with recipients of UCBT, Haplo recipients were more likely to have AML (69% versus 40%, p=<0.001), and were transplanted more recently (2011 versus 2009, p=0.001), had a longer median interval from CR1 to transplant (139 versus 126 days, p=0.07), and had more frequently advanced phase of disease at time of transplant (35% versus 17%, p=0.001).Median follow-up was 19 months and 25 months, (p=0.007) for Haplo and UCBT, respectively. The type of conditioning regimen (MAC or RIC) was similar between both groups, with MAC representing 60% and 56% for Haplo and UCBT, respectively.For Haplo, the most frequently used regimens were Thiotepa-Busulfan-Fludarabine (TBF) for MAC and Treosulfan-based regimens for RIC. Graft versus host disease (GVHD) prophylaxis included CsA+MMF (41%), Sirolimus (15%), while 163 patients received post-transplant Cyclophosphamide (Cy). For UCBT cases, the most common MAC regimens were TBF for 33% of cases, CyFluTBI-12Gy for 27% and CyTBI12Gy for 17%. The most frequently used RIC was CyFluTBI-2Gy in 72% of the cases. GVHD prophylaxis was CsA+MMF in 70% of cases.In univariate analysis, cumulative incidence (CI) of neutrophil engraftment was 92% vs 84% (p=<0.001) for Haplo and UCBT; CI of acute GVHD was 27% vs 32% (p=0.11) and for chronic GVHD it was 30% vs 25% (p=0.06) for Haplo and UCBT. For non-relapse mortality (NRM), relapse incidence (RI) and leukemia-free survival (LFS) outcomes were analyzed separately according to disease status, and no statistically significant differences were observed between Haplo and UCBT.According to disease status, for patients in CR1 (n=610), 2 years RI was 27% versus 28%, p=0.67; NRM 26% versus 29%, p=0.30; and 2 years LFS 48% versus 43%, p=0.16; for Haplo and UCBT, respectively.For patients in CR2 (n=502), 2 years RI was 33% versus 28%, p=0.51; NRM 33% versus 33%, p=0.93; and 2 years LFS 34% versus 39%, p=0.61, for Haplo and UCBT, respectively.For patients in advanced disease status (n=334), 2 years LFS was 11% versus 14%, p=0.92 for Haplo and UCBT, respectively.Infections and GVHD were the most common causes of transplant-related deaths in both groups, (infection 30% in both groups, GVHD 15% and 9%, after Haplo and UCBT, respectively), and 40% of deaths were due to disease recurrence in both Haplo and UCB recipients.In multivariate analysis, UCBT was associated with lower incidence of chronic GVHD (HR= 0.62; p<0.001) and higher NRM (HR= 1.28; p=0.04) when compared to Haplo. No statistically significant differences were observed between Haplo and UCBT for RI (HR= 0.87; p=0.24) and LFS (HR= 1.06; p=0.47). Factors independently associated with lower LFS were disease status at transplant (HR 2.69, p=<0.001), and use of ATG (HR 1.28, p=0.001).In conclusion, in this retrospective analysis, non TCD Haplo and UCBT showed similar RI, NRM, and LFS, highlighting that both approaches are valid for this population of patients. Longer follow-up, more homogeneous transplant strategies (stem cell source, type of conditioning regimen and GVHD prophylaxis) are needed for further evaluation. While waiting for the results of the BMT CTN trial on non TCD Haplo using post-transplant Cy and double UCBT both in the RIC setting, the choice of the specific approach for Haplo or UCBT should be likely based on transplant centre expertise and policy. DisclosuresNo relevant conflicts of interest to declare.

Is There Any Effect of Killer Cell Immunoglobulin-like Receptor (KIR) on Outcomes after Single Unrelated Cord Blood Transplantation?

The effect of killer cell immunoglobulin-like receptor (KIR) ligand incompatibility on outcomes after unrelated cord blood transplantation (UCBT) has been controversial. Eurocord found that KIR ligand mismatching was associated with decreased relapse incidence (RI) and improved overall (OS) and leukemia-free survival (LFS) for patients with acute lymphoblastic leukemia (ALL) and for those with acute myeloid leukemia (AML). Recently, the Japanese registry found no association between KIR ligand matching and LFS or OS in 643 UCBT recipients with acute leukemia. However, both studies have analysed the KIR ligand matching effect using low resolution typing of HLA-A,-B,-C and HLA-DRB1 high resolution.With the aim to clarify the KIR effect on outcomes (mainly RI and OS) in a larger series of single-UCBT recipients in the era of HLA-allele typing, we have analysed 1098 patients with AML and ALL reported to Eurocord and CIBMTR. All patients received single UCBT and myeloablative conditioning regimen. HLA matching was defined using high resolution typing or imputation for HLA-A,-B,-C and DRB1. Patients and donors were categorized by their KIR-ligand expression for HLA C group 1 or 2 and Bw4 as KIR ligand matched or mismatched. Patients included in the earlier Eurocord analysis were excluded. Univariate and multivariate models were built to analyse the effect of KIR ligand matching on outcomes. Results: None of the 8/8 HLA-matched transplants were KIR ligand mismatched, therefore they were excluded. Since HLA-match and KIR ligand mismatch were confounded, we conducted 2 separate analyses: a) 6-7/8 HLA-matched (n=501) and b) 3-5/8 HLA-matched transplants (n=586). In the group of 6-7/8 HLA matched, 291 recipients (58%) were KIR ligand-matched and 210 (42%) were mismatched. There were no statistically significant differences, between these two groups for gender, age, CMV serostatus, type and remission disease status, cell dose, conditioning regimen, in vivo T-cell depletion, transplant period and follow-up (around 40 months). In the group of 3-5/8 HLA matched, 176 recipients (30%) were KIR ligand-matched and 410 (70%) were mismatched. In this HLA group (i.e 3-5/8), KIR ligand-matched patients were younger (<16y, p=0.02) compared to the KIR ligand-mismatched patients. Other characteristics were similar between the KIR ligand matched and mismatched groups. In multivariate models for outcomes in both HLA groups (6-7/8 HLA and 3-5/8 HLA), KIR-match status was not associated with non-relapse mortality (NRM), RI, LFS and OS. However, KIR ligand-mismatch was associated with lower risks of grade 2-4 acute GVHD for transplants that were 3-5/8, HLA-matched (Hazard ratio, HR= 0.63, p=0.001) but not for transplants that were 6-7/8 HLA-matched. KIR ligand-matching was not associated with chronic GVHD. The effect of KIR ligand-mismatching in the GVH direction, HVG direction and bi-directional were also examined and findings were consistent with the main analysis. Lower acute GVHD rates in the worst HLA-match group (3-5/8) with KIR ligand mismatch did not translate into a survival advantage when compared to similarly HLA-matched KIR ligand matched group. Disease-specific analysis were undertaken to further explore the effects of KIR ligand matching for ALL and AML separately. For patients with ALL, KIR match status was not associated with NRM, RI, LFS or OS in either HLA group. For patients with AML KIR ligand match status was not associated with any transplantation outcome after 6-7/8 HLA-matched transplants. However, KIR ligand mismatching was associated with higher NRM (HR1.94, p=0.02) and lower OS (HR 1.51, p=0.03) after 3-5/8 HLA-matched transplants. In conclusion, in the setting of 6-7/8 HLA-matched transplants KIR ligand match status was not associated with leukemia recurrence or survival. Our observation for AML, in the 3-5/8 HLA-matched group with KIR ligand mismatching is contradictory to the earlier Eurocord report. We hypothesize the observed differences may be attributable to better HLA-matching in the current analysis. Taken together, the data does not support selecting units based on KIR ligand match status as categorized in this analysis, when donor-recipient HLA-match considers allele-level HLA typing. It remains to be seen whether assignment of KIR ligand match status by genotyping will offer additional information. DisclosuresNo relevant conflicts of interest to declare.

Decreased Nonrelapse Mortality after Unrelated Cord Blood Transplantation for Acute Myeloid Leukemia Using Reduced-Intensity Conditioning: A Prospective Phase II Multicenter Trial

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m2). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 107/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (<3.4 × 107/kg; P = .001) were associated with increased NRM, and use of 2 or more induction courses to obtain CR1 was associated with increased relapse incidence (P = .04). Leukemia-free survival (LFS) at 2 years was 35%, and the only factor associated with decreased LFS was secondary AML (P = .04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high-risk AML. (EUDRACT 2006-005901-67).

Relative incidences and outcomes of Clostridium difficile infection following transplantation of unrelated cord blood, unrelated bone marrow, and related peripheral blood in adult patients: a single institute study.

Clostridium difficile is a major cause of nosocomial diarrhea. The incidence and prognosis of C. difficile-associated diarrhea (CDAD) has not yet been assessed in adult patients after unrelated cord blood transplantation (uCBT). The medical records of 135 adult unrelated cord blood transplant recipients were reviewed retrospectively to investigate the clinical features of CDAD after uCBT. These data were compared to medical records of 39 unrelated bone marrow transplant recipients and 27 related peripheral blood stem cell transplant recipients as controls. A total of 17 recipients developed CDAD, with onset occurring at a median of 22 days (range, 0-56 days) after transplantation. Among the unrelated cord blood transplant recipients, 11 (9%) developed CDAD. These results were comparable with those of CDAD after unrelated bone marrow transplantation (uBMT) (2/39, 6%) and related peripheral blood stem cell transplantation (rPBSCT) (4/27, 16%) (P=0.37). Fifteen of the infected recipients were successfully treated with oral metronidazole, vancomycin, or cessation of antibiotics. The remaining 2 recipients who developed CDAD after uCBT died of other causes. The development of CDAD did not negatively affect overall survival after uCBT. These data indicate that the incidence and prognosis of CDAD after uCBT are comparable with those after uBMT and rPBSCT.

Pre-Engraftment Syndrome after Unrelated Cord Blood Transplantation: A Predictor of Engraftment and Acute Graft-versus-Host Disease

Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 107/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity.

Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d'Histocompatibilite et d'Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis

Graft failure is a major complication after unrelated cord blood transplantation. Presence of HLA-antibodies before cord blood transplantation may impact graft failure. To analyze the effect of anti-HLA antibodies on unrelated cord blood transplantation outcomes, we analyzed 294 unrelated cord blood transplant recipients after reduced intensity conditioning regimen. The majority of the patients (82%) were transplanted for malignancies, 60% with double-unrelated cord blood transplant, 63% were HLA mismatched. Retrospectively, pre-unrelated cord blood transplant serum was tested for HLA-Ab using Luminex™ platform. Results were interpreted as mean fluorescence intensity (MFI) against donor-specific mismatch. Among 62 recipients (23%) who had anti-HLA antibodies before unrelated cord blood transplant, 14 patients had donor specific anti-HLA antibodies (DSA) (7 were donor-specific anti-HLA antibodies for single unrelated cord blood transplant and 7 for double unrelated cord blood transplant). Donor specific anti-HLA antibodies threshold ranged from 1620-17629 of mean fluorescence intensity (MFI). Cumulative incidence of Day-60 neutrophil engraftment was 76%: 44% for recipients with donor specific anti-HLA antibodies and 81% in those without donor specific anti-HLA antibodies (P=0.006). The cumulative incidence of 1-year transplant related mortality was 46% in patients with donor specific anti-HLA antibodies and 32% in those without antibodies (P=0.06). The presence of donor specific anti-HLA antibodies was associated with a trend for decreased survival rate (42% vs. 29%; P=0.07). Donor specific anti-HLA antibody in recipients of unrelated cord blood transplant is associated with graft failure and decreased survival. Patient's screening for donor specific anti-HLA antibodies before unrelated cord blood transplantation is recommended before choosing an HLA mismatched cord blood unit. Whenever possible it is important to avoid selecting a unit for which the patient has donor specific anti-HLA antibodies.

Similar Survival, but Better Quality of Life After Myeloablative Transplantation Using Unrelated Cord Blood Versus Identical Sibling Hematopoietic Cells in Adults with Hematologic Malignancies: A Single Institute Analysis.

AbstractAbstract 3134HLA-identical sibling allogeneic hematopoietic stem cell transplantation (HSCT) is the best therapeutic option for high-risk hematological disease, but it is limited by lack of availability of a suitable donor for most candidate patients. At our institution our center, unrelated cord blood transplantation (UCBT) was used as the first alternative option for patients who lack an HLA-matched related donor in the last decade. We retrospectively analyzed the clinical outcomes of UCBT versus HLA-identical sibling HSCT for adult patients with hematologic malignancies.Between April 2000 and May 2012, 194 consecutive adult patients with malignant hematological diseases received UCBT (77 patients; median age 21y, r 14–46; male 49) and related bone marrow transplantation (BMT) and/or peripheral blood stem cells transplantation (PBSCT) (117 patients; median age 30y, r 14–53; male 75). Diagnoses in two groups (UCBT/Sibling) included de novo AML (n = 23/32), ALL (n = 30/26), CML (n = 17/47), MDS/AML (n = 3/8), mixed phenotype acute leukemia (MPAL) (n = 3/1), NHL (n = 1/2), and MM (n = 0/1)). Overall rates of high-risk patients were 84.4% for UCBT recipients and 50.4% for BMT/PBSCT recipients(P<0.05). 11.6 percent of UCB grafts and 100% sibling grafts were HLA-identical (antigen level for HLA-A and B, allelic for DRB1, respectively). All patients received myeloablative conditioning regimens and CsA plus mycophenolate mofetil as GVHD prophylaxis.The median number of nucleated cells and CD34+ cells infused were 0.36 (r 0.19–0.69)×108 and 0.21(r 0.06–0.52)×106 per kilogram of the recipient’s body weight for UCBT recipients, and 5.68 (r 2.02–12)×108 and 3.63(r 0.67∼14.99)×106 per kilogram for BMT/PBSCT recipients (P=0.000). The primary engraftment rate was 96.1% (UCBT) and 100% (BMT/PBSCT). The median time to 0.5×109/L ANC was 19 days (r 12–35) and 12 days(r 10–18)(P = 0.000) and the median time to 20×109/L platelets was 36 days(r 14–90)and 15 days(r 11–17)(P = 0.001); hematopoietic recovery was significantly delayed after UCBT. The cumulative incidence of total acute GVHD (47.3% vs.22.2%, P = 0.001), early transplantation-related mortality (TRM) before day +100 (13.0% vs.3.4%, P<0.05), and infection (58.4%vs. 12.0%, P<0.05) was higher in UCBT recipients. Median follow-up was 42.2 months (range, 4.5–123.2 months) for BMT/PBSCT recipients and 22.2 months (range, 3.0–110.2 months) for UCBT recipients. There was no significant difference in cumulative incidence of grades ?to ? acute GVHD (9.4% vs. 5.0% P = 0.247), relapse rate (14.3% vs. 14.5%, P=0.962), and 3 year over survival (OS) (59.6% vs. 64.1%, P=0.123). But the cumulative incidence of chronic GVHD (18.8% vs. 44.1%) and extensive chronic GVHD (0% vs. 18%) was lower in UCBT recipients (P<0.05). The estimated 9-M CI of discontinuing immunosuppressive therapy (IST) while alive was 80%, and long-term survivors of UCBT had better quality of life.Our data shows similar survival, but better quality of life after myeloablative transplantation using UCB versus identical sibling hematopoietic cells in adults with hematologic malignancies. HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor. Disclosures:Sun:Anhui Provincial “115” Industrial Innovation Program (2009): Research Funding; the Fund of the Key Medical Project of Anhui Provincial Healthy Department (2010A005): Research Funding; Key Scientific and Technological Project of Anhui province “Twelfth Five-Year Plan” (11010402164): Research Funding.

Cord-Blood Hematopoietic Stem Cell Transplant Confers an Increased Risk for Human Herpesvirus-6-Associated Acute Limbic Encephalitis: A Cohort Analysis

Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease.

Unrelated Cord Blood Transplantation in India: Breaking the Cost Barrier

Abstract 4768 Background –India, with more than a billion population, has a huge burden of blood and cancer disorders many of which can be cured only by hematopoietic stem cell transplantation (HSCT). More than 1500 transplants have been done till 2005 over a 20 year period in about 10 centers out of which 880 have been allogeneic HSCT and all have been from matched related donors (MRD).Unrelated HSCT is the only option for the patients without a MRD. It is almost impossible to find an unrelated matched donor in India due to ethnic diversity and lack of unrelated donor registries. Some public cord blood banks have been set up in India. So finding a suitable cord blood unit within India is possible. Unrelated Cord Blood Transplant (UCBT) is the only feasible option for patients who need to undergo unrelated HSCT in India but lack of experience and huge costs are perceived barriers. Data from USA showed mean cost of graft for pediatric UCBT was $58,910 and mean cost per day survived in first 100 days (excluding graft cost) was $4522 ((Majhail NS et al. Pediatr Blood Cancer 2010;54:138–143). The costs of UCBT among children in India have not been described previously. Method -We calculated the costs of UCBT within the first 100-days among four children who received UCBT at Sir Ganga Ram hospital from April 2008 to Dec 2010. We also analyzed costs of transplantation in relation to patient age, weight, single vs. double cord, conditioning, Graft vs. Host Disease (GVHD) and mean duration of stay before day 100. Results -The 100-day probability of overall survival was 100%. The mean cost per day survived (excluding costs of graft acquisition) was $402 (range $360-460)) for UCBT recipients. Average total cost of each UCBT was $43500 (Range $32000-52000). Average duration of stay in hospital in first 100 days was 89 days (range 75–100). All grafts were procured from a public cord bank in India. Average cost of graft per cord unit was $5000. Diagnosis was thalassemia major-2, Familial Hemophagocytic Lympho Histiocytosis (HLH)-1 and AML-1. Lowest cost was for AML ($32000) and highest was for Pesaro class III thalassemia major ($52000). Mean age was 2.75 years (range 1–5 year). Mean weight was 12.25 kg (range 10–16 kg). Mean cell dose infused was 7 × 107 nucleated cells/kg weight of recipient (range 3–10 × 107nucleated cells/kg). Conditioning was Busulfan and Cyclophosphamide (BuCY) and Rabbit Anti-Thymoglobulin (ATG) for two patients (1 Thalassemia, 1 AML) costing $1500 per patient, Fludarabine & Melphalan and Campath for HLH costing $2500 and Treosulfan, Thiotepa, Fludarabine and ATG for class III thalassemia costing $7500. Mean cost per day for single cord was $385 and for double cord UCBT was $420. One patient rejected the graft. Three engrafted at median of 32 days (range 28 –39 days). GVHD was seen in two patients (both with double cord). CMV reactivation was seen in all cases. Invasive aspergillosis was seen in one patient who had thalassemia and it lead to highest expenditure. Campath based conditioning was associated with maximum hospital stay in child with HLH. All had Lansky score >90 pre-transplant No one needed dialysis, mechanical ventilation or hepatic veno-occlusive disease. Conclusions -Total cost of UCBT in India is less than the cost of the UCBT graft in USA and mean cost per day in India is almost one tenth of cost per day in USA. Low cost of UCBT in India would make this treatment feasible for many more patients who need to undergo unrelated HSCT. Disclosures:No relevant conflicts of interest to declare.

Comparison of Unrelated Cord Blood Transplantation and HLA-Mismatched Unrelated Bone Marrow Transplantation for Adults with Leukemia

Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.

Cytomegalovirus infections in unrelated cord blood transplantation in pediatric patients: incidence, risk factors, and outcomes

Stem cells from umbilical cord blood (CB) have increasingly become a viable alternate source of progenitor cells for hematopoietic cell transplantation (HSCT). Cytomegalovirus (CMV) is thought to contribute significantly to HSCT morbidity and mortality. Retrospective case-control study in patients at tertiary care center. We determined the incidence, risk factors and outcomes for CMV infection and disease after unrelated cord blood transplantation (UCBT) in children. Between 2003 and 2007, 73 pediatric patients underwent UCBT and 68% of recipients were CMV seropositive. The overall incidence of CMV infection, early and late CMV infection was 58.9% (43/73), 62.8% (27/43), and 37.4% (16/43), respectively. in patients with early CMV infection, 6 of 27 (22%) patients progressed to develop CMV end-organ disease including pneumonitis and retinitis. High levels CMV antigenemia ≥70 infected cells by pp65 antigenemia assay + PMNs, P=.237) were associated with a higher risk of progression to CMV disease. The development of CMV infections was higher in CMV-seropositive recipients (P<.001) and in those who developed graft-versus-host-diseases (GVhD) (P<.001). other risk factors for CMV infection include the use of high-dose corticosteroids (P<.001) and older age of the recipient at the time of transplant (P<.002). Late CMV infection was strongly associated with a previous history of early CMV infection (P<.001). CMV infection is a significant complication in UCBT recipients in pediatric patients and is associated with an increase in transplant-related morbidity and mortality. Risk factors for CMV infections after UCBT include GvHD, use of corticosteroids, underlying diseases (hematologic malignancies) and older age. Late CMV infection was strongly associated with a previous history of CMV infection.