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Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment >20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). The incidence of GF after HCT using human leukocyte antigen (HLA) matched donors is lower than 5%; however, a higher incidence is observed when considering HLA mismatched donors or alternative donor sources and the use of reduced intensity conditioning (RIC) regimens. In the absence of autologous recovery, a second HCT is necessary to attempt preventing death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after a GF with different types of donor sources report a wide range of overall survival (OS) and transplant related mortality (TRM), however studies including a large number of patients receiving a second transplant with umbilical cord blood (UCB) are scarce. In this retrospective study, using registry data from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT), we report the outcomes of 247 umbilical cord blood transplants (UCBT) performed after GF following a previous HCT. Data were analyzed separately for patients with malignant (n=141) and non-malignant diseases (n=106). UCB was the most frequent stem cell source that resulted in GF (65.0% and 68.9%, for malignant and non-malignant diseases, respectively), and most of the reported GF occurred within 100 days after HCT (92.3% and 85.9%). The most frequent diagnosis in malignant diseases was acute leukemia (64.5%), mainly acute myeloid leukemia (AML). In non-malignant diseases, the diagnoses most often reported were inborn error of metabolism (IEM) (37.7%), followed by bone marrow failure syndrome (BMF) (34.0%) and primary immune deficiency (PID) (21.7%). In malignant and non-malignant diseases, we observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% CI 51.4- 67.9%) and 60.4% (95% CI 51.7- 70.6%), in a median time of 23 and 24 days, and a 3-year OS of 28.9% (95% CI 21.8- 37.3%) and 49.1% (95% CI 39.5- 58.8%). TRM at 100 days and at 3 years for malignant diseases was 39.9% (95%CI 32.5 - 49.1%), and 57.5% (95%CI 49.4 - 66.8%). In multivariate analyses, none of the characteristics were statistically significantly associated with engraftment or overall survival. Although survival for patients requiring a second transplant is not optimal, UCB remains a valid life-saving option for some patients with GF as it is an immediately available source of stem cells in severely ill patients. The most appropriate stem cell source for salvage transplants remains controversial, as it depends on multiple factors including center choice, donor availability, underlying disease and existing comorbidities. Disclosures Peffault De Latour: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Jazz Pharmaceuticals: Honoraria; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding.

Background: Pediatric patients younger than two years of age with acute myeloid leukemia (AML) commonly receive a chemotherapy-based myeloablative conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). The optimal choice of cytotoxic agents is still controversial. Methods: A retrospective EBMT-registry based study was conducted to investigate the impact of different chemotherapy-based conditionings on the outcomes in young children. Children younger than two years of age receiving a first HSCT of bone marrow (BM), peripheral blood stem cells (PBSC) or cord blood (CB) from matched siblings (MSD) or unrelated donors (UD) in first complete remission (CR1) between 2000 and 2019 were included. Busulfan/Cyclophosphamide (BuCy) and BuCy/Melphalan (BuCyMel) were the most frequent combinations on which this analysis focused. The primary endpoint was leukemia-free survival (LFS). Multivariate analysis adjusting for differences between the conditioning regimens and risk factors influencing outcome was performed using the Cox's proportional hazards regression model. Results: 289 patients (56% male) transplanted at a median age of 1.2 years (IQR 0.9-1.6) after BuCy (164, 57%) or BuCyMel (125, 43%) were included. 184 (64%) patients received BM, 71 (24%) CB and 34 (12%) PBSC from UD (201, 70%) and MSD (88, 30%). In-vivo T-cell-depletion (TCD) was performed in 160 (58%, missing data 14) of the HSCTs with anti-thymocyte-globulin (ATG, 153) or alemtuzumab (7). Ex-vivo TCD was performed in 13 (5%, missing data 3) of the HSCTs. Graft-versus-host-disease (GvHD)-prophylaxis was Cyclosporin-A-based in 90% of the HSCTs. Median follow-up (FU) was 4.9 years (95% CI 3.9-5.5). After a median FU of 4 years, 4-y-LFS after BuCyMel (74.3%, 95% CI 65.1-81.4) was significantly better compared to BuCy (59.7%, 95% CI 51.2-67.2), hazard ratio (HR) 0.56 (95% CI 0.35-0.90, P=0.02). Overall survival (4-y-OS) after BuCyMel (77.2%, 95% CI 68.1-84.0) was significantly better compared to BuCy (66.6%, 95% CI 58.0-73.8), HR=0.58 (95% CI 0.35-0.97, P=0.04). No significant differences were found in the probability of relapse (4-y-RI (whole cohort) 26.2% (95% CI 21.0-31.7), HR of BuCyMel 0.59 (95% CI 0.34-1.02), P=0.06), non-relapse mortality (4-y-NRM (whole cohort) 7.8% (95% CI 5.0-11.4), HR of BuCyMel 0.49 (95% CI 0.19-1.24), P=0.13) and incidence of acute grade II-IV GvHD at day 100 (day-100-aGvHD II-IV (whole cohort) 36.8% (95% CI 31.2-42.5), HR of BuCyMel 0.59 (95% CI 0.35-1.01), P=0.06). Incidence of chronic GvHD (4-y-cGvHD (whole cohort)) was 9.8% (95%-CI 6.3-14.2). The donor type had no significant influence on the outcome. Conclusion: Bu-based conditionings of HSCT for infants with AML at high risk of relapse offer a high probability of cure. Conditioning with three alkylators (BuCyMel) resulted in better LFS and OS compared with two alkylators (BuCy) without significantly increasing the risk of both NRM and aGvHD. Future trials will evaluate the impact of the more recently introduced alkylator Treosulfan within the conditioning of HSCT in pediatric AML. Disclosures Peters: Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Moraleda: Pfizer: Other: Educational Grants, Research Funding; Sanofi: Other: Educational Grants, Research Funding; MSD: Other: Educational Grants, Research Funding; ROCHE: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Takeda: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Sandoz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Educational Grants, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Educational Grants, Research Funding; NovoNordisk: Other: Educational Grants, Research Funding; Janssen: Other: Educational Grants, Research Funding; Celgene: Other: Educational Grants, Research Funding; Amgen: Other: Educational Grants, Research Funding. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Corbacioglu: Gentium/Jazz Pharmaceuticals: Consultancy, Honoraria.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality offering cure or long-term survival for many hematologic malignancies, and non-malignant diseases in children. HLA-matched siblings are considered the best donors because of reduced risks of transplant-related complications and better clinical outcome. According to the National Marrow Donor Program Guidelines, the maximum amount of bone marrow harvest is limited to 20ml/kg donor's body weight. The aim of this retrospective study was to assess the optimal bone marrow harvest volume in pediatric donors needed to obtain the desired CD34+ cell count. METHODS: We reviewed medical charts of 553 pediatric (age at harvest RESULTS: 288 out of 553 donors were male. 155 (28%) were below 5 years of age at harvest, 189 (34.2%) were between 5-10 and remaining 209 (37.8%) were 10 years and above, with a median of 8.4 years (range: 0.2-17.9). Primary indication for transplant among 131 (23.7%) of our pediatric recipients were Malignant Disorders, Non-Malignant Disorders in 214 (38.7%) and Primary Immunodeficiency and Histiocytic Disorders in 208 (37.6%). GCSF priming was carried out in 219 (39.6%) donors. The minimum desired CD34+ cell count of ≥3.0X10^6 per Kg of recipient weight was reached in 517 (93.5%) harvests. Post infusion Absolute Neutrophil Counts (ANC) recovery within Day+28 was recorded among 472 (85.4%) of the transplant naïve recipients, while in 72 (13%) cases ANC never recovered and in remaining 9 (1.6%) time to recovery was beyond Day+28. ANC recovery within Day+28 was significantly associated with CD34+ cell dose of ≥3.0X10^6 per Kg of recipient weight (n=441, 93.4% vs. 31, 6.6%; P-Value 54 (9.8%) of our donors required PRBC transfusion; among whom 34 (63%) were below 5 years of age at harvest, 15 (27.8%) 5-10 years and remaining 5 (9.3%) were 10 and above (P-Value CONCLUSION: Our study confirmed that CD34 cell count were significantly higher among younger donors. The use of Higher CD34 cell dose is significantly associated with engraftment. Priming with G-CSF had significant impact on CD34+ cell count. These large data confirm the suggestion that the volume of bone marrow harvested can be decreased among younger donors without significantly changing the overall CD34 cell count. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) is a diffuse curative option for transfusion dependent thalassemia (TDT) and sickle cell disease (SCD). To verify transplant activity, distribution, demography, policies and outcomes the Hemoglobinopathy Registry was established inside the European Group for Blood and Marrow Transplantation (EBMT). After a previous analysis limited to TDT for the 2000-2010 period data (BMT 2016; 51:536-41), we performed an updated report considering TDT and SCD patients transplanted in the last eighteen years (years 2000-2017). METHODS: Data on pediatric patients transplanted between Jan 1st, 2000 through Dec 31st, 2017 were extracted by the EBMT promise Hemoglobinopathy registry database. Only first transplants were considered. Data are expressed as median with range unless specifically indicated. Survival probabilities were calculated with the method of Kaplan and Meier and expressed as means and 95% confidence intervals (95%CI). Differences between survival probabilities were tested by means of the log-rank test. RESULTS: In the above-specified period 3856 consecutive pediatric patients affected by TDT (2936, 76%) or SCD (920, 24%) were transplanted in 166 HCT centers distributed in 36 countries in Europe, Asia and Africa. Median age at transplant was 7.2 years (range 0.48-17.9). 3342 (87%) transplants were performed on patients Figure 1 reports pediatric transplant activity inside the EBMT showing an increased numbers of patients transplanted after year 2010. After a median follow up of 24 months, the 2 years overall survival (OS) and event-free survival (EFS) were 91% (95%CI 90-92) and 86% (95%CI 85-87) for the entire population. In TDT, OS and EFS were 90% (95%CI 89-92) and 84% (95%CI 82-85), respectively. In SCD, OS and EFS were 94% (95%CI 92-96) and 92% (95%CI 90-94), respectively. In both diseases no outcome difference was recorded on the basis of year of transplant (data not shown). Source of hematopoietic cells was bone marrow in 70% of TDT transplants and 81% of SCD transplants. In both diseases better results were recorded with the use of bone marrow versus peripheral blood [OS 91% versus 85% (P< 0.001); 95% versus 84% (P= 0.004) for TDT and SCD, respectively]. Similar results were recorded when EFS was analyzed. 176 patients received hematopoietic cells from single cord blood donors. Of them only 21 were from an unrelated donor. 119 patients received cord blood + bone marrow. Results of related HLA identical cord blood were similar to that of HLA identical related bone marrow (data not shown). Transplantation from an HLA identical sibling offered the best results in OS and EFS compared to other donor options (P< 0.001), both for TDT and SCD. Transplant results by donor type are reported in table 1. The threshold age for optimal transplant outcomes is confirmed 14 years, with OS 92% (95%CI 91-93), EFS 87% (95%CI 85-88) versus OS 85% (95%CI 82-89), EFS 81% (95%CI 77-85) ( P The two years incidence of cumulative extensive chronic graft versus host disease was 4.1% in TDT and 4.4 % in SCD (P=ns). CONCLUSIONS: Allogeneic HCT for TDT and SCD is a widely available curative approach; the procedure has been increasing and internationally performed during the years with excellent results. The emerging gene therapy approach will have to be compared to these well-established results. Disclosures Zecca: Chimerix: Honoraria. Forni:Novartis: Other: travel expenses, Research Funding; Celgene: Research Funding; Roche: Consultancy; Shire: Research Funding; Apopharma: Other: DSM Board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Novartis: Consultancy, Speakers Bureau; Riemser: Research Funding; Cellgene: Consultancy. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Celgene: Honoraria, Other: Chair DMC.

Fanconi anemia (FA) cells are characterized by genomic instability which places FA patients (pts) at risk for malignancies; leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Simultaneous presence of both host- and donor-derived cells in the recipient often referred to as mixed chimerism (MC) is observed in a large proportion of patients after HCT with non-malignant disorders. In FA patients however, MC might have a unique implication and the persistent existence of FA cells represents a management dilemma as the lingering FA cells may theoretically evolve into a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome of those with MC. From January 1995 until December 2017, 163 FA pts underwent allogeneic HCT at our center; chimerism data at last contact were available on 100 pts who are the subject of this analysis. Females (51) had a mean age at HCT of 8.7 (SD:3.0, Min-Max: 2.0-14.1) years whereas in males (49) it was 8.1 (SD:3.4; Min-Max: 1.4-17.4) years (P-Value: 0.415). Donor was HLA matched family member in 78 pts, Haplo-identical family member in 17 (92 of them were bone marrow and 3 peripheral stem cells); 3 had unrelated cord blood. Total body irradiation was used in 24 pts. Median time to ANC and platelets recovery was 14 and 22 days respectively. Cumulative incidence of overall aGVHD Grade III or above was 4%. Median follow up time was 67.2±14.6 months (95% CI: 38.7-95.7) from HCT date (Min: 7.3, Max:188.1). Chimerism analysis at last follow up showed full chimerism (100%; Myeloid/lymphoid) in 46 pts; 54 had MC defined as the presence of any residual recipient cells. No statistically significant association was noted between full and MC pts in the incidence of aGvHD (P-Value: 0.331). The 10-year cumulative probability of Overall Survival (OS) was 0.904±0.042. No significant difference was observed in OS between full and MC pts (0.954±0.032 vs. 0.883±0.059, P-value: 0.943) with 4 deaths in each group. New malignancy occurred in 4 pts; 2 in each group. In full Chimerism pts: Acute Mixed Lineage Leukemia and carcinoma and in MC pts: acute myeloid leukemia and acute lymphocytic leukemia, (P-Value=1.00). Graft failure occurred in 2 pts in the mixed chimerism group vs none in the full chimerism group (P-Value=1.0). We conclude that mixed chimerism in FA pts does not appear to have an adverse effect on outcome in our follow-up period; longer follow-up time however is needed to confirm the validity of this statement. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION Fanconi anemia (FA) is an inherited bone marrow failure syndrome that carries a high risk of transformation to myelodysplasia (MDS) and acute leukemia. Hematopoietic stem cell transplantation (HSCT) is used to treat FA patients in clonal evolution. The roles of chemotherapy before HSCT and the intensity of conditioning regimens in transformed FA patients are controversial, because of the high sensitivity of FA patients to DNA-damaging agents increases the risk of severe toxicities, the duration of aplasia, the risk of infective complications thus limiting the possibility to administer full dose cytoreductive treatments. The sequence chemotherapy-HSCT has been reported by some groups (MehtaPA et al Pediatr Blood Cancer 2007, Talbot A et al Haematologica 2014, Mitchell R et al Br J Haematol 2014, Ayas M et al J Clin Oncol 2013), but conclusive information is lacking because of small number of patients described without a risk factors' analysis. The aim of this retrospective study is to report the outcome of a large cohort of transformed FA who underwent allo-HSCT and to define the factors that may impact on its outcome. PATIENTS AND METHODS The study was conducted on behalf of the Severe Aplastic Anemia (SAAWP) and Chronic Malignancies Working Parties (CMWP) of the EBMT and was based on data of patients who underwent allo-HSCT between 1999-2016 for transformed FA, defined as a diagnosis of FA in presence of any hematological malignancies or cytogenetic abnormalities, registered in the EBMT Data Base. Clinical and biological information of the disease and details on transplant procedures and outcome were collected by a specific form distributed to Centres participating in the study. RESULTS Data of 71 patients (35 males-36 females) affected by transformed FA (42 MDS, 25 AL, 4 with cytogenetic abnormalities but without blasts) undergoing allo-HSCT were collected from 25 Centres . A matched related donor (MRD) was used in 31% of cases, an unrelated donor (UD) in 56.3% and a mismatched related donor (MMRD) in 12.7%. Bone marrow was the main source of cells (54.3%) followed by cord blood (22.9%), peripheral blood (21.4%) and bone marrow plus peripheral blood (1.4%). The median age at allo-HSCT was 12.7 years (range 9.3-23.4). Thirty seven (52.1%) patients received a chemotherapy before HSCT. Pre-HSCT status of malignancy in available patients was complete remission (CR) in 24% (n = 12/50) and an active disease (no-CR) in 76 % patients (n = 38/50). The conditioning regimen included total body irradiation (TBI) in 37 (52.1%) (radiation dose: ≤ 4.0 Gy in 30; > 4.0 Gy in 7), busulphan (BUS) in 16 (22.6%), no-TBI nor BUS in 18 (25.3%). Median follow-up was 93.7 months (71-110.6). GvHD prophylaxis and transplants' details are summarized in Table 1. All patients engrafted. Median time for neutrophils was 17 days (14-23) and it was 25 days (23-42) for platelets. The 2-and 5-year overall survival (OS) probability were 54% (41-66%) and 45% (32-57%) respectively; the 2- and 5-year event-free survival (EFS) (events being death, relapse and graft loss) 52% (40-65%) and 45% (32-58%). The cumulative incidence of relapse were 15% (7-24%) and 21% (11-31%), , of non-relapse mortality (NRM) were 37% (25-49%) and 39% (27-51%) respectively at 2 and 5-year. Most frequent causes of death were GvHD (33.3%), infections (23.3%) and relapse of malignancy (16.7%). Patients transplanted in CR, (neither blasts, nor major dysplastic features) and from matched related donor had a significantly better outcome (5-year OS: CR 83% (62-100%) vs no-CR 36% (19-52%) [p 0.01], MRD 60% (37-83%) vs UD 47% (31-64%) vs MMRD 12% (0-35%) [p 0.03]; 5-year EFS: CR 83% (62-100%) vs no-CR 34% (17-51%) [p 0.01], MRD 61% (38-83%) vs UD 48% (31-64%) vs MMRD 12% (0-35%) [p 0.02]; 5-year NRM: CR 0% vs no-CR 44% (27-61%) [p 0.007]) vs those engrafted in no-CR and from no-MRD. (Fig 1 a, b, c). No other tested variable (therapy before transplant and conditioning regimen) significantly affected the outcome. CONCLUSION This study on large cohort of FA patients transplanted because of transformation shows that allo-HSCT from MRD has a better outcome and that CR from malignancy before transplant appears to be a major determinant for a favorable outcome. Disclosures Peffault De Latour: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amyndas Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years but is still poor for patients who failed or relapsed after immunosuppressive therapy (IST) and don't have a matched donor. Recent use of eltrombopag shows blood count improvements in 40% of cases, but most patients refractory to immunosuppressive therapy, are also unresponsive to eltrombopag. In this situation, hematopoietic stem cell transplantation (HSCT) using alternative donor sources (mismatched unrelated donors, cord blood, and haploidentical family donors) may be curative but are also associated with a high risk of morbidity and mortality. Moreover, ethnic minorities have limited access to an alternative donor, especially in the adult population. Haploidentical transplantation using post-transplant cyclophosphamide (Haplo-PTCy) has been shown to facilitate engraftment and shows GvHD rates comparable to those of matched sibling HSCT in hematologic malignancies. However, few papers have been published on Haplo-PTCy in the context of aplastic anemia. We conducted a retrospective analysis of 36 patients (72% male), who received an haplo-PTCy for aplastic anemia in 22 EBMT centers from June 2010 to March 2017. Haplo-PTCy was the first transplantation for 81% patients (second, 11%; third, 8%). The non-myeloablative preparatory regimen included anti-thymocyte globulin in 33% of patients and low dose TBI in 58% of patients. Donors were father (n=12, 35%), mother (n=12, 35%), brother (n=5, 15%), sister (n=3, 9%), cousin (n=1, 3%) and daughter (n=1, 3%). The stem cell source was mainly bone marrow (55%). All patients received cyclophosphamide 50mg/kg/day IV on days +3, and +4 post-transplant and 75% received tacrolimus or cyclosporine plus mycophenolic acid. The primary endpoint was the probability of OS. Secondary study endpoints included probability of neutrophil recovery (ANC 500/ μL for at least 3 consecutive days), platelet recovery (platelets 20 000/ μL for at least 3 consecutive days, and 7 days after the last transfusion), cumulative incidences of acute and chronic GVHD and relapse-free survival without Grade III-IV acute GvHD and without extensive chronic (GRFS). Thirty-two patients were diagnosed with moderate (7%), severe (52%) or very severe idiopathic aplastic anemia (41%), while 4 patients were transplanted for congenital aplastic anemia (3 Fanconi Anemia and 1 Diamond Blackfan). The median age was 19.4 years (range 2.5-45.4 years; 58% adults). Median disease duration before haplo-PTCy was 11.3 months (1.9-201.2). Thirty patients (83%) received pretreatment (77% anti-thymocyte globulin plus cyclosporine, 12% eltrombopag, and 1 patient (3%) received androgens). Cumulative incidence (CI) of neutrophil recovery at day 60 was 78% (64-91) with a median time of 21 days (18-26). Cumulative incidence (CI) of platelet recovery at day 60 was 60% (44-76) with a median time of 31 days (22-185). The CI of grade II-IV acute GvHD was 26% (12-41%) (grade II 19% (7-32%), grade III 6% (0-13%) and no grade IV). CI of chronic GvHD was 17% (5-30) at 1 year (6% (0-13%) extensive) and a CI of 22% (7-37) at 2 years (only limited, there was no new case of extensive cGvHD after one year). With a median follow-up of 24.6 months (15.9 - 38.2), the estimated probability of overall survival (OS) was 78% (64-91) at 1 year and 74% (60-89) at 2 years. Of note, among the 4 patients with inherited disorders, 2 died [1 infection (Diamond Blackfan) and 1 aGvHD (Fanconi Anemia)] and 2 are alive at month 12 and month 15 of follow-up, respectively. Nine patients died during the study. The main cause of death was infection (n=6, 67%). Finally, the GRFS (alive, full donor chimerism, without previous grade III-IV GvHD and without extensive cGvHD) was 58% (41-75) at 2 years. In conclusion, with a median follow-up of 2 years, Haplo-PTCy leads to 74% overall survival in 36 patients with aplastic anemia, with almost 60% of the patients being free from GvHD complication. In a population with no other therapeutic options, our data suggests haplo-PTCY is a feasible option. However, prospective well-designed trials are urgently needed before the inclusion of Haplo-PTCy in the treatment strategy of aplastic anemia. Disclosures Bloor: Janssen: Research Funding; AbbVie: Research Funding. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Russell:Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau; Daiichi Sankyo: Consultancy. Kerre:Celyad: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

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 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 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 In multivariate analysis, UCBT was associated with higher risk of NRM (HR 2.36, p 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. Disclosures Locatelli: 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.

Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children ( In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

Background: Prognostic scoring systems for allogeneic stem cell transplantation (HSCT) are of clinical value when determining a leukemic patient's suitability for this curative, but risky, procedure. Several such scores have been developed over the years for HSCT from sibling or unrelated donors, but no predictive score has been developed specifically for umbilical cord blood transplantation (UCBT). Although individual parameters have been identified to be associated with UCBT outcomes in acute leukemia (AL) patients, integrative tools for risk evaluation in this setting are lacking. We sought to develop a prediction model for overall survival (OS) (primary objective) and leukemia free survival (LFS) (secondary objective) at 2 years following UCBT in acute leukemia patients. Methods: A retrospective, international registry-based study, of 3140 acute leukemia patients who underwent UCBT from 2004 through 2014. Inclusion criteria were patients with AL receiving single or double cord blood units transplantation. Median follow up was 30 months. The dataset was geographically split into a derivation (65%) and validation set (35%). A Random Survival Forest was utilized to identify predictive factors. Top predictors were introduced into a Cox regression model, and a risk score was constructed according to each variable's hazard. Results: The median age at UCBT was 21.9 years. The 2 years OS rate was 47.7% (95% CI: 45.8-49.6). After identifying the top predictive variables, the UCBT risk score (Table 1) was constructed using 9 variables (disease status, diagnosis, cryopreserved cell dose, age, center experience, recipient cytomegalovirus sero-status, degree of HLA mismatch, previous autograft and anti thymocyte globulin administration). Over the derivation and validation datasets, a higher score was associated with decreasing probabilities for 2 years OS and LFS, ranging over the validation set from 0.72 (0.64-0.8, 95% CI) and 0.68 (0.6-0.76, 95% CI) to 0.13 (0.06-0.27, 95% CI) and 0.14 (0.07-0.28, 95% CI), respectively (Figure 1). An increasing score was also associated with increasing hazard of the predictive outcomes (Table 2). The score's discrimination (AUC) over the validation set for 2 years OS and LFS was 68.26 (64.25-72.27, 95% CI) and 66.95 (62.88-71.02, 95% CI), respectively. Calibration was excellent. Conclusion: We have developed the first integrative score for prediction of overall survival and leukemia free survival in acute leukemia patients undergoing a UCBT. The score is simple and stratifies patients into distinct risk groups. Table 1 The UCBT Risk Score Table 1. The UCBT Risk Score Table 2 Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Table 2. Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Figure 1 Overall survival stratified by the UCBT risk score over the validation data set Figure 1. Overall survival stratified by the UCBT risk score over the validation data set Disclosures Bader: Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Medac: Consultancy, Research Funding; Novartis: Consultancy, Honoraria.

Background: Umbilical cord blood transplantation (UCBT) is a potentially curative therapy acute leukemia (AL) patients. Transplantation benefit must be balanced against risks, such as transplant related mortality and relapse. The complex nature of hematopoietic stem cell transplantation data (HCT), rich in interactions and possibly nonlinear associations, has motivated us to apply machine learning (ML) for predictive modeling. ML is a field of artificial intelligence and is part of the data mining approach for data analysis. Our group has recently reported on a ML based prediction model for short term HCT outcomes (Shouval R et al; JCO 2015). Using a ML algorithm, the perspective of the current study was prediction of leukemia free survival (LFS) at 2 years after an UCBT, while exploring variables' importance and interactions. Patients & Methods: A cohort of 3,149 UCBT were analyzed. Inclusion criteria encompassed patients at all ages, undergoing an UCBT (single/double unit) in EBMT centers from the year 2004 to 2014, for AL, in all disease status. All conditioning and graft versus host disease prophylaxis regiments were included. A total of 24 variables were considered, including the number of total nucleated cell dose (TNC), donor and recipients HLA typing, as well as recipient, disease and transplant characteristics. The Random Survival Forest (RSF) ML algorithm was applied for model construction and data exploration. RSF is known to be adaptive to data, is able to automatically recover nonlinear effects and complex interactions among variables, and yields nonparametric prediction over test data. The analysis pipeline consisted of prediction model development, assessment of variable importance by their minimal depth from the tree trunk, and exploration of the top ranking variable with dependence plots. The latter promotes understanding of non-trivial associations between variables and outcomes. Results : The 2 years LFS was 49%, with a median follow up of 30 months. A RSF model of 1000 trees was developed, with each tree constructed on a bootstrap sample from the original cohort. A prediction error of 36.0% was calculated. The 10 most predictive variables (in ascending order) were disease status, age, TNC harvested and infused, recipient CMV serostatus, interval from diagnosis to UCBT, transplant year, previous autologous transplant, and use of anti-thymocyte globulin (ATG). Selected findings from exploration of variables-outcome relationship with dependence plots included a varying effect of TNCs in specific subpopulations. Increasing the number of infused TNCs had a positive effect on predicted LFS in patients receiving HLA mismatched (2 or more HLA mismatch) (figure) or single unit CB grafts, and patients in earlier disease status or older age. ATG administration was associated with worse LFS, whether unadjusted or adjusted to all other variables. However, there was an additional negative effect in advanced disease status patients, recipients of HLA mismatched or single CB units grafts, and older patients. Patients in 1st complete remission (CR) had higher predicted LFS as compared to those in 2nd CR. However, in patients receiving a HLA mismatched or a double CB graft, the difference in LFS between CR1 and CR2 was attenuated. Younger age had a favorable impact in early disease status, but lost its positive effect in advanced disease. Conclusions: A prediction model for LFS 2 years post UBCT was developed using the RSF ML algorithm. Variables were ranked according to their predictive contribution. Disease status, age, and TNC count were found to be the most important factors. Dependence plots revealed interactions and nonlinear associations between variables and the outcome, such as the effect of cell dose on HLA disparity. Apart from the study's clinical findings, it carries a methodological significance. A novel ML approach for prediction, variable selection and data exploration, accounting for long term time to event outcomes, has proved useful in the field of HCT. Figure 1. Variable marginal dependence coplot of predicted LFS at 2 years against TNC, conditional on HLA matching. Individual cases are marked with blue circles (alive or censored) and red `x's (event). Linear smooth (a linear extrapolation of the prediction function), with shaded 95% confidence band, indicates trends of variable dependence. Figure 1. Variable marginal dependence coplot of predicted LFS at 2 years against TNC, conditional on HLA matching. Individual cases are marked with blue circles (alive or censored) and red `x's (event). Linear smooth (a linear extrapolation of the prediction function), with shaded 95% confidence band, indicates trends of variable dependence. Disclosures Mohty: Janssen: Honoraria; Celgene: Honoraria. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Bader:Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Riemser: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

Osteopetrosis (OP) is a genetic disease characterized by increased bone density due to osteoclast dysfunction, leading to life-threatening multi-systemic complications in early childhood. Haematopoietic stem cell transplantation (HSCT) is the only curative approach for most children with OP and can effectively prevent serious complications such as blindness, bone fractures, hydrocephalus and cranial nerve compression. Since timing of transplant is critical in OP, umbilical cord blood is an attractive stem cell source, due to its prompt availability. We analysed the outcomes of unrelated umbilical cord blood transplantation (UCBT) in 45 children with osteopetrosis transplanted in EBMT centers between 1996 and 2012, using data reported to Eurocord. Median age at UCBT was 6 months (1.1 month - 7.4 years). Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allelic level) in 14 or HLA mismatched at 1 (n= 23) or 2 (n= 7) loci. Information on conditioning regimen was available for 42 patients; it was myeloablative (mostly busulfan-based) in 40 children and reduced intensity in 2 patients. GvHD prophylaxis consisted mainly of cyclosporine combined with either prednisolone (n= 20), or methotrexate (n=6), or mycophenolate mofetil (n=3). Anti thymocyte globulin (ATG) or alemtuzumab was given to 37/40 patients. Median number of infused total nucleated cell (TNC) and CD34+ was 13x107/kg and 3.4x105/kg, respectively. Median follow-up for survivors was 44 (range 4-144) months. Neutrophil recovery with donor chimerism was documented in 27/45 patients; 19/25 evaluable patients presented full donor engraftment, while 6 children presented mixed donor chimerism. Median time to neutrophil recovery was 20 (range 10-60) days. Eighteen patients experienced graft failure and 3/18 are alive at last follow up. Information on treatment post-graft failure was available 7/18 children: 6 patients underwent a second HSCT and 3 of them survived. Stem cell dose was associated with a trend for a better probability of donor engraftment: the cumulative incidence of donor engraftment was 46% in patients who received a CD34+ cell dose2x105/kg versus 0% in children receiving grafts with a CD34+ cell dose < 2x105/kg (p=0.001). According to HLA disparities, 3-year probability OS was 54% versus 58% versus 0% in patients receiving a 6/6, 5/6 and 4/6 HLA-mismatched graft, respectively (p=0.01). Interestingly, 4/4 children receiving a treosulfan-based myeloablative regimen achieved donor engraftment and 3 children are alive at last follow up. These data suggest that transplantation of unrelated UCB is a valid alternative for children with OP without a matched sibling or a suitable matched unrelated adult donor. The use of CB units mismatched at >1 HLA locus should be avoided due to worse survival. The incidence of primary graft failure was high and therefore the optimization of the conditioning regimen and/or the use of CB units containing a high TNC and CD34+ cell dose must be considered in this setting. The use of treosulfan-based conditioning regimens is worth further investigation, as well as the use of defibrotide prophylaxis to reduce the risk of VOD in this population of high risk patients. Disclosures: No relevant conflicts of interest to declare.

Post-transplant erythrocytosis is an ominous complication of kidney transplantation, occurring in the first 8 to 24 months after surgery in 10% to 15% of transplant recipients; this is frequently associated with significant thromboembolic events and sometimes death. In patients undergoing allogeneic hematopoietic cell transplantation (HCT), erythrocytosis has not been previously well described. At our institution, we observed that some aplastic anemia (AA), and Fanconi anemia (FA) patients developed progressively increased hemoglobin (HB), hematocrit (HCT) and RBC readings on long term follow up. Thus, this study was conducted to assess the validity of this observation in AA/FA patients post HCT, and its impact on their health. Patients and Methods From January 1993 until December 2011, 144 pediatric patients underwent successful allogeneic HCT for AA or FA; median age at HCT 11.6 years (range, 6.6 -15). All patients included were alive at the time of the analysis, and had sustained engraftment; all have had a follow up time of ≥ 12 months. For those who underwent more than one HCT, only events after the last HCT were included. We retrospectively examined the HB levels as an indicator for erythrocytosis (Corresponding RBC, HCT, WBC, and platelet counts were also collected). HB values of 150, and 160 gm/l were considered the trigger value in females and males, respectively. Patients who reached this value were studied for higher values on follow up, and only those whose HB persisted for at least 3 months above trigger value were included in the analysis; 29 patients (15 females, 14 males) were identified after causes of secondary erythrocytosis were ruled out. Erythrocytosis was defined as HB ≥ 160 gm/l in females, a HB ≥ 170 gm/l in males. Results Median time to trigger HB was 51.4 months (range, 15-121) in females, and 65 months (range, 23.3-114) in males, and median age at trigger HB was 14.7 years (range, 8.6-21.4) in females, and 16.9 years (range, 13.4-20.6) in males. Median highest HB reached was 160 gm/l (range, 151-162) in females, and 172 gm/l (range, 164-189) in males, with a median time of 67 months (range, 17-164) in females, and 103 months (range, 23.3-206) in males; the median age at highest HB was 16 years (range, 9.7-24.8) in females, and 20.2 years (range, 13.4-27.4) in males. Upon follow up, the HB fell below the trigger level in 16 patients (9 females, 7 males) (55.2%), at a median time of 37.2 months from the trigger value (range, 3.6-104). Seventeen patients qualified for the diagnosis of erythrocytosis (12%); 8 females, and 9 males. In all 8 females and in 4 males, HB fell below the erythrocytosis value upon follow up. All HB values correlated positively with HCT and RBC, no correlation was detected with platelet count or WBC. On univariate analysis, patients with older age at HCT (≥ 10 years) appeared to be more likely to develop elevated HB (P=0.003); and those who had radiation in the conditioning regimen were less likely to develop elevated HB (P=0.008). Three of the males with persistent erythrocytosis were tested further and all 3 had normal erythropoietin levels and were negative for JAK-2 mutations. None of the 29 patients had any adverse clinical symptoms during the follow up visits, and no thromboembolic events were reported. Conclusion A proportion of patients with AA/FA who undergo HCT may experience elevated HB on long term follow up; 12% subsequently qualifying as erythrocytosis, with the highest reading requiring between 1.5-2 years to evolve. Unlike erythrocytosis post renal transplant, the phenomenon we are describing in our patient cohort does not appear to be associated with any adverse symptoms, or any increased risk of thrombosis. More in depth investigation to study the potential pathophysiology behind it is currently underway at our institution, together with further exploration of this observation in patients with other illnesses undergoing allogeneic HCT. Disclosures: No relevant conflicts of interest to declare.

Avascular necrosis (AVN) of the bone is a painful and debilitating complication of allogeneic hematopoietic cell transplantation (HCT) that is associated with significant morbidity and often requires surgery. Risk factors for its development in pediatric allogeneic HCT recipients are not well described. To assess risk factors for AVN in children and adolescents following allogeneic HCT, we conducted a nested case-control study with a matched cohort of 638 patients reported to the Center of International Blood and Marrow Transplant Research who were ≤ 21 years of age, received their first allogeneic transplant between 1990 to 2008 in the United States and had survived ≥ 6 months from HCT. Overall, 160 cases with AVN were identified. Each case was matched with up to 3 controls by same year of HCT, similar length of follow-up and by transplant center (478 controls). Cases and controls were confirmed via central review of radiology, pathology and/or surgical procedure reports. The median age for cases was 15 (range 2-21) years, 49% were male, 65% had acute leukemia, 65% had received high-dose total body irradiation (TBI) based conditioning regimen, and 65% had received unrelated donor HCT. Among cases, 18% had a history of acute graft-versus-host disease (GVHD) while 56% had a history of chronic GVHD prior to development of AVN. Median time from HCT to diagnosis of AVN was 14 (range Disclosures: No relevant conflicts of interest to declare.

Although HCT is an accepted component of the treatment strategy for relapsed/refractory pediatric NHL, only few studies have reported on the outcome for these patients. Most have reported on small numbers of patients, with survivals ranging from 27% to 75%. Clinical data were retrospectively retrieved for patients with NHL who had undergone HCT. Pre-HCT information, including pathologic diagnosis, response to first- and second-line therapy and pre-HCT disease status were collected, in addition to details of the transplant process and patient and disease outcome. Between 1996 and 2012, 28 pediatric patients with NHL underwent HCT. Primary diagnosis for these patients included Burkitt lymphoma (n=13), Large B-cell lymphoma (n=4), T-Lymphoblastic lymphoma (n=4), NK/T cell lymphoma/leukemia (n=3), Peripheral T-cell lymphoma (n=2), B-lymphoblastic lymphoma ((n=1) and anaplastic large cell lymphoma (n=1). The median age at HCT was 7.65 years (mean 8.2; range 1-14.3). Twenty had suffered a relapse of their disease, while five had primary progression; three patients with NK/T lymphomas underwent HCT as part of their first-line therapy. Fourteen patients had autologous (autoHCT) and 14 had allogeneic HCT (alloHCT). Among alloHCT, 11 had matched-related grafts while 3 had unrelated umbilical cord blood (UCB) grafts. At the time of HCT, 23 patients were in CR (CR1=7, CR2=15, CR3=1), and 5 had partial responses. HCT conditioning was myeloablative for all patients; in 18 patients, it was TBI-based. Fourteen patients suffered recurrence of their lymphoma post HCT at a median of 1.17 months from HCT (mean 6.2; range 0.63-42); 4 died in CR due to transplant-related toxicity, of these 3 were post alloHCT and one post autoHCT. Three patients have developed secondary malignancies (SMN; 2 post alloHCT and 1 post autoHCT). 10 patients were alive at last follow-up, all of whom were in CR. The 5-year estimated OS from SCT is 38.7%, with and EFS of 26%. There was no difference in 5-year OS or EFS among patients who received alloHCT v. autoHCT (OS 28.6% v. 49%; p=0.53, EFS 14.3% v. 37.5%; p=0.25) and among patients who did or did not receive TBI (OS 33.3% v. 48%; p=0.37, EFS 27.8% v. 18.8%; p=0.66). OS/EFS for patients with Burkitt lymphoma was 23.1%. Of the three patients with NK/T cell lymphoma two remain alive in CR 13.7 and 5.1 years after HCT. The outcome of relapsed/refractory non-Hodgkin lymphoma of childhood remains suboptimal. In addition to a high post-HCT relapse rate of 50%, HCT-related toxic mortality and SMN contribute to the poor outcome for this cohort of patients. Disclosures: No relevant conflicts of interest to declare.

Most pediatric patients with Hodgkin lymphoma are cured of their disease with standard combined-modality first-line therapy. Those who relapse are subjected to salvage chemo-radiotherapy, and patients who respond often undergo either autologous or allogeneic HCT, with a reported outcome ranging from 40%-60%. Variables affecting the outcome of such patients are not clearly defined. This study retrospectively reviewed the clinical characteristics and outcome of patients who underwent HCT at our institution. Between 1995 and 2012, 29 pediatric (age The outcome of patients with relapsed/refractory HL following HCT is encouraging, as a majority of patients survive free of their lymphoma. Timing of relapse/progression remains an important prognostic factor and patients who fail early may be considered for novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Introduction Haematopoietic stem cell transplantation (HSCT) is indicated in patients affected with severe congenital neutropenia (SCN) who transformed into myelodysplasia/acute myeloid leukemia or in low responders to granulocyte colony stimulating factor (G-CSF) therapy. The outcome of HSCT in SCN is not well known because the experience is based on single case report or on small series. Aim of the study describe outcomes of HSCT in SCN patients in a large cohort using EBMT data base. Methods and Patients all patients registered in the EBMT data base affected with severe congenital neutropenia (severe neutropenia diagnosed early in life with bone marrow block at promyelocytes stage in the bone marrow and G-CSF dependency) were considered eligible for the study. Data regarding HSCT and outcome were extracted from the “general” EBMT registry, while data on the history of disease before HSCT, was collected through a specific CRF sent to all the participating centers. Here we report preliminary of this survey. Results A total of 119 patients from 19 participating countries were considered eligible for the study; 66% of the eligibile patients originated from Western Europe and 34% from Eastern Europe and the Eastern Mediterranean area (Iran, Israel, Saudi Arabia,Turkey and Russia). Females were 51% of the cohort. Median age at diagnosis of neutropenia was 0.35 years (0-35.4y), while median age at first transplant was 4.8 years (range 0.2-43y). Four patients were affected with MDS at time of transplant. The cell source was bone marrow (BM) in 56%, peripheral blood (PB) in 26% and cord blood (CB) 18%. Fiftypercent of patients were engrated from a related and 50% from an unrelated donor. Conditioning regimen was myeloablative in 86% and at reduced intensity (RIC) in 14% of the cohort Engraftment was documented in 91%; 5% has no engraftment while 4% lost the engraftment for a total of 10 patients. Chimerism was assessed only in 30% of the patients. Six of the 10 patients who had graft failure died after first transplant. Four underwent a second HSCT and 2 are alive2 died (2 alive and 2 death).Overall 22 patients (18.5%) died while the remaining 97 were alive (81.5%). Causes of death were GVDH 23%, Infection 23%, organ failure 18% and “other causes” 27%. Nine percent of patients died because of relapse/progression of the disease. Transplant related mortality was assessed at 17% on the whole cohort. Acute GVDH grade 1-2 was documented in 31% grade 3-4 in 14% and no GVDH in 54%. The 5-year OS and EFS rate was respectively 77% and 70 % in the whole cohort. The 5-year OS according to HLA identical donor and matched unrelated was respectively 83% and 79% (p=0.99, log-rank). Also the OS according to source of cells (5-year OS: CB 85%, PB 79% and BM 62% was not significant (p =0.13). Likewise no significant difference was found in EFS (CB 85% BM 75% and PB 52% p =0.08). OS by age of patients (5-year OS: 82 % for patients aged 0-2y, 83 % for age 2-5 y, 83% for age 5-10 and 60% for subjects aged above 10y) (p=0.07) and by period of HSCT: (90% between 2008-2012, 75% between 2001-2007 and 64% before 2000) were again not significant. No difference was also seen in OS and EFS according to myeloablative conditioning regimen and RIC. Conclusion this preliminary analysis indicate that the 5-year survival in transplanted SCN patients is close to 80% with no difference between matched related and unrelated donor. TRM is still a not negligible and close to 17%. There is a trend towards a more favourable survival in patients younger than 5 years at time of transplant, in those transplanted with cord blood and after the year 2000. Disclosures: Marsh: Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Dufour:Pfizer: Consultancy, Research Funding.

The treatment of AML in children utilizes intensive chemotherapy and often myeloablative hematopoietic cell transplant (HCT). This results in significant myelosuppression, necessitating blood product transfusions. Repeated PRBC transfusions result in an increase in the body iron load which can lead to secondary hemochromatosis and organ dysfunction, particularly the heart and liver. Patients with hemoglobinopathies on chronic PRBC transfusions require iron chelation therapy usually after 10-20 units transfused. While patients with AML receive multiple transfusions, there is little data on the number or volume of PRBC transfused or the estimate of the iron load received. This retrospective study evaluated the number and volumes of PRBC transfusions administered to pediatric ( Twenty-two patients with AML were diagnosed and treated at our institution between January 2010 and December 2012. There were 13 girls and 9 boys with a median age at diagnosis of 7.5 years (mean 6.95; range 0.4-13.2). One patient died early of sepsis without achieving complete remission (CR), and another died in CR following her last course of chemotherapy. Eight patients underwent HCT following myeloablative conditioning with busulfan, cyclophosphamide and etoposide; the remaining received chemotherapy alone. For patients who completed their chemotherapy the cumulative anthracycline dose was 450 mg/m2. Patients received a median of 17.5 PRBC transfusions (mean 16.6; range 3-28) during the course of their treatment. The cumulative PRBC transfusion volume was 185.4 ml/kg (mean 175.8; range 24.87 – 311.58), which translates to a median iron dose of 129.8 mg/kg (mean 123.1; range 17.4 – 218.1). The median serum ferritin level for those patients who were tested (n=12) was 1794.5 mg/L (mean 9074.5; range 699 – 78500). The median projected hepatic iron content, based on the transfused iron burden was 12.24 mg/g liver dry weight (mean 11.61; range 1.64 – 20.58); 17 (77.3%) patients had projected hepatic iron concentrations in excess of 7.0 mg/g, and none were 10 percentage point reduction in their left ventricular ejection fraction (LVEF; range -11% to -45%) however only one patient is on cardiac failure medications. Cardiac T2* MRI studies are being conducted to evaluate cardiac iron status for patients in this cohort. 13 patients were alive in CR at a median follow-up duration of 1.83 years (mean 2.16; range 0.27 – 3.43). Pediatric patients with AML receive large volumes of PRBC transfusions during their treatment and as a consequence accumulate high total body iron. This is in excess of the threshold for chelation therapy, used to prevent organ dysfunction, in patients with hemoglobinopathies. In addition, AML patient also receive significant cardio-toxic medications which may compound the effect of iron on the myocardium. With improvements in long term survival for patients with AML the addition of iron chelation therapy must be studied in order to prevent long term toxicity of AML therapy. Disclosures: No relevant conflicts of interest to declare.