ALBERT

Description: 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 (

Description: Introduction: BMT is the only proven curative treatment available for haemoglobinopathies. However, the number of patients who can benefit is seriously restricted by the lack of HLA-matched related donors not suffering from the condition and the limited number of unrelated donors available for the ethnic groups in which these conditions are prevalent. In order to expand the donor pool, haploidentical transplantation with a post-infusion of stem cells cyclophosphamide approach has been developed for young adults, but whilst well tolerated it has resulted in relatively high rates of rejection and the need for a prolonged period of immunosuppression1. Materials (or patients) and methods: 16 consecutive related haploidentical transplants (13 for sickle cell disease and 3 for β halassaemia major) were performed at St. Mary's Hospital, London, from June 2013 to May 2015. The donor was a parent in 15 cases and a sibling in one case. The median age was 10 years of age (range 3 to 18). All patients lacked a suitable HLA-matched related donor and an unrelated search had not identified a 10/10 or 9/10 donor. Endogenous haemopoieis was suppressed with hypertransfusions, hydroxycarbamide 30 mg/kg and azathioprine 3 mg/kg for at least two months pre-transplantation. The conditioning included fludarabine 150 mg/m2, thiotepa 10 mg/kg was added, cyclophosphamide 29 mg/kg, TBI 2 Gy and ATG (Thymoglobulin) 4.5 mg/kg. GvHD prophylaxis was provided with cyclophosphamide 50 mg/kg on days +3 and +4, MMF and sirolimus. The median survival was 8.19 months post-transplantation (1.28-22.96) and half of the patients are 〉150 days post-transplantation and have completed all treatment. The source of stem cells was G-CSF primed bone marrow in all cases, aiming ≥8 x 108 TNC/kg [median 9.97 x 108 TNC/kg (2.35-20.5), 3.88 x 106 CD34+/kg (1.12-9.21)]. Results: All patients engrafted, though one patient subsequently suffered secondary graft failure following macrophage activation syndrome and died. The median neutrophil engraftment was 17 days (range 16 to 29). The median platelet engraftment 〉50 x109/L was 32 days (range 20 to 64). All 15 surviving patients are cured from the manifestations of the original disease. One patient suffered VOD following autologous rescue with limited conditioning for secondary graft failure. Infectious complications occurred at a higher rate than seen for related transplants for the same conditions at our institution. Acute GvHD ≥ grade II occurred in two patients (12.5%, skin and gut GvHD respectively) responding to treatment with MSC and one patient was treated for chronic GvHD (6.3%). The median time to cessation of immunosuppression was 124 days (108-189). All patients but one achieved ≥90% donor fraction both in whole blood and T cells at day +180, with only such patient requiring continuation of immunosuppression (day +28: 93.3% patients ≥95% donor and 6.7% patients ≥90-94% in whole blood, and 73.3% patients ≥95% donor, 13.3% patients ≥90-94%, 6.7% donor ≥50-89% and 6.7% donor

Description: Abstract 2335 CMV viraemia and disease remains a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT). We investigated the impact of low dose alemtuzumab conditioning in paediatric matched sibling allogeneic BMT for haemoglobinopathy on immune reconstitution (early and late CD3/4+, CD3/8+, CD3-/CD56+ cell recovery) and subsequent viral infections in 18 consecutive transplants (14 β thalassaemia major and 4 sickle cell anaemia). A secondary aim was to investigate the impact of immune reconstitution on graft versus host disease but due to the extremely low incidence of acute and chronic graft versus host disease with this protocol (acute grade II to IV 11.6% and chronic 4.6%) we were unable to assess this. Transplant protocol: following hypertransfusion to suppress endogenous haemopoiesis, patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6). Graft versus host disease prophylaxis was provided with ciclosporin for six months and methotrexate 10 mg/m2 on days +4 and +7. All transplants used BM as source of stem cells. CMV PCR surveillance was undertaken twice weekly and CMV reactivation was treated with intravenous foscarnet or ganciclovir, followed by secondary prophylaxis with valganciclovir. Routine peripheral blood immunophenotyping of lymphocyte subsets was performed at 60-, 90-, 120-, 150- and 180- days post-BMT. Results: the median age of transplant recipients was 7 years (range 2 – 17 years) and median follow up 254 days (range 203–378). The median CD3/CD4+ cell count rose above 200 cells/μl by day 180 and above 300 cells/μl by day 254 following the withdrawal of immune suppression at six months (fig 1A), the median CD8+ cell count increased earlier, to 〉200 cells/μl by day 60 and 300 cells/μl by day 180 (fig 1B) and the median CD56+ cell count reached 200 cells/μl by day 60 and plateaued thereafter (fig 1C). Overall, CMV reactivation occurred in 13 patients (72.2%) after a median interval of 35 days following BM infusion (range day-1 to day +72): 10/13 patients (76.9%) in whom both recipient and donor were CMV positive (CMV +/+); 1/3 patients in whom recipient was CMV negative and donor CMV positive (CMV -/+); and in 1/1 who was CMV positive with a CMV negative donor (CMV +/−). Significantly there was no clinical CMV disease in any patient and with the use of oral valganciclovir there were no subsequent CMV reactivations. CMV reactivation occurred in patients with lower CD4+ cell counts at day 60 (67 cells/μl) compared with the CMV-unaffected group (a median CD4+ count 298 cells/μl; p= 0.0262). Four patients experienced other viral infections: HHV6 infection requiring foscarnet on day +85 (n=1), urinary BK virus not requiring treatment (n=2) and parainfluenza pneumonitis requiring ribavarin on day +12 (n=1). Conclusion: Low dose alemtuzumab conditioning is associated with rapid CD4+ cell recovery (CD4+ 〉200 cells/μl by day +180) in children undergoing allogeneic matched related donor BMT for haemoglobinopathy. Although there is a high frequency of CMV reactivation (72.2%) in patients with low CD4+ counts at day 60 (median CD4+ count 67 cells/μl), no clinical CMV disease was seen and subsequent reactivations of CMV were prevented by the use of valganciclovir secondary prophylaxis whilst awaiting full immune reconstitution. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1330 Veno-occlusive disease (VOD) remains a major cause of morbidity and mortality in children undergoing haematopoietic stem cell transplantation (HSCT) for thalassaemia. We investigated the impact of demographic characteristics, iron load (pre-transplant ferritin, hepatic iron concentration), hepatic fibrosis (Ishak staging), Pesaro risk class and defibrotide prophylaxis on the occurrence of VOD in 52 consecutive children (median age 6 years, range 2 – 18 years) undergoing myeloablative HLA-matched related donor HSCT for beta thalassaemia major (Pesaro class I n=27, class II n=23 and class III n=2). Following hypertransfusion to suppress endogenous haematopoiesis patients were conditioned with oral busulfan 14 mg/kg (days -9 to -6), cyclophosphamide 200 mg/kg (days -5 to -2) and alemtuzumab 0.3 mg/kg (days -8 to -6), except 2 Pesaro class III patients who received fludarabine instead of alemtuzumab. Graft versus host disease prophylaxis was ciclosporin for six months and methotrexate 10 mg/m2 on days +4 and +7. Forty patients had a liver biopsy prior to HSCT for Ishak staging of hepatic fibrosis. VOD was diagnosed in 18 (35%) according to Seattle criteria. The median onset of VOD was day +10 post-HSCT (range: 6 – 27 days); one patient developed late VOD on day +27. All patients had weight gain and hepatomegaly and the median peak bilirubin was 39 μmol/L (17 - 196). 13 patients (72%) had USS evidence of ascites and 3 (16%) patients had pleural effusion. Only 2 patients had reversal of portal blood flow on Doppler study. All patients who developed VOD were treated with defibrotide. Three (17%) patients required admission to intensive care for strict fluid balance and diuretic infusion and/or respiratory support without mortality. The incidence of VOD was highest in the pre-school children (10/22; 45%) compared to those aged 5–8 years (4/15; 27%) and 〉 8 years (4/15; 27%), although this difference was not statistically significant (p=0.13). No significant difference was noted in the gender (male=10/22; female=8/30, p=0.23) or ethnic origin (Middle-eastern=11/29; Asian=6/22, p=0.55). Pesaro risk class was associated with the occurrence of VOD: class I, 6/27 (22%); class II, 11/23 (47%), class III 1/2 (p=0.051). VOD occurred in 5/12 (41%), 7/20 (35%) and 2/7 (28%) of patients with hepatic iron 7 mg/g DW respectively (p=NS). The severity of hepatic fibrosis was significantly associated with the development of VOD: no fibrosis vs ≥ Ishak stage 3 fibrosis, p=0.024 (Fig. 1); stage 0 VOD 5/19 (26%); stage 1 VOD 2/9 (22%); stage 2 VOD 2/6 (33%); stage 3 VOD 3/5 (60%); and stage 4 VOD 1/1 (100%). To reduce the risk of VOD risk-adjusted defibrotide prophylaxis was introduced (hepatic iron concentration 〉4 mg/g dry weight and/or hepatic fibrosis ≥ stage 2). 5/19 (26%) developed VOD before introduction of defibrotide prophylaxis compared to 13/33 patients (39%) developed VOD after the introduction of defibrotide prophylaxis (p=0.34). Of the patients who developed VOD, 2/5 (40%) patients developed multiorgan failure requiring intensive care admission pre introduction of defibrotide prophylaxis whereas only 1/13 (8%) did subsequently. In summary, Pesaro risk class ≥2 and hepatic fibrosis ≥ stage 3 are significant risk factors for the occurrence of VOD. The degree of hepatic damage due to iron load is a predictor of VOD rather than hepatic iron concentration per se. Although introduction of defibrotide prophylaxis did not prevent VOD in this cohort, severe VOD only occurred in 1 patient, suggesting defibrotide prophylaxis may limit VOD in this high risk patient population. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Multiple myeloma (MM) is a remitting-relapsing malignancy with variable clinical outcome. Certain cytogenetic abnormalities, either present at diagnosis or emerged at later stages, predict for poor outcome and highlight the clinical importance of MM genetic heterogeneity. Whole genome and exome sequencing studies reveal a complex intraclonal genetic landscape, organised in linear and branching Darwinian patterns, which evolves in space and time. Clones with a more complex genetic architecture may be more fit to escape treatment and those patients are likely to have a worse clinical outcome. Clinical multicolour flow cytometry (MFC) is routinely used in MM diagnosis and detection of minimal residual disease. Previous studies have shown that MM cell subpopulations with discrete phenotypic features correspond to genetic subclones, therefore it is plausible that MFC data captures clonal heterogeneity. On that basis, we propose that clustering analysis of MM phenotypic subpopulations could be clinically relevant. Methods: We retrospectively analysed clinical MCF data at diagnosis from 44 patients eligible for autologous stem cell transplantation (AutoSCT) and 14 ineligible patients and data from 52 relapsed patients after first AutoSCT. All patients were treated between 2012 - 2018. The 8-colour MCF marker panel included CD138, CD38, CD56, CD45, CD20, CD19, cytoplasmic kappa and lambda light chains (cytLC). Data was analysed in FlowJo software and MM plasma cells were identified as CD38high, CD19-, cytLC+, within their FSC-A/SSC-A physical gate. The gated events were exported in a new fcs file. Clustering analysis was performed in Cytofkit, a R-based Bioconductor package, using the Rphenograph, Cluster-X and FlowSOM algorithms. All fcs files were subjected in the same clustering analysis, but CD56 positive and CD56 negative cases were analysed separately to offset bias from differential CD56 expression. Parameters inserted in the algorithms were FSC-A, CD138, CD38, CD45, CD20 and CD56. The number of clusters was produced by FlowSOM (k=4) and only clusters with size 〉1% of the total events were accepted. Results: At diagnosis, FlowSOM identified 1 (n=32, 56.1%) or 2 clusters (n=19, 33.3%) in most cases. Three clusters were found only in 5 patients (8.8%) and 4 clusters in 1 patient (1.8%). The number of clusters at diagnosis did not correlate with cytogenetic risk group or ISS. Also, the number of clusters did not predict for depth of response or relapse free survival post AutoSCT. On the contrary, phenotypic patterns at relapse post AutoSCT were more complex, with 1 cluster identified in 2 patients only (3.8%), 2 clusters in 23 (44.2%), 3 clusters in 24 (46.2%) and 4 clusters in 3 patients (5.8%). Patients with 〉2 clusters (n=27) had a shorter survival post relapse (median 17 months - 95% CI, 7-26.6) compared to those (n=25) with 1-2 phenotypic clusters (median not reached, Log rank p=0.06). A phenotypic cluster characterised by CD138low/- at relapse, was also associated with adverse outcome and higher risk cytogenetics. In 14 patients with available serial samples at diagnosis and relapse we observed 3 patterns of phenotypic evolution: a. sustained pattern, b. change of dominant cluster and c. emergence of completely new subpopulations. These evolving phenotypes resemble changes in clonal composition over time observed in genetic studies. Conclusion: Clinical MCF, in addition to routine diagnostics, can be informative of MM biological and clinical heterogeneity. Particularly in the relapsed setting, complex phenotypic patterns identified by clustering analysis may be of prognostic value. Validation of this preliminary study results in larger patient cohorts or clinical trials, could provide a useful and readily available tool for patient stratification and prognosis. Disclosures Apperley: Novartis: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau. Karadimitris:Celgene: Research Funding; GSK: Research Funding; Gilead: Honoraria.

Description: Abstract 1945 Introduction: Identification of prognostic indicators which predict outcome of allogeneic stem cell transplantation (allo-SCT) is important for selection of patients who may benefit from the procedure. The European Group for Blood and Marrow Transplantation (EBMT) proposed a scoring system for CML which, after modification, also predicted outcomes for patients transplanted for other hematologic malignancies. We have recently shown that the level of C-reactive protein (CRP) measured shortly before transplantation is another important prognostic factor in patients undergoing myeloablative allo-SCT. Patients and Methods: In this study we tested the value of CRP together with other known prognostic factors in 187 consecutive patients who underwent reduced intensity HCT in a single institution from 1995 through 2010. Disease stage was assessed in accordance with EBMT criteria. Preconditioning serum CRP levels were measured at a median of 15 days before stem cell infusion using a standard latex immunoassay. The median age at HCT of the 116 (62%) males and 71 (38%) females was 49 (range 15–67) years. Fifty seven patients (31%) were transplanted in early stage, 34 (18%) in intermediate stage and 96 (51%) in late stage of their disease. The diagnoses included: AML (n = 36; 19%), Hodgkin and non-Hodgkin lymphoma (n = 42; 23%), CML in first chronic phase (n = 29; 16 %), advanced phase CML (n = 21; 11%), MDS (n = 15; 8%), myeloma (n = 16; 9%), ALL (n = 7; 4 %), myelofibrosis (n = 5; 3%), and other (n = 16; 9 %). Patients were transplanted after conditioning containing fludarabine in combination with busulfan (n = 81, 43 %), cyclophosphamide (n = 37, 20 %), and melphalan (n = 47, 25 %); and lomustine, cytarabine, cyclophosphamide and etoposide (LACE) conditioning (n = 21; 11 %). Donors were HLA matched (n = 116; 62 %) and 1 – 2 antigen mismatched (n = 8; 4 %) siblings, matched (n = 46; 25 %) and 1–2 antigen mismatched unrelated (n = 11; 6%), and HLA haploidentical family members (n = 6; 3 %). Results: In univariate analysis, factors associated with day 100 non-relapse mortality (NRM) were disease stage, preconditioning CRP level and donor and recipient HLA match; whereas disease stage, CRP level, HLA match and number of previous allogeneic stem cell transplantations were associated with overall survival. In multivariate analysis only two factors showed independent prognostic value: disease stage (early / intermediate versus late) and CRP level (above versus below 10 mg/L). A CRP level 〉 10 and late disease stage predicted for higher NRM (RR: 1.83, CI 1.1 – 3.1, P =.021) and (RR: 1.78, CI 1.0 – 3.0, P =.037), and inferior survival (RR: 1.61, CI 1.1 – 2.4, P =.016) and (RR: 1.58, CI 1.1 – 2.3, P =.023) respectively. The day 100 NRM was 31% (95% CI 22 – 44) for patients with elevated CRP, and 13 % (95% CI 8–21) for those with normal CRP (P =.002; figure) and 20 % (95% CI 15–27) for the whole cohort. The 5-year survival was 41 % (95% CI 27 – 56) for patients with normal CRP, 21% (95% CI 12 – 35) for those with elevated CRP (P =.004) and 34 % (95% CI 25 – 44) for the whole cohort. Conclusion: There is no obvious explanation for increased NRM and reduced survival in patients with elevated CRP before initiation of conditioning. Nevertheless our findings provide evidence that preconditioning level of CRP constitutes a key prognostic factor in allo-SCT and should be integrated into existing risk assessment tools when considering allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 11 Stem cell transplantation (SCT) is currently the only curative option for sickle cell disease. Cerebrovascular disease (CVD) is one of the main indications to undertake this procedure as even with best conventional approaches there is a significant risk of recurrence or progression and there is evidence that SCT arrests disease progression, though more detailed study of outcomes is awaited. Early studies of SCT in sickle cell disease showed a high rate of neurological complications that led to the optimization of protocols. We conducted a retrospective analysis of related SCT in children with severe SCD between 2001 and 2010 at our institution to study the effect of transplantation. 20 patients (11 male, 9 female) received a BMT for sickle CVD (n=11) or recurrent vaso-occlusive crises (n=9). One patient with CVD was a second procedure following primary graft failure in a previous sibling transplant. CVD was investigated with clinical history and examination, transcranial Doppler ultrasound, magnetic resonance imaging/magnetic resonance angiography and psychometric testing using WISC-IV: 7 patients had no evidence of CVD, 5 had silent infarcts, 6 ischaemic stroke and 2 Moya-Moya disease. The median age at transplantation was 136 months (range 34 – 210 months). Donor source was HLA-matched siblings in 18 patients, one 9/10 mismatched sibling and HLA-matched relative in another. Bone marrow was used in all (n=19) but one patient who received combined bone marrow and umbilical cord. All patients (n=18) but two received conditioning with oral busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg; 1 patient received fludarabine 160 mg/m2, treosulfan 42 mg/m2, thiotepa 10mg/kg and ATG (Thymoglobulin) 11.25 mg/kg and 1 patient received oral busulfan 16mg/kg, cyclophosphamide 200 mg/kg and antilymphocyte globulin (45 mg/kg). GvHD prophylaxis was provided with ciclosporin and short course methotrexate (n=18), ciclosporin and MMF (n=1) and ciclosporin alone (n=1). Mean cell dose was 3.70 × 108 TNC/kg (range 1.45 – 6.16 × 108 TNC/kg). Neutrophil engrafment (〉0.5 × 109/L) occurred at a median of 19.5 days (range 12 – 28 days) and platelet engrafment (〉50 × 109/L) at median of 26 days (range 21 – 52 days). The median follow up is 974 days (range 270 – 3622 days). 18 patients achieved stable donor haemopoiesis, one patient suffered secondary graft failure due to Parvovirus B19 infection and one patient died on day +21 post-transplant due to sepsis and multi-organ failure. No significant sickle related neurological events occurred during these transplants. All 18 patients with long-term engraftment achieved radiological stabilization of the underlying CVD. Imaging performed at least 12 months post SCT showed no further changes from pre-transplant images. There were no clinical neurological events after SCT. Psychometric testing demonstrated improvements in all areas in patients transplanted for silent infarcts, particularly those affecting processing speed. In summary, SCT appears safe even in patients with severe CVD, arrests further progression and shows functional improvement. Disclosures: No relevant conflicts of interest to declare.

Description: Blood and marrow transplantation (BMT) is the only proven curative treatment available for haemoglobinopathies. From October 2010 to May 2013 thirty-eight patients with haemoglobinoapathies received a BMT at St. Mary’s Hospital, London. The conditioning included fludarabine 160 mg/m2, treosulfan 42 g/m2, thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg or 11.25 mg/kg (FTTA). GvHD prophylaxis was ciclosporin for six months and MMF until molecular evidence of donor engraftment. Patients with SCD received clonazepam CNS prophylaxis whilst on immunosuppression. Endogenous haemopoiesis was suppressed with hypertransfusions for at least six weeks pre-transplantation to minimise the risk of rejection. All patients had iron load assessed by MRI T2* and FerriScan and hepatic fibrosis staged by liver biopsy pre-transplantation. Patients with liver fibrosis Ishak ≥3 were given defibrotide prophylaxis. Twenty-six patients suffered from thalassaemia major (TM) and from 12 sickle cell disease (SCD). Patients with TM were Pesaro class I or II. Patients with SCD were transplanted for stroke or recurrent vaso-oclusive crisis and/or acute chest syndrome not responding to hydroxycarbamide. The median age was 7 years (range 2-17). The median follow-up was 10.18 months (range 1.02 -25.1). Thirty-six patients received stem cells from a related donor (31 matched sibling bone marrow, 2 matched other relatives, two 9/10 mismatched siblings, and one 9/10 mismatched other relative) and 2 from unrelated donors (1 fully matched and one 9/10 mismatch). The source of stem cells was bone marrow (BM) in 32 patients, mixed BM and cord blood (CB) in 3 patients, CB in 2 patients and PBSC in one patient. The median cell dose 3.61 x108 TNC/kg (range 0.58 -9.77) and 5.99 x108 TNC/kg (range 1.15 -14.23). All patients engrafted, though one related CB transplant suffered secondary graft failure on day +26 due to disseminated adenovirus infection. The median neutrophil engraftment occurred on day +12 (range 9-21). Three patients (7.8%) suffered VOD, presenting at a median of 9 days (7-11) which was successfully treated with defibrotide. Acute GvHD grade 1 occurred in 1 patient (2.6%) and grade ≥2 in 5 patients (13.2%), which resolved in all patients including 2 who received MSC. cGVHD 〉day +100 post-transplantation was limited in 2 (7.9%) and extensive in 2 patients (5.3%) and fully resolved in all cases with appropriate treatment. Two patients have died of a transplant related cause: a related CB transplant for TM of disseminated adenovirus infection on day +31 and a related BM transplant for SCD of an intracranial haemorrhage on day +185 due to immune thrombocytopenia and parvovirus B19 infection. Chimerism studies in whole blood demonstrated donor haemopoiesis as follows: day +28: 94% 〉95% and 6% 〉90-95%; day +90: 93.2% 〉95%, 3.4% 〉90-95% and 3.4% 〉80-90%; day +120: 84% 〉95%, 8% 〉90-95%, 4% 〉50-80% and 4% 95%, 24% 〉90-95%, 4% 〉80-90%, 4% 〉50-80% and 4% 95%, 25% 〉90-95%, 8.3% 〉80-90% and 4.3% 〉50-80%; day +360: 61.5% 〉95%, 30.8% 〉90-95% and 7.7% 〉30-50%. Donor T-cell lymphopoiesis was day +28: 100% (28 – 100), day +90: 99% (16-100), day +150: 96% (36-100), day +180: 96% (54-100) and day +360: 94.5% (78-100). In conclusion, FTTA leads to high levels of long-term donor engraftment and enables the use of mismatched and unrelated donors for transplantation in haemoglobinopathies with limited toxicity Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because a human leukocyte antigen (HLA) matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. The likelihood of finding a 10/10 (HLA-A, B, C, DRB1 and DQB1) matched donor varies among ethnic groups, with the lowest probability among individuals of African descent. To date, few series of SCD patients transplanted with an unrelated donor (UD) have been reported, but the high rates of rejection and chronic graft versus host disease (cGvHD) have limited its widespread application. Patients and methods: We report the results of a retrospective, registry based, survey on 70 UD HSCT performed in patients (pts) with SCD from UD in 22 European Society for Blood and Marrow Transplantation (EBMT) centers between 2005 and 2017. Data were collected from the EBMT database and missing information was updated by the centers. Median follow up was 38 (range 2-154) months. Most pts were HbSS (n=54; 78%), had positive serology for CMV (80%), and a Karnofsky score 〉80% (98%). Eighteen pts had a major ABO incompatibility. Recurrent vaso-occlusive crisis (n=58), cerebral vasculopathy (n=23) and acute chest syndrome (n=24) were the main indications for HSCT. Red blood cell (RBC) transfusions pre-HSCT were reported in 97% of pts of whom 53% received more than 20 transfusions; 14% of the transfused pts had RBC alloantibodies. Hydroxyurea pre-HSCT was used in 65% of pts. Median age at HSCT was 9.6 years (range 2-43) with 87% of pts being ≤ 16 years. Stem cell source was bone marrow (BM) in 55 pts (79%) and peripheral blood (PBSC) in 15 (21%). The median number of infused TNC /kg was 3.6 x 108 for BM and 7.1 x 108 for PBSC; the median number of infused CD34/kg was 4.4 x 106 for BM and 8.3 x 106 for PBSC. HLA matching at high resolution typing was 10/10 (HLA-A, B, C, DRB1 and DQB1) in 31, 9/10 in 17 and 8/10 in 4 of the patient-donor pairs; intermediate resolution typing was available for 10 (10/10 or 9/10) and the HLA information was missing for the remaining 8 patient-donor pairs. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) and busulfan- cyclophosphamide (12%). GvHD prophylaxis was cyclosporine plus methotrexate in 59%. Anti-thymocyte globulin was used in 90% and alemtuzumab in 9% of pts. Results: The cumulative incidence (CI) of neutrophil engraftment at 60 days was 93% (95% CI 76-100), with median time to engraftment of 18 days; platelet engraftment at 180 days was 90% (95% CI 83-98) with a median time of 20 days. Ten pts had graft failure (5 primary and 5 secondary) of whom 6 had a second transplant and were all alive at last FU (median 9.5 months after second HSCT). The CI of grade II-IV aGVHD at 100 days was 23% (95% CI 15-36), and 8 pts (11%) had grade III-IV. Acute GVHD was more frequent in patients who received PBSC (PBSC 42.9%, BM 18.2%, p=0.062). Three-year CI of cGVHD was 23% (95% CI 15-36), 7 pts (10%) had limited and 9 (13%) extensive cGvHD. Three-year overall survival (OS) was 90±4%; three-year event free survival (EFS) (considering death and graft failure as events) was 76±6%; HLA matching between donor and recipient was the most important factor for OS and EFS. Considering only pts-donor pairs with high resolution HLA typing available (n=52), 3-year OS was 96±4% in 10/10 group compared to 77±11% in 9/10 plus 8/10 group (p 0.065), 3-year EFS was 85±7% vs 62±12% (p 0.040), respectively. No significant differences between the groups were observed in CI of neutrophil engraftment, aGVHD and cGVHD. Conclusion: UD HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor. Nevertheless, efforts are still needed to improve outcomes after UD HSCT. Our results indicate that using a 10/10 HLA matched UD improves both OS and EFS compared to donors with 1 or more mismatches; so, when such a matched unrelated donor is not found, using an haplo relative or an unrelated cord blood as donor source should be evaluated. A prospective trial is in preparation to evaluate the use of haploidentical donors for HSCT in SCD (EudraCT number: 2018-002652-33). Disclosures No relevant conflicts of interest to declare.