ALBERT

Description: Chronic Graft-versus-Host Disease (cGVHD) has a negative impact on transplant related death and quality of life after hematopoietic stem cell transplantation. In an attempt to thoroughly assess cGVHD after double umbilical cord blood transplantation (dUCBT), we used the major revised consensus criteria (NCC 2005) proposed by the National Institutes of Health (NIH) in 2005. Material and methods: This is a retrospective study using Eurocord-EBMT database. A specific questionnaire including the NCC 2005 characteristics and features was sent to each transplant centers for collecting data. Eligible pts were adults 〉18years, who received dUCBT for hematological malignancy in an EBMT center between 2006 and 2014, achieved neutrophil engraftment, survived ≥100 days and developed cGVHD. Results: A total of 154 pts were included. Median age at dUCBT was 43 years (18-70). The primary diagnosis was acute myeloid leukemia in 40%, acute lymphoblastic leukemia in 21%, myelodysplastic/myeloproliferative disease in 19%, and other hematological disorders in 20%. The majority of pts was transplanted in CR, including 51% in CR1, 37% in CR2. Reduced intensity conditioning regimen (mainly with low dose total body irradiation) was used in 60% of cases. 24% pts received anti-thymocyte globulin before transplant. Cyclosporine and mycophenolate mofetil (MMF) was the most common (79%) combination for GVHD prophylaxis. 70% (n=107) of pts received gender mismatched grafts, and 59% had 1-2 major ABO incompatibility. Most (〉80%) grafts had 2 HLA mismatches with the recipients. Median number of total nucleated cells at cryopreservation was 5.1(2.3-13.3) ×107/Kg. All pts achieved neutrophil engraftment in a median of 25 days and 89% had full donor chimerism at day 100. Median follow-up was 27.5 (3-103) months, 45 pts relapsed and 60 pts died (28 of relapse, 12 of GVHD and 20 of other TRM). Grade II-IV acute GVHD occurred in 88 pts in a median time of 24 (6-106) days. Grade III-IV aGVHD was reported in 43 pts, mainly with skin and gastrointestinal (GI) tract involvement. Median time for cGVHD onset was 219 (47-2056) days, and most of these were reported within the first 1.5-2 years. Based on Seattle criteria, cGVHD was limited in 73 (47%) pts and extensive in 81 (53%) pts. According to NIH criteria (NCC2005), global cGVHD severity was scored as mild in 67 (44%), moderate in 53 (35%) and severe in 33 pts (21%). cGVHD presented mainly as one or two organs involvement, with skin being the most common site. 56% pts (n=86) had a single organ involvement (mainly skin n=60; 38%). Skin, GI tract, and oral mucosa were the top three affected sites (93%; n=143), both in solo and multiple involvements. 23 patients had 〉 3 affected organs, skin being most common (n=20; 87%). No joint or fascia involvement was reported as a single organ involvement in any grade. Mild and moderate cGVHD presented as one or two organs involvement, mainly affecting skin, GI and oral mucosa. Severe cGVHD often involved skin, GI, lung and liver. Severe GI tract cGVHD was mostly reported as a single organ involvement. Severe lung involvement was reported in 12 pts (8%). Major functional impact by scoring grade 3 was observed in skin (n=7), GI (n=8), liver (n=5), eye (n=3), oral mucosa (n=2), and lung (n=5). Twenty %pts (n=31) received only topical or no treatment, for 1 or 2 organs involvement and mild to moderate grade cGVHD. The first line treatment of cGVHD included systemic steroids +/- calcineurin inhibitors (CNI) or MMF based regimen, and was used in 72% pts (n=111). cGVHD resolved in 94 pts (61%), and remained clinically significant in 57 pts (mild, n=14; moderate, n=20 and severe, n=23). Among the 12 pts who died of cGVHD, there was multiple organs involvement in most cases; and 6 pts had severe lung cGVHD. Conclusion: According to NCC 2005 criteria, we report that, after dUCBT, cGVH was usually mild with skin being the most common site resulting, in this small group of patients, in a relatively low incidence of severe cGVH with as a consequence a better survival and quality of life. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria.

Description: Introduction and Aim: HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly offered to patients with high-risk acute myeloid (AML) or lymphoid leukemia (ALL). Unfortunately, graft manipulation employed to overcome the HLA barrier significantly delays immune reconstitution, posing the patients at risk of infections. Accordingly, non-relapse mortality after haplo-HSCT clearly extends beyond day 100 post-transplant. Over the years, different approaches have been investigated to speed-up immune reconstitution. In the absence of validated immune biomarkers, it is however difficult to evaluate the clinical impact of accelerated immune reconstitution. The aim of this EBMT retrospective study is to explore immune-cell counts early after haplo-HSCT as predictive of its overall outcome. Methods and Patients: Among AML and ALL patients in the EBMT database who underwent haplo-HSCT in the period 2001-2012, criteria for study entry were survival beyond day 100 and availability of differential immune-cell counts (CD3+, CD4+, CD8+ T cells, CD19+ B cells, CD16+/CD56+ NK cells) within this period. Accordingly, statistical analysis was landmarked at day 100. Of 259 patients meeting these criteria (age 2-70, median 33), 67 (26%) were children. The underlying disease was AML in 162 cases (63%), while ALL in the remaining (including 5 cases of bi-phenotypic leukemia). Fifty-two percent of patients were transplanted in CR1. The stem-cell source was G-CSF mobilized peripheral blood in all but one patient (〉99%) and 171 received TBI (66%). The graft was manipulated in 199 patients (78%), including CD34-selection (50%), ex vivo T-cell depletion (15%) or both (13%). Female-to-male transplants were 68 (26%), while 204 (79%) recipients were CMV seropositive. Sustained hematopoietic engraftment was reached in 246 patients (95%) Results: The estimated overall survival at 2yrs was43%. The estimated cumulative incidence of death due to relapse was 33%, while that of death due to other causes was 35% (51% of those were infections) The occurrence of grade III-IV GVHD and of chronic GVHD was 9% and 18% (7% extensive), respectively. As expected, overall survival was better in children (62% vs 36%, P=0.002 by Log-rank), who clearly had a lower incidence of death due to causes other than relapse compared with adults (10% vs 37%, P=0.0001). Negative prognostic factors for overall survival were any disease state other than CR1 at time of transplantation (P=0.002) and CMV seropositivity (P=0.009). Type of leukemia, TBI or graft manipulation had no effect on the outcome. By day 100 post-transplant, patients reached the following median immune-cell counts: 100 CD3+ T cells (range 0-2576), 30 CD4+ T cells (0-1714), 48 CD8+ T cells (0-1880), 276 CD16+/CD56+ NK cells (18-3581), 21 CD19+ B cells (0-790). Importantly, CD3+ counts above the first quartile (1Q) of the entire data set (29 cells per microL) were significantly associated with a better overall survival (P=0.0005 by Log rank) and a lower incidence of death due to causes other than relapse (P=0.002 by Gray test). The same held true for CD8+ counts (1Q: 15 cells per microL; P=0.003 on overall survival; P=0.0004 on death due to other causes). CD4+ counts also showed similar correlations, but at higher values (above the median). None of the other immune-cell counts analyzed correlated with clinical outcome. Strikingly, when challenged in multivariate analysis taking into account age category, CMV seropositivity, graft manipulation and CR1 status at transplant, CD3+ and CD8+ counts above the 1Q adjusted to fit optimal cut-off points were still significantly associated with a better overall survival (P=0.006 and P=0.015, respectively), but only CD8+ values associated with a lesser risk of death due to causes other than relapse (P=0.026). Conversely, similarly adjusted median CD4+ counts failed to show any association. Conclusions: Contrary to what is generally accepted, these results indicate that an accelerated CD8+, but not CD4+, T cell reconstitution associates with a more favorable clinical outcome after haplo-HSCT, likely due to its protective role against opportunistic viral infections. Moreover, they suggest that yet to be validated CD8+ cut-off points, rather than the commonly used arbitrary value of 200 CD4+ T cells per microL, should be considered as surrogate biomarkers in clinical trials. Disclosures Bonini: MolMed S.p.A: Consultancy.

Description: Identifying pre-transplant risk factor before allogeneic transplantation (HSCT) is important, regardless of the graft source. Nonetheless, it has been demonstrated that disease type and status at the time of HSCT significantly affect outcome. Disease risk index (DRI) has been recently defined for stratifying large and heterogeneous cohorts of patients (pts) undergoing HSCT. The original DRI included all hematological malignancies (except very rare diseases) and was able to define 4 distinct groups with different outcomes, dividing patients by disease type and status and considering cytogenetics that turned to be determinant for acute myeloid leukemia and myelodysplastic syndromes (MDS). Recently, DRI was refined by including rare diseases and improving MDS stratification by blast percentage, cytogenetics and response to prior therapy. DRI has been demonstrated to be applicable to pts undergoing HSCT regardless of age, conditioning regimen and graft source, and it has also been validated in pts undergoing T-cell depleted HSCT. Currently, there are no available reports on large cohort of pts undergoing umbilical cord blood transplantation (UCBT). Our aim was to determine the impact of DRI after UCBT. We retrospectively analyzed 2337 adults who underwent UCBT between 2004 and 2014, were reported to Eurocord and had available data for DRI scoring. Diagnosis was acute leukemia (AL) in 66% of the cases; 56% of AL were transplanted in first complete remission (CR), 39% in CR2 and 6% in 〉CR2. The median age at UCBT was 43 (range 18-76) years. Cytomegalovirus (CMV) serology was positive in 62% of pts; 45% of pts were female. Performance status at UCBT was 90% in 44%. Fifty-two percent of pts received double and 48% single UCBT. Conditioning regimen was reduced intensity (RIC) for 52% of pts, and the most common regimen was cyclophosphamide+fludarabine+low dose total body irradiation (2Gy) for 72% of pts. Cyclosporine A (CsA) and mycophenolate mofetil (MMF) were used for graft-versus-host-disease (GVHD) prophylaxis in 61% of the pts. Anti-thymocyte globulin (ATG) was given in 41% of pts. Median TNC at cryopreservation was 4.2 x 107/Kg (range 0.4-13) and 56% of pts received a graft with 2or more HLA mismatches.The median follow-up was 30 (range 1-120) months. Overall survival (OS) and progression free survival (PFS) were 44% and 38% at 2 years, respectively. Refined DRI stratified pts in 4 subgroup (low risk, n=352, intermediate, n=1303, high, n=544, and very high-risk, n=138). OS was 56±3% for pts with low-risk DRI, 48±2% for intermediate-risk DRI, 31±2% for pts with high-risk DRI and 26±4% for pts with very high-risk DRI (p

Description: Background: In acute lymphoblastic leukemia (ALL) in CR1, the indications of allogeneic stem cell transplantation (allo-SCT) remain under debate, given the recent availability of new therapeutic tools including novel chemotherapy agents, monoclonal antibodies and T cell cellular therapies as well as sensitive molecular techniques to assess minimal residual disease (MRD). In contrast, allo-SCT for ALL in CR2 is a well-established procedure. At the same time, unmanipulated grafts are increasingly used in the haplo-setting, and innovative regimens for GvHD prophylaxis have been adopted with encouraging results. Aims : The current study aimed to compare the outcomes of ALL patients (pts) who do not have a matched sibling and received allo-SCT in CR2 from a matched-unrelated donor 10/10 (MUD) versus alternative donors: unrelated donor 9/10 (UD), cord blood unit (CBU) and haplo-identical T replete donor (HD). Methods: Patients with ALL in CR2 who underwent a first allo-SCT with a MUD or an UD, a CBU or HD, reported between 2005 and 2015 to the registry of the EBMT ALWP, were included. The major endpoints were to assess overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM), and graft-versus-host disease-free, relapse-free survival (GRFS) Results: Four hundred twenty eight pts received a MUD 10/10, 171 pts an UD 9/10, 148 pts a CBU and 94 a T replete HD. Median age was lower in the CBU group compared to the other groups (26.1 yrs (18-76) vs 31.6 (18-74) , p18months (DxTx〉18 m)(HR=0.66, 95%CI, 0.54-0.81, p18m, KS ≥90% and the year of transplant. In multivariate analysis for RI, only DxTx〉18m was a protective factor (HR=0.49, 95%CI, 0.38-0.65, p18m and the year of transplant were associated with better GRFS (HR=0.69, 95%CI, 0.57-0.84, p