ALBERT

Description: Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age

Description: Cyclophosphamide (CY) associated to high dose total body irradiation (TBI) or busulfan (BU) is the gold standard of myeloablative conditioning regimen (MAC) in allogeneic hematopoietic stem cell transplantation (HSCT). In unrelated transplants, anti-T cell serotherapy (ATG/ALG) is often added as immunosuppressive drug. Recently, new drugs such as fludarabine (FLU) or thiotepa (TT) have also shown their value in conditioning regimen. However, no MAC has shown to be significantly superior to the conventional TBICY or BUCY. Unrelated cord blood transplantation (UCBT) has been increasingly used in adult patients lacking a HLA-matched donor, but the impact of MAC in this setting is unknown. In order to do so, we analyzed 226 patients who underwent single UCBT after MAC for leukemia [acute lymphoblastic leukemia (n=80), acute myeloid leukemia (n=86), myelodysplasia (n=33), chronic myeloid leukemia (n=27)]. According to IBMTR classification, 60% of patients had early- or intermediate-risk disease status at transplantation. All patients were transplanted from January 2000 to February 2008 in Europe. Median age was 33 years (18–60) and median follow-up was 21 months (2–96). UCB grafts had ≥ 2 HLA incompatibilities in 62% of cases; median nucleated cell dose infused was 2.5 × 107/kg. Ninety-three percent of patients received ATG/ALG before day 0. Three groups of MAC were observed: group 1- TBICY or BUCY (n=82; 36%), group 2- CY+TT (mostly associated to BU) (n=73; 32%) and group 3- FLU based regimens (mostly associated to intravenous BU 9.6 mg/kg and TT 10 mg/kg) (n=71; 31%). Graftversus- host disease (GVHD) prophylaxis consisted of cyclosporine and corticosteroids in 77% of patients. Patients-, disease- and transplant-related factors were compared among the 3 conditioning groups. All 3 groups showed the same frequency of diagnosis and status of the disease at transplantation. Group 1 (TBICY or BUCY), included a higher number of patients with negative CMV serology, transplanted before 2004, ≥ 2 HLA disparity and higher number of infused cells compared to group 2 and/or group 3. There was no statistical difference of those characteristics between group 2 and 3. Cumulative incidence of 60 day-neutrophil recovery (〉500/mm3), 180 day-platelet recovery (〉20000/mm3), 100 day-acute GVHD, 100 day non-relapse mortality (NRM) and relapse at 2 years were 80±3%, 52±3%, 24±3%, 28±3% and 24±4%, respectively. Two-year disease-free survival (DFS) was 37%±5 for patients transplanted in remission and 22±5% for those in more advanced phase (p=0.001). The association of groups of MAC and outcomes are shown in the table below. In a center effect adjusted multivariate analysis, among other variables such as CMV recipient serology, disease status and HLA disparity, groups 2 and 3 confirmed an increased incidence of neutrophil recovery [hazard ratio (HR)=0.44 (95% CI 0.32–0.60)] and platelets recovery [HR=0.52 (95% CI 0.34–0.79)]. However, none of the conditioning regimens were associated with acute GVHD, 100-day NRM or DFS. Conclusion: these findings support the use of fludarabine and/or thiotepa based MAC as a strategy to improve neutrophil/platelet recovery after single UCBT in patients with leukemia. Further prospective randomized trials should be performed to address this issue. Conditioning regimens Neutrophil recovery (day+60) Platelets recovery (day+180) AGVHD (II–IV) (day +100) NRM (day +100) DFS (2 years) Group 1 - TBICY or BUCY (n=82) 71±5% 39±5% 17±4% 28±5% 28±6 Group 2 - CY+TT (± BU or TBI) (n=73) 78±5% 53±6% 37±6% 38±6% 29±5 Group 3 - FLU (+ BU + TT) (n=71) 92±4% 66±6% 18±5% 17±4% 35±7 P (overall)

Description: Single center studies have demonstrated promising results in recipients of unrelated umbilical cord blood transplantation (UCBT) treated with a reduced intensity conditioning (RIC). However, little is known about risk factors for outcomes with this strategy. We retrospectively evaluated outcomes after RIC-UCBT in 176 patients with hematological malignancies: 116 had acute leukemia (21 ALL, 77 AML, 18 secAML), 36 lymphoid/plasma-cell diseases (6 Hodgkin, 24 NHL, 4 CLL and 2 Myeloma) and 24 myelodysplastic/myeloproliferative diseases (14 MDS and 10 CML). Median follow-up was 12 months (3–80) and median age 45 years (16–76). At transplant, 51% of patients were in advanced phase of disease and 30% had a previous autologous transplants. The conditioning regimen varied according to disease and centre; however, 95% received Fludarabine (FLU)-containing regimen, 55% being FLU-CY-TBI(2Gy), and ATG/ALG was added in 23%. GVHD prophylaxis consisted most commonly (72%) of CsA+MMF. All received a single UCB unit graft that was HLA identical (6/6) (HLA A and B low resolution and DRB1 allelic typing) in 6%, 5/6 in 27%, 4/6 55% and 3/6 in 11%. The median total nucleated cell dose infused was 2.7 × 107/kg. Median time to neutrophil recovery was 20 days (5–56) and probability of neutrophil recovery was 78±3% at day-60. Chimerism analysis at 3 months was complete in 64%, mixed in 16% and absent (autologous reconstitution) in 19%. In multivariate analysis, cell dose (〈 vs 〉2.7 × 107/kg, HR=1.6, p=0.02), HLA compatibility (5–6/6 vs 3–4/6, HR=1.5, p=0.04) and use of FLU+CY+TBI versus other regimens (HR=1.7, p=0.01), were independently associated with neutrophil recovery. At day-100, probability of acute GVHD II–IV was 30% (18% grade II; 6% grade III, 6% grade IV), and no risk factor was associated with its incidence. At 1 year, probability of chronic GVHD was 30%. TRM was 38% at 1 year, being 19% for patients given low dose TBI (

Description: Background: Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of UCB in elderly and unfit patients without an HLA identical donor. KIR ligand incompatibility between donor and recipient might favor Natural Killer (NK) cell alloreactivity after UCBT in AML patients (Wilhemze et al, 2009), although contradictory results were reported (Brunstein et al, 2009). We previously reported the results of the biological NK cell reconstitution after RIC-UCBT in a French prospective phase II multicentric trial (Rio et al, 2015). We showed that NK cells generated from RIC-UCBT exhibited features of transient immaturity and stable activation, correlating with a high ability to produce IFN-γ and a quick restoration of the ability both to produce TNF-α and degranulate (Souchet et al, ASH 2013). The aim of the present study is to analyze the impact of KIR ligand incompatibilities and NK cell reconstitution on OS, DFS and TRM after RIC-UCBT in a prospective trial. Materials and methods: Seventy-six patients with a de novo or secondary AML in complete remission were enrolled in 23 centers from Oct. 2007 to Sept. 2009. Peripheral blood samples were collected during the first year following UCBT in order to realize an extensive prospective phenotypic and functional study of NK cells. DNA samples were also collected in recipient and cords blood to perform KIROTYPE and HLA-C allelic typing. NK biological data were available at M1 for 54 patients. The inhibitory Killer-Immunoglobin Receptors (KIR) KIR2DL1, and KIR2DL2/3 bind KIR ligand C2 and C1 respectively, resulting in inhibition of NK-cell mediated lysis. Recipients and UCB were classified into C1 or C2 family depending on their HLA-C typing (C1-C1, C1-C2 or C2-C2). Results: Among the 54 patients, 35 events occurred (relapse or TRM). Median EFS and OS were 13.2 and 18.3 months, respectively. Recipients C2-C2 had a significant worse EFS and OS than C1-C1 or C1-C2 (median EFS C2-C2=3.8 month vs 15.1 month for C1-x; p=0.002); median OS C2-C2 3.8 months vs 29.9 months for C1-x; HR=6.12, IC95% [2.069; 18.113], p=0.001). High intracellular staining of CD107a, reflecting the capacity of NK degranulation with HLA negative K562 target, correlated with better OS. CD107a expression was divided in 2 groups at median (=51%). Median OS of CD107 (0-50%) was 12.8 months vs 20.9 months for CD107a (51-66); p=0.029. Relapse risk was highly increased in recipients C2-C2 (HR=5.04 (IC 95% [1.23; 20.56], p=0.02). Low expression of CD16 (HR=0.97, IC95% [0.937; 0.999], p=0.043), high expression of HLA-DR (HR=1.08, IC95% [1.031; 1.123], p=8e-04) on NK cells, and recipients C2-C2 (HR=9.44, IC95% [1.311; 67.882], p=0.026) significantly increased the risk of TRM. The inhibitory KIR2DL1 receptor binds to C2 ligands. Of interest, KIR2DL1 was significantly decreased on C2-C2 recipients NK cells at M1, as compared to C1-x recipients NK cells. On the contrary, KIR2DL2/3 and KIR3DL1 restored promptly, suggesting a sequential expression of KIRs. As interaction between inhibitory KIRs and their ligands are essential for NK cells to become functional ("licensing" process), we can hypothesize that the weaker expression of KIR2DL1 on C2-C2 NK cells alters the licensing process, rendering the NK cells hypo-responsiveness. Conclusion: Recipient C2-C2 is correlated with a worse outcome (EFS, OS, relapse, TRM) after RIC-UCBT in a prospective trial for AML patients. Weak capacity of degranulation and low expression of CD16 are associated with worse OS and increased TRM, respectively. These features can reflect an alteration of the NK licensing process and might have impact on clinical outcome after UCBT. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3460 Autoimmune diseases (AD) have been reported after haematopoetic stem cell transplantation (HSCT) and most commonly autoimmune cytopenias (AIC) are observed. Proposed risk factors are unrelated donor HSCT and presence of chronic graft-versus-host disease (GVHD). Use of CB cells is increasing as an alternative source of adults HSC for allotransplant however incidence and risk factors of AD after CBT have not been described. Since CB lymphocytes are immature and most of the CBT are HLA mismatched, we hypothesize a high incidence and diversity of secondary AD and. Therefore, we conducted a retrospective study in order to describe incidence, nature and risk factors for secondary AD after CBT. We include CBT recipients reported to EUROCORD up to December 2008. All centres were asked to participate to the survey even if they did not observe any case of AD after CBT. For those with AD, detailed information on diagnosis, treatment and outcome were asked. Median follow-up was 44 months (3.2-217). 42 out of 651 patients (pts) from 35 centres had developed at least one secondary AD at a median of 198 days (27-4267) after CBT. The remaining 609 pts without secondary AD served as control group (nonAD). Characteristics of both groups are given in table 1. Cumulative incidence of secondary AD after CBT was 5±1% after 3 years and 6.5±1% after 10 years. Diagnosis of secondary AD were autoimmune haemolytic anemia (AIHA) in 16, autoimmune thrombopenia (ITP) in 9, EVANS syndrome in 6, autoimmune thyroiditis in 3, glomerulonephritis in 2, Graves disease, psoriasis, psoriasis arthritis, immune neutropenia, ulcerative colitis and vasculitis in 1 patient each. Three pts developed ITP followed by AIHA. Median time to develop a AIC was 180 days (27-4267) and non-hematological AD was 322 days (70-1117), respectively (p=0.13). At onset of AD, 3 pts had acute GvHD, 6 chronic GvHD and in 10 pts an infection. In multivariate analysis adjusted for differences between the two groups, the following factors were associated with higher incidence of secondary AD: 1) age

Description: Abstract 2266 We conducted a national retrospective analysis on 63 patients (pts) with either myeloid or lymphoid BC CML who underwent a first allogeneic stem cell transplantation as consolidation therapy for BC, since 2000 in France and look at whether 1st and 2nd generation TKIs ±chemotherapy prior to transplant may impact on outcome. There were 46 males and 17 females, and the median age at transplant was 34 (range 3–63) years and the median delay between BC and transplant was 19.6 (2.3-113) months. Thirty six (57%) pts were in chronic phase (CP), 3 (5%) in accelerated and 24 (38%) in BC at CML diagnosis. Twenty three pts received 1 line of treatment, 26 pts 2 lines, and 14 pts 3 or more lines for CML treatment before BC. For BC treatment, 25/63 (39%) pts had chemotherapy without TKI and 29/63 (46%) had TKIs combined or not to chemotherapy (6 chemo+dasatinib, 4 chemo+imatinib, 8 dasatinib alone, 1 dasatinib and imatinib, 9 imatinib, 9 unknown). At transplant 35/63 (55%) were considered in 2nd CP and 28 (45%) still in BC. The majority of the pts had an identical sibling donor (42/63: 66%), 1 mismatched related, 7 matched unrelated, and 13 mismatched unrelated. Fifty-six (89%) pts had a standard conditioning regimen, 7 (11%) pts a RIC regimen and 39 (62%) had a TBI. The stem cell source was bone marrow in 33/63 (52%) pts, PBSC in 24/63 (38%) and cord blood for 6/63 (10%). Fourteen transplants were sex-mismatched (female donor for male recipient). The EBMT-Gratwohl score was low (1+2+3) for 35/63 (55%) pts, intermediate (4) for 14 pts and high (5) for 9 pts, (and 6) for 3 pts and undetermined for 2 pts. The median follow-up since transplant was 25 (range 0.43–109) months. The overall median time for neutrophil recovery (neutrophils 〉 0.5 109/l) was 20 days. Fourty-one (65%) pts had an aGVHD (29 grade i-II and 12 grade III-IV) with no statistical differences between stem cell sources (p=0.4 for cord vs BM and 0.58 for PBSC vs BM). The cumulative incidence of chronic GVHD (14 extensive, 10 limited) was 43% at latest follow-up, more frequent in RIC transplant. The cumulative incidence of CML relapse was 38% at 2 yrs and multivariate analysis demonstrated the significant impact on relapse of the status at transplant in favour of disease control prior to transplant [HR 2.22 (1-4.93, p=0.05] and unexpectedly, no impact of BC treatment with or without TKIs prior to transplant and of other variables. The median overall survival (OS) was 22 months (see Figure 1). The TRM was 33% at latest follow-up, and it was significantly negatively influenced by the EBMT score (p=0.0077 for scores ≥ 4), BC status at diagnosis (p=0.04). The OS was not improved when using standard conditioning regimens (p=ns), but was improved by disease status at transplant (2nd CP better than persistent BC, p=0.01) and transplant with cord blood and BM stem cell sources over PBSC (p=0.011). Multivariate analysis on OS detected as significant adverse prognosis factors EBMT score ≥5 (HR=4.63 EBMT 5, and 4.77 EBMT 6). The types of treatment of BC CML had no significant impact (with or without stratification on chemotherapy). The median progression-free survival (PFS) was 5.8 months (see Figure 2). The PFS was not significantly improved by standard conditioning regimens but again was improved by disease control prior to transplant (2nd CP better than persistent BC, p=0.001) and with cord blood and BM stem cell sources over PBSC (p=0.057). Multivariate analysis on PFS detected as significant adverse prognosis factors EBMT score ≥5 (HR=5.82 EBMT 5, and 3.82 EBMT 6), but again, the types of treatment of BC CML prior to transplant had no significant impact. In conclusion, this analysis suggests that OS and PFS rates are significantly improved when compared to figures from the pre-TKI era. The use of 1st or 2nd generation TKIs alone or combined to chemotherapy does not seem to influence transplant results. CML status and the EBMT score are the major factors that can significantly influence transplant outcome. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 534 Introduction: There is increasing information about reduced intensity conditioning regimen AlloHSCT (Allogeneic Hematopoietic Stem Cell Transplantation) in children. The safety of this approach is now well established but data regarding efficacy are limited and the role in pediatric cancer has yet to be defined. Materiels and methods: We report results of a French pediatric AlloHSCT protocol with ATG-fludarabine (180 mg/m2) - Busilvex (3.2 at 4.8 mg/kg/d for 2 days) conditioning regimen. Related, unrelated bone marrow (BM) and Peripheral blood stem cell (PBSC) donors and Cord blood units (CB) were allowed. In case of CB a TBI 2 grays, Cyclophosphamide 50 mg/kg, Fludarabine 100 mg/m2 conditioning regimen was recommended. GVH prophylaxis consists in cyclosporine alone. A rapid discontinuation of systemic immunosuppression and re-injecting donor lymphocytes to initiate graft-versus-tumor effect are based on tumor assessment and blood chimerism. Inclusion criteria are children with malignancies that can be potentially cure by allograft but a conventional conditioning regimen being impossible due to toxicity and children with solid tumor or hematological malignancy remaining unresponsive to the reference strategies according to French best practices in pediatrics. Results: From April 2007 to April 2010, 40 RIC AlloHSCT were performed in 10 different French pediatric graft centers: 13 Hodgkin Lymphoma, 7 acute myeloblastic leukaemia, 2 acute lymphoblastic leukaemia, 6 neuroblastoma, 8 rhabdomyosarcoma, 3 desmoplastic tumor and 1 Ewing sarcoma. Median age at transplantation was 15 years and median time from diagnosis to transplant was 18 months. Before transplant, 15 patients are in complete response and 25 patients (14/18 solid tumors) have active disease (11 progressive, 14 partial response). 21 had already received a myeloablative therapy (18 autograft and 3 allograft). Graft source was PBSC in 17 cases (7 related and 10 unrelated), BM in 18 (10 related and 8 unrelated), and 5 CB. The RIC Bu-flu conditioning regimen permits rapid engraftment without major toxicity contrary to the Cy-TBI in CB. 1 patient had primary graft failure: 1 CB and 5 patients experienced secondary graft failure: 3 CB, 1 PBSC and 1 BM. Median time to reach an ANC of 0.5 109/l was 16 days. Median time to reach a platelet count of 20 × 109/l was 2 days. Platelet count did not decrease below 20 109/l in 10 allografts. At day 30 post-transplant, chimerism is mainly donor for 30 and partial for 6 children. At day 100 post transplant, 4 out of 6 with initial mixed chimerism were converted into full donor chimerism. 8 patients received DLI and 17 patients experienced acute graft versus host disease (GvH) (2 grade IV and 15 grade ≤ II). A low day 365 TRM of 5% is reported in these heavily pre-treated patients. With a median follow-up of 15 months, the estimated 2 yr overall survival (OS) was respectively 57 % (71% for hematological malignancies and 42% solid tumors) (fig 1) and event free survival (EFS) 36% (50% for hematological malignancies and 19% solid tumors). Univariate analysis of EFS and OS showed no effect of related versus unrelated stem cell sources and BM versus PBSC. Our analysis identified a group of patients, who had no measurable disease at transplant, with a 2 yr OS and EFS of 86%. In term of efficacy, we observe a graft versus lymphoma effect in patients with advanced active Hodgkin lymphoma. Concerning solid tumors, all children included had a very bad prognosis and detectable disease before transplant. Our results may suggest that an immune-mediated effect cannot be excluded in some refractory solid pediatric tumors particularly in neuroblastoma. The main cause of failure of this approach is disease progression. Immunologic approaches after transplantation may help cure more of these very-high-risk patients. Conclusion: Even if further follow up is needed, this prospective study suggest that RIC regimen provides promising outcome in children previously not eligible for myeloablative AlloHSCT. This study “RICE” was registered at www.clinicaltrials.gov as NCT 007 50 126 Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 3116 We evaluated in this study the efficacy and toxicity of a pilot tandem auto-HSCT strategy followed by reduced intensity conditioning (RIC) and allogeneic HSCT with the post-allo-HSCT introduction of bortezomib and donor lymphocyte infusion (DLI) in high risk multiple myeloma (MM) patients (Group1). We compared our results to those observed after traditional tandem auto-RIC-allo-HSCT without bortezomib after allo-HSCT (Group2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the IFM previous prospective studies. Matching variables were: diagnosis date, age, gender, β2 microglobulin, cytogenetics and induction treatment, the matching ratio was 1:3. Groups 1 & 2 included MM patients of age ≤ 65 years who previously received vincristine, doxorubicin and high-dose dexamethasone (VAD) or bortezomib plus dexamethasone (VD) as induction treatment followed by auto-HSCT. Only patients who achieved at least a partial response (PR) after auto-HSCT were included. Patients must have an HLA identical related or unrelated donor, and at least one of the following factors: β2 microglobulin level 〉3mg/L, del13, t(4;14) or del17p. The conditioning regimen combined fludarabine 30 mg/m2/d (d-5→d-1), busilvex IV 3.2 mg/kg/d (d-4, d-3) and ATG 2.5 mg/kg/d (d-2, d-1). GVHD prophylaxis consisted on cyclosporine A 3mg/Kg from day -1 with the addition of methotrexate at days 1, 3 and 6 in case of ABO incompatibility. In group1, by day 90 post-allo-HSCT, patients not in CR received 4 cycles of bortezomib 1.3 mg/kg (21 days cycle, on days 1, 4, 8 and 11); if the CR was not achieved, increasing doses of DLI were administered. Allo-HSCT groups included 25 patients (12 in group1 and 13 in group2), 18 males and 7 females with a median age of 51 years [28–67], there were 15 IgG, 6 IgA and 4 light chains MM. Fourteen (56%) patients had del13, 7 (28%) del17 and 17 (68%) had β2 microglobulin level 〉3mg/L. Induction treatment was VAD in 16 (64%) patients and VD in 9 (36%). Twenty-one (84%) patients received high dose melphalan (200 mg/m2) while the rest received a dose of 140 mg/m2; auto-HSCT was performed after a median time of 5.5 months [3.6–15.3] from diagnosis. The median time between auto-HSCT and allo-HSCT was 3.8 months [2.5–8.5]. The stem cell source was peripheral HSC in 22 (88%) of cases and the median number of infused CD34+ cells was 6.1×106cells/Kg (range: 2–13) from 16 identical siblings and 9 HLA (10/10) matched unrelated donors. Sex matching was as follow: F→M:9, F→F:3, M→F: 4 and M→M:9 and for ABO compatibility, 18 (72%) were compatible, 1 had minor incompatibility and 6 major incompatibility. At allo-HSCT, one patient was in CR, 4 in very good partial response (VGPR) and 20 patients were in PR. The matched population included 36 controls for group1 and 39 for group2. At Day 90 after allo-HSCT, all patients engrafted, 10 patients were in CR and 15 patients were in less than CR. Nine patients in group1 received bortezomib, 3 reached a CR while the 6 others were still in PR and received increasing doses of DLI. There were 8 acute GVHD [7 grade II (3 in group1) and 1 grade III in group1] and 11 chronic GVHD [3 lim. (all in group1) and 8 ext. (1 in group 1)]. No GVHD reactivation was observed after DLI. At the last follow-up, 14 patients are alive (9 in group1 and 5 in group2), 10 patients were in durable CR1 post-allo-HSCT and 4 patients in PR after DLI; 11 patients died (3 in group1: all from progression; 8 in group2: 5 from progression and 3 from TRM). After a median follow-up of 55 months [3–142], the median OS was not reached in group1 vs. 65 months (51-NR) in its matched patients (p=0.027); and it was 96 months (49-NR) in group2 vs. 91 months (32-NR) in its matched patients (p=0.77). The median PFS was 49 months (29-NA) in group1 vs. 25 months (21–35) in its matched patients (p=0.0045); and it was 31 months (22-NR) in group2 vs. 28 months (21–40) in its matched patients (p=0.0776). The encouraging results observed in group1, in terms of OS, PFS and toxicity are due to the introduction of IV busilvex and better ATG administration schedule in addition to the immunomodulating role of bortezomib in the elimination of the residual disease. In addition, we showed a good GVL effect after DLI with a durable stability of the disease without any important GVHD complication. According to our promising results, we should reconsider the allo-HSCT in the context of first line treatment for high risk MM patients. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 1198 Poster Board I-220 Background: Unrelated cord blood transplantation is an alternative option to treat patients with high risk hematologic malignancies in the absence of an HLA identical donor. Results of UCBT in patients with MDS or secondary leukaemia (sAML) have been scarcely published. Method: We performed a survey to identify predictors of outcomes in a large cohort of 108 adults with MDS or sAML reported to Eurocord-Promise data bases (62 centres in 17 countries in Europe) and transplanted with an UCBT from 1998 to 2007. Sixty-seven patients were transplanted for sAML (secondary to MDS in 42 cases) and 41 for MDS. Worst status before UCBT for MDS was RA in 4, RAEB1 in 10, RAEB2 in 14, CMML or RAEBt in 9, unclassified in 4 patients. IPSS classification at transplantation was low, intermediate 1, intermediate 2, high or missing in 8, 12, 7, 6 and 8 patients, respectively. For patients with sAML, 48% were transplanted in CR1 at UCBT. Median age at UCBT was 43 years (from 18 to 72 years). Median time from diagnosis to UCBT was 10 months. Transplant characteristics: 77 patients received a single and 31 a double UCBT. UCB grafts had ≥ 2/6 HLA mismatched in 60 % of cases. Myeloablative conditioning regimen (MAC) was given to 57 patients whereas 51 patients received a reduced intensity conditioning regimen (RIC). GVHD prophylaxis consisted in CSA+MMF in 52, CSA+steroids in 43 and other combinations in 13 patients. Median number of collected nucleated cells was 3.4 for single and 4.6 × 107/kg for double UCBT. Median follow-up was 25 months. Results: cumulative incidence (CI) of neutrophil recovery at day 60 was 82±4% with a median time to achieve more than 500 ANC/mm3 of 23 days. Neutrophil recovery was independently associated with number of CD34+ cells/kg (〉 1.1 × 105, Hazard Ratio (HR), 1.79; P= .02) and advanced disease status (intermediate 2 or high MDS and sAML not in CR; HR, 1.92; P= .007). CI of grade II-IV acute GVHD at day 100 and chronic GVHD at 2 years were 26±4% (II n=18, III n=6, IV n =6) and 42%±8, respectively. Two-year non-relapse mortality was significantly higher after MAC (62% vs. 34%, p=0.009). In counterpart, 2-year relapse rate was higher after RIC (14% vs 29%, p=0.02). Two-year DFS and OS were 30 and 34%, respectively. In univariate analysis, among patient-, disease- and transplant- factors studied only patients with high risk disease at maximal pre-transplant stage or transplanted 〉 18 months after diagnosis had significant poorer DFS (disease risk: 49% vs. 22%; time: 35% vs. 15%). However, in multivariate analysis, the only factor associated with decreased DFS was advanced disease (HR: 2.05; p= .01). Conclusion: These data indicate that UCBT is an acceptable alternative option to treat adults with high risk MDS or sAML without a HLA-matched related or unrelated bone marrow donor. Controlled disease at time of transplantation improves outcome. More investigations are needed to compare these results with outcomes after other stem cell sources from unrelated HSCT donor. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2547 Introduction. Minimal residual disease (MRD) eradication in patients with chronic lymphocytic leukemia (CLL) treated by standard chemo-immunotherapy regimens correlates with improved outcome. However, there is limited information about the interest of negative MRD after allogeneic stem cell transplantation (allo-SCT). In this study we investigated whether blood phenotypic remission could impact post-transplant outcome in patients with CLL. Methods. We retrospectively included patients who underwent allo-SCT for CLL and with post-transplant MRD monitored by four or six-colour flow cytofluorometry in blood samples (sensitivity≥10−4). Prognostic impact was evaluated on overall survival (OS) and progression-free survival (PFS). Each of these parameters was evaluated according to the best response and to the 12 month-MRD status, using log-rank test. Results. Thirty-three patients from 4 hematology departments were included. Median age at transplant was 54 years (range, 41 to 66 years). The median number of prior chemotherapy regimens was 3 (range, 1 to 6) including autologous stem cell transplantation in 48% of the patients. Status at transplant was available in 27 patients and 11% of them had negative MRD, 26% haematological complete response (CR), 59.% partial response (PR) and 4% had refractory disease. Twenty-two patients (67%) received a reduced intensity conditionning regimen. Conditioning regimen included serotherapy (antithymoglobulin n = 10, alemtuzumab n = 1, rituximab n = 1) in 12 patients. Twenty-two patients (67%) were transplanted with HLA identical sibling donor. The median number of MRD evaluations after transplant was 5 (range, 1 to 23). Response to transplant: After transplant, 16 patients achieved negative MRD, 15 patients achieved haematological CR, 1 PR and 1 did not respond to transplant. Among the 16 patients with phenotypic remission, negativation of MDR was obtained before the cessation of immunosuppressive therapy for 15 of them (94%) and median time to negativation was 7 months (range, 2 to 20 months). In patients achieving phenotypic remission chronic GVHD rate was 75% versus 44% in patients with post-transplant detectable MRD. Post-transplant outcomes: With a median follow-up of 27 months, the 2-y OS and the 2-y PFS were respectively 84% and 53%. Cause of death (n = 8) was progression in 4 cases and transplant related mortality in 4 cases. Impact of phenotypic remission: The achievement of phenotypic remission (whatever the time of evaluation) correlates with better PFS: 2-y PFS was 85% in these patients versus 27% in the other patients (p = 0.012). Considering the 19 patients with MRD evaluation available at 12 months after transplant, 2-y PFS was 100% in 12-month-negative-MRD patients (n = 10) versus 17% in positive-MRD patients at that date (p = 0.003) No relapse was observed in the group of patients who achieved phenotypic remission at 12 months post-transplant (figure). Conclusion. These data suggest that achievement of post transplant negative MRD in patients with CLL is associated with a long-term control of the disease and better PFS. In our series, no relapse occurred in patients with negative MRD at 12 months post transplant. These results could lead to decrease immunotherapy and to administrate donor lymphocytes to patients with post-transplant persistent positive MRD. Disclosures: Leblond: ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.