ALBERT

Description: Mitochondria are fascinating organelles, which fulfill multiple cellular functions, as diverse as energy production, fatty acid β oxidation, reactive oxygen species (ROS) production and detoxification, and cell death regulation. The coordination of these functions relies on autonomous mitochondrial processes as well as on sustained cross-talk with other organelles and/or the cytosol. Therefore, this implies a tight regulation of mitochondrial functions to ensure cell homeostasis. In many diseases (e.g., cancer, cardiopathies, nonalcoholic fatty liver diseases, and neurodegenerative diseases), mitochondria can receive harmful signals, dysfunction and then, participate to pathogenesis. They can undergo either a decrease of their bioenergetic function or a process called mitochondrial permeability transition (MPT) that can coordinate cell death execution. Many studies present evidence that protection of mitochondria limits disease progression and severity. Here, we will review recent strategies to preserve mitochondrial functions via direct or indirect mechanisms of MPT inhibition. Thus, several mitochondrial proteins may be considered for cytoprotective-targeted therapies.

Description: Non-GPS localization has gained much interest from researchers and industries recently because GPS might fail to meet the accuracy requirements in shadowing environments. The two most common range-based non-GPS localization methods, namely Received Signal Strength Indicator (RSSI) and Angle-of-Arrival (AOA), have been intensively mentioned in the literature over the last decade. However, an in-depth analysis of the weighted combination methods of AOA and RSSI in shadowing environments is still missing in the state-of-the-art. This paper proposes several weighted combinations of the two RSSI and AOA components in the form of pAOA + qRSSI, devises the mathematical model for analyzing shadowing effects, and evaluates these weighted combination localization methods from both accuracy and precision perspectives. Our simulations show that increasing the number of anchors does not necessarily improve the precision and accuracy, that the AOA component is less susceptible to shadowing than the RSSI one, and that increasing the weight of the AOA component and reducing that of the RSSI component help improve the accuracy and precision at high Signal-to-Noise Ratios (SNRs). This observation suggests that some power control algorithm could be used to increase automatically the transmitted power when the channel experiences large shadowing to maintain a high SNR, thus guaranteeing both accuracy and precision of the weighted combination localization techniques.

Description: Key Points The prognostic impact of time from diagnosis to treatment in AML is offset by other factors such as age, secondary AML, or genetic abnormalities. Waiting a short period of time to characterize leukemias better and design adapted treatments at diagnosis seems possible.

Description: Background Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for MDS patients (pts). Due to transplant-related mortality, only pts with short life expectancy are referred to HSCT, usually those with IPSS int-2 or high risk. The aim of this prospective study was to compare outcome in candidates for HSCT according to donor availability: no donor, HLA-matched sibling donor, 10/10 HLA-matched unrelated donor and 9/10 HLA-mismatched unrelated donor. Method SFGM-TC and GFM centers that had agreed on general recommendations concerning the management of MDS pts participated to the study (16 centers). Transplant indications were int-2 or high IPSS, int-1 with refractory thrombocytopenia or proliferative CMML. Pts were registered in this study if older than 50 years, when they acquired an indication for HSCT and in the absence of comorbidity contraindicating HSCT. A donor research was initiated at registration including HLA-matched sibling donor, HLA-matched unrelated donor (10/10) or mismatched donor for one allele. Other alternative donors (mismatched unrelated cord blood or 〉 1 mismatched donor) were not accepted. Transplantation was scheduled upfront if bone marrow blasts 〈 10% at inclusion or after treatment with AML like anthracycline-aracytine chemotherapy (CT) or azacitidine (AZA) if marrow blasts 〉 10% ideally within 6 months if a donor was identified. Recommended reduced intensity conditioning regimen consisted in fludarabine, busulfan and anti-thymoglobulin with peripheral stem cells (PB) as source of stem cells. Characteristics of pts and disease were compared within 3 groups: no donor, HLA-matched donor (sibling or 10/10), HLA-one mismatched donor (9/10). Overall and disease free survivals (OS, DFS) were compared using Kaplan Meier estimates. Cumulative incidences of complete remission and disease-related mortality were compared using Gray-test. Results From April 2007 to January 2013, 163 pts were included: 34 (21%) pts had no donor; 115 (71%) pts had an HLA-matched donor (34% sibling and 37% unrelated) and 14 (9%) pts had an HLA mismatched donor. Groups were well-balanced for age, gender, time from diagnosis to inclusion, WHO classification, bone marrow blasts at time of inclusion, cytogenetic (IPSS) and IPSS classification. WHO classification at time of inclusion was: AML post MDS in 12, RAEB1 in 29, RAEB2 in 82, CMML1 or 2 in 20, RCMD in 14 and other MDS in 6 pts. Cytogenetics were favorable in 49 (30%), intermediate in 37 (23%) and poor in 74 (45%) pts. IPSS was int-1 for 8%, int-2 for 69% and high for 23% of pts. Median follow-up was 38 months. 117 pts were treated by AZA and 40 by CT. Bone marrow blasts 〈 10% were achieved in 68% and 57% for pts without and with donor, respectively. 69% of pts with HLA-identical donor and 57% of those with HLA-mismatched donor were transplanted. Some pts with donors were not transplantation because of excess of marrow blasts in most pts (〉 10% in 3, 〉 20% in 20 pts), comorbidities contraindicating the transplantation acquired after inclusion (9 pts), early deaths (7 pts) and other causes in 3 pts. Four other pts scheduled for transplantation have not been transplanted yet. Probability of complete remission 12 months after inclusion was: 39% (95% CI: 22-55), 49% (95%CI: 40-58) and 46% (95%CI: 17-71) for pts without a donor, with an HLA-compatible donor and with HLA-mismatched donor. Disease-related mortality at 48 months was not significantly different in the 3 groups: 50 % (95%CI: 29-68), 38% (95%CI: 27-49), 51% (95%CI: 17-77). DFS was also not different in 3 groups: 18% (95%CI: 7-44), 25% (95%CI: 16-37) and 9% (95%CI: 1-57). In contrast, OS at 48 months was better in pts with HLA-compatible donor than in pts without donor or those with HLA-mismatched donor: 35% (26-49), 17% (6-43) and 8% (1-55), respectively, p=0.011 (Figure 1). The poor survival observed in pts transplanted with an HLA-mismatched donor may be due to their small number and requires further analysis in a larger cohort. Outcome was not different in pts receiving PB from HLA-matched sibling or from HLA 10/10 matched unrelated donor. Conclusion In a prospective study, we observed that int-2 or high risk MDS pts with a HLA-matched donor have an improved life expectancy as compared to pts without donor. This study confirmed that they should be referred to the transplantation before acquisition of comorbidity contraindicating HSCT. Disclosures: No relevant conflicts of interest to declare.

Description: Background Unrelated cord blood transplantation (UCBT) after reduced intensity conditioning regimen (RIC) has extended the use of cord blood in elderly patients and those with co-morbidities without an HLA identical donor, although relapse post transplant remains a concern in high risk AML patients. HLA incompatibilities between donor and recipient might enhance Natural Killer (NK) cell alloreactivity after allogeneic hematopoietic stem cell transplantation (HSCT). We previously observed that the quality of NK cell reconstitution was impaired after haploidentical HSCT, impacting on graft versus leukemia (GvL) effect, but was preserved after UCBT in a small cohort of patients. Methods To evaluate RIC-UCBT in patients with acute myeloid leukemia (AML), a prospective phase II multicentric trial was conducted in France, whose primary objective was to show a reduction in non-relapse mortality (NRM) from 40% (based on registry data) to 20%. Seventy-nine patients were enrolled for a de novo or secondary AML in complete remission (CR). The conditioning regimen consisted of cyclophosphamide (50mg/kg) + fludarabine (200mg/m2) + total body irradiation (2Gy), CsA +MMF as GVHD prophylaxis and GCSF from day +1. Patients were enrolled in 23 centers from October 2007 to September 2009. Engraftment rate was 87 % at day+60. At 2 years, overall survival, incidence of relapse and LFS were respectively 44%, 46% and 35%. Peripheral blood samples were collected following UCBT in order to realize an extensive phenotypic and functional study of NK cells. Studies were started at 1 month (M1) post UCBT with available samples for 62 out of the 69 included patients, and were compared to 20 healthy donors and 15 cord blood (CB). Results Total CD3+ T-cells were 117 /mm3 at M1 (range 0-934), and 465 /mm3 at M3 (range 0-2917). CD19+ B-cells were 36/mm3, (range 0-524) and 342/mm3 (range 0-2990) at M1 and M3 respectively. NK cell recovery was prompt, representing 47% of the total lymphocyte population at M1 (186 CD3-CD56+ NK cells/mm3), 30% at M3 (239/mm3; range 2-767) and decreasing to normal rate at M6 (20% of lymphocytes). At M1 post-UCBT, NK cells exhibited high rate of CD56bright, NKG2A, and KIR2DL4 associated with a decreased expression of CD8 and CD161, compared to CB and healthy donors. These immature characteristics were transient and return to normal value from M3 or M6 post-UCBT. Interestingly, we also observed a significant increased expression of the activation markers CD69, and HLA-DR during the whole period of the study, compared to CB and healthy donors, which probably reflects a persistent proliferation state of the NK cells. On the other hand, NK cells post-UCBT were indistinguishable from CB and healthy donors control samples for other receptor tested such as NKp30, NKp46, NKp80, and NKG2D. Notably, Expression of KIR2DL1 was decreased at M1 and M3 but reached similar values to controls at M6, whereas, KIR3DL1 was increased during the whole study. To determine the significance of these phenotypic features, we assessed polyfunctional ability of NK cells following UCBT by a combined analysis of the degranulation (CD107a), and the production of IFN-γ and TNF-α. This study reveals that NK at M1 post-graft exhibited a transient higher ability to produce IFN-γ than healthy donors (p

Description: Autologous stem cell transplantation (ASCT) is recommended for younger patients with newly diagnosed multiple myeloma. Achieving complete response (CR) or at least very good partial response (VGPR) is a major prognostic factor for survival with 20% to 30% of patients achieving CR after ASCT. Bortezomib has shown synergistic effects with melphalan and no prolonged hematologic toxicity. In this Intergroupe Francophone du Myélome (IFM) phase 2 study, 54 untreated patients were enrolled between July and December 2007 to receive bortezomib (1 mg/m2 × 4) and melphalan (200 mg/m2) as conditioning regimen (Bor-HDM). Overall, 70% of patients achieved at least VGPR, including 17 patients with CR (32%) after ASCT. No toxic deaths were observed. Bortezomib did not increase hematologic toxicity. Only 1 grade 3 to 4 peripheral neuropathy was reported. A matched control analysis was conducted comparing our cohort with patients from the IFM 2005-01 trial (HDM alone). Patients were matched for response to induction therapy and type of induction: CR was higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction therapy. These results suggest that Bor-HDM is a safe and promising conditioning regimen. Randomized studies are needed to assess whether this conditioning regimen is superior to HDM alone. This trial was registered at www.clinicaltrials.gov as NCT00642395.

Description: Allogeneic stem cell transplantation (SCT) can induce long-term disease-free survival in refractory follicular lymphomas (FL) but is impaired by high rate of transplant-related mortality (TRM). Reduced conditioning followed by allogeneic SCT is a promising concept in FL, allowing a graft-versus-lymphoma (GVL) effect while reducing the TRM. We piloted a clinical trial using this approach in relapsed/primary refractory low-grade lymphomas. From 1998 to 2003, 31 patients (pts) with an HLA-identical sibling have been enrolled. Main pts characteristics were : age = 49 years (range, 32–61 y); grade : I/II FL = 26; FL with histologic transformation = 5; gender = 16 male and 15 female; ≥ 2 prior therapies before transplantation = 23; primary refractory = 8; stage IV = 22; Bulky disease = 16; mean LDH rate before transplantation = 335 UI/l (range, 205–858); residual disease at transplantation (partial response (PR) + progression) = 20. Previous treatments were as follow : anthracyclins = 26, alkylants = 21, anti-CD20 = 15, purine analogs = 7, autologous SCT = 6, radiotherapy = 5. The conditioning regimen was IV fludarabine 30 mg/m²/day (from day −5 to −2); PO busulfan 2 mg/kg/day (from day −7 to −6); antithymocyte globulin (ATG) 2.5 mg/kg/day (from day −4 to −3). 14/31 (45%) and 17/31 (55%) pts received peripheral blood and bone marrow stem cells respectively with a median number of CD34+ cells of 5 x 106/kg (range, 1.8–11.9). Graft-versus-host-disease (GVHD) prophylaxis consisted in cyclosporine A alone. All patients achieved complete donor (〉 95%) chimerism after allogeneic SCT. Median duration of neutropenia (〈 0.5 G/L) and thrombocytopenia (〈 25 G/L) were 3 days (range, 0–16) and 3 days (range, 0–29) respectively. 8/31 pts (26%) had CMV reactivation but no CMV disease. 3/31 (10%) developed grade II–IV acute GVHD. 10/31 (32%) developed chronic GVHD (5 moderate and 5 extensive). The median follow-up time was 20 months. The TRM was 19% (6/31). Causes of death were aGVHD = 1, auto-immune hepatitis = 1, bacteraemia = 2, pulmonary toxoplasmosis = 1 and Lyell syndrome = 1. Overall response rate was 97% (21 CR + 9 PR) at day 100 and at 1 year (24 CR + 6 PR). The estimated 2-year overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS) rate were 75%, 65% and 85% respectively. 2 relapses occurred. Both were treated by anti-CD20, achieved CR and are still alive. Donor age, Bulky disease and LDH were significant for EFS. Altogether, these data suggest that non-myeloablative SCT can induce a high rate of durable remissions with reduced toxicity in this poor risk population.

Description: Introduction: ASCT is recommended for young patients (pts) with newly diagnosed MM. The achievement of Complete Response (CR) or at least Very Good Partial Response (VGPR) is the main prognostic factor for survival after ASCT. However, only 40–50% of patients achieve CR and VGPR with current HDM regimen. BOR has demonstrated significant activity in relapsed/refractory pts, a synergistic effect with Melphalan (MEL) and a lack of prolonged hematological toxicity. The combination of BOR and HDM is therefore a logical approach to attempt to improve CR+VGPR rates after ASCT. Methods: In July 2007, the IFM initiated an open-label, multicenter, phase II study. Fifty-seven pts with symptomatic de novo MM were enrolled to receive BOR and HDM as conditioning regimen before ASCT. The choice of induction therapy was not specified in the protocol, and was made on an individual-patient basis by the treating clinician. BOR (1 mg/m2) was delivered on days −6, −3, +1, +4 and MEL (200 mg/m2) on day −2. Peripheral blood stem cells (median 4 × 106 CD34/kg, range 2–12) were infused on day 0. The primary endpoint was the CR+VGPR rates at 3 months post ASCT. The secondary endpoint was the safety profile of this regimen. Baseline characteristics of the pts were: median age = 58; ISS= 1 in 30, 2 in 15 and 3 in 12 cases; chromosome 13q deletion in 27 of 52 assessable; chromosome 17p del in 3 and t(4;14) translocation in 6. Twenty-nine pts received VAD induction therapy while 18 received a BOR-Dexamethasone (DEX) based regimen. Seven pts needed more than 2 lines of therapy to achieve response before ASCT and 3 pts had already received a first course of HDM. Overall response rates before ASCT were: CR=2, VGPR=6, partial response (PR)= 33 and stable disease (SD)=16. Results: All pts but one were assessed for response at 3 months after ASCT. Twenty pts (36%) achieved a CR and 17 (30%) a VGPR. One patient was non-responder. Among the 3 pts receiving a tandem ASCT, no CR or VGPR was observed after BOR+HDM. In the VAD induction group, 12 pts (43%) achieved CR and 7 (25%) VGPR. In the BOR-DEX based induction group, 7 pts (39%) achieved CR and 6 (33%) VGPR. All results are summarized in table 1. From the standpoint of safety, BOR did not increase hematological toxicity. Median duration of neutropenia (〈 0.5 × 109/l) and thrombocytopenia (〈 50 × 109/l) was 7 (range 1–15) and 8 (range 3–31) days respectively. Grade 3/4 extra-hematological toxicities were limited: mucositis in 22 cases (39%), peripheral neuropathy in 1 case. Other toxicities included: erythroderma in 30%, headache in 20%, hallucinations in 9% and grade 2 peripheral neuropathy in 3 cases (preexisting ASCT). Five serious adverse events were reported: 1 pulmonary embolism, 1 seizure, 1 acute cholecystis and 2 pneumonias. No toxic death was observed. Conclusions: These results suggest that BOR (1 mg/m2) and HDM is a safe and highly effective conditioning regimen in frontline MM pts with almost 70% achieving CR and VGPR. This compares favorably to the updated results of the IFM 2005/01 trial (comparing BOR-DEX versus VAD as induction prior to ASCT in de novo MM pts) reported in last ASH meeting (Harousseau et al.). A matched case-control study will be conducted between our cohort and the pts of the IFM 2005/01 trial. Table 1: IFM VEL/MEL IFM 2005/01 VAD n=28 BOR-DEX n=18 ≥ 2 lines n=7 VAD n=110 BOR-DEX n=112 CR 43% 39% 14% 20% 34% ≥ VGPR 68% 72% 71% 50% 64% ≥ PR 93% 100% 86% SD 7% 0 0 PD 0 0 14%

Description: Although allogeneic hematopoietic stem cell transplantation is presently the only curative option for many patients with AML or MDS, relapse remains the main cause of morbidity and mortality. Strategies are therefore developed to prevent relapse. Post-transplant immune intervention with administration of prophylactic or pre-emptive donor lymphocyte infusion (DLI) and/or chemotherapy maintenance using DNA-demethylating agents such as azacitidine (aza) is being investigated. The exact mechanism of action of aza remains obscure and might be due in part to tumor antigen upregulation or other gene induction by tumor cells causing an immune response. We enrolled, in a clinical trial (ClinicalTrials.gov Identifier:NCT01541280), patients (pts) with high risk AML or MDS and candidates for allo-HSCT transplantation to receive azacitidine (aza) and DLI post-transplant as prophylactic treatment with the primary objective to reduce the relapse rate at 2 years following allo-HSCT and secondary objectives to increase disease free survival at 2 years post-transplant, increase overall survival at 2 years, investigate feasibility and safety of maintenance strategy combining chemotherapy and immunotherapy and follow the incidence and severity of acute and chronic GVHD. High risk AML was defined as AML in CR1 with unfavorable cytogenetics, AML in CR2 or greater remission, refractory AML or in relapse prior allogeneic transplantation. High risk MDS was defined as MDS with intermediate-2 group and higher risk group according to IPSS criteria. Aza was scheduled to begin between d+56 and d+112 post-transplant at the doses of 32 mg/m²/d sc for 5 days every 28 days for up to a total of 12 cycles if the pt had not acute GVHD 〉1 or severe infection. The first DLI was started following 3 cycles of aza and discontinuation of immunosuppressive prophylaxis, and if the pt had no clinical signs of GVHD, uncontrolled infection or a recent history of gr〉2 acute GVHD. Two other DLI were scheduled every 8 weeks after the 5th and 7th cycle of aza. The doses of DLI 1, 2 and 3 were respectively 5x106, 1x107, 5x107 CD3+cells/kg for related donor, and 1x106, 5x106, 1x107 CD3+cells/kg for unrelated donor. Sixty-four patients were pre-included prior transplantation, 30 pts were subsequently included, 20 pts with AML and 10 pts with MDS, median age 58 y (22-70). The status at transplantation was: CR1 = 16 pts (53%), CR2 = 6 pts (20%), refractory = 5 pts (16%), upfront transplantation for MDS = 3 pts (10%). Cytogenetics was normal or intermediate for 15 pts and unfavorable for 15 pts (namely 8 pts with complex caryotype). Conditioning was myeloablative for 11 pts, reduced for 19 pts (including 2 sequential). Donors were unrelated volunteers in 18 pts (60%).The time between allografting and first aza cycle was 66 days (38-93). The median number of cycles of aza administered was 5 (1-12) with 10 pts (33%) completing the 12 cycles. Forty one DLI were injected in 17 pts: 5 pts received one DLI, 2 pts received 2 DLI, 8 pts received 3 DLI. Two additional pts received 4 and 5 DLI because of a mixed chimerism. The first DLI was given at a median of 142 d (129-221) post transplantation. Aza was well tolerated, but was discontinued in 20 pts: because of GVHD (n=11), relapse (n=5), GVHD/infection (1pt), sudden death due to heart failure (n=1), withdrawal of consent (n=2, one after 1 cycle and another after 5 cycles). Four months following transplantation, 24 (80%) demonstrated full donor chimerism (〉95%) in CD3+ cells. Nine patients developed grade 1 to 3 acute GVHD (CI 29.8±9%), 6 who did not receive DLI and 3 following DLI (grade 1 n=2, grade 2 n=3, grade 3 n=4). No grade 4 acute GVHD was observed. Nine pts developed chronic GVHD (2 limited, 7 extensive), 3 who did not receive DLI, 6 following DLI. Twenty patients are alive. With a median follow-up from the allotransplant for those alive of 36 months (range 12 - 46 months), the survival at three years is 66%. Causes of death were infection (n=1), relapse (n=8), sudden death due to heart failure (n=1). The median time to relapse was 5 months (2.5-9) and the cumulative incidence of relapse at 3 years 28.1±8.5%. These results confirm that aza is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse. The incidence of GVHD following aza + DLI was not overwhelming. Analysis of T cell population and immune response as well as comparison to matched-pair control are currently performed and will be presented. Disclosures Moreau: Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria.

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.