ALBERT

Beschreibung: Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p

Beschreibung: Double umbilical cord blood (dUCB) allogeneic transplantation following low dose TBI, cyclophosphamide and Fludarabine (TCF regimen)-based reduced-intensity conditioning regimen (RIC) is increasingly used in adults lacking a suitable related or unrelated donor. Currently, there is little data regarding the impact on long-term outcome of CD3+ T cell chimerism (TCC) in this particular setting. Thirty-six adults with various hematological diseases and who receieved dUCB conditioned with TCF were included in this retrospective study. Peripheral blood CD3+ TCC was considered until day +100 post-tranplant in order to determine the impact of full versus mixed chimerism on long-term outcomes. Twenty-nine and 7 patients were documented with full and mixed CD3+ TCC, respectively, within the first 100 days post-transplant. With a median follow-up of 36 months, 3 year-OS, DFS, and relapse incidence were 61%, (95% CI 43-75); 50% (95% CI 32.5-66) and 28% (95% CI 16-44), respectively. In univariate analysis, a full CD3+ TCC was associated with a better 3-year DFS : 59% (95% CI 39-75.5) versus 14% (95% CI 7-46), (HR=0.24 [0.09-0.65], p=0.005) and a lower cumulative incidence of relapse : 24% (95% CI 21.5-57) versus 78% (95% CI 52-99), (HR=0.18 [0.05-0.5], p=0.004). In multivariate analysis, a full CD3+ TCC remained associated with a lower incidence or relapse (HR=0.17, 95% CI 0.028-0.99, p=0.049). CD3+ TCC has no impact on GVHD and NRM in this study. In conclusion, in our study, full CD3+ TCC was independently associated with a lower risk of relapse after dUCB TCF RIC allogeneic transplant in adults, highlighting the need to develop immunotherapy approaches allowing for early conversion to full chimerism after dUCB. Abstract 2479. Table 1 Patients, sustained cord blood and transplantation characteristics. Patients, sustained cord blood and transplantation characteristics Full TCC (n=29) Mixed TCC (n=7) p No.of patients % No.of patients % Patients characteristic Age at transplant, years, median (range) 57 (22-69) 47 (17-64) NS Sex female 14 48 3 43 NS Hematological malignancy : Lymphoid / myeloid 14 / 15 48 / 52 3 / 4 43 / 57 NS Statut at transplant : RC / RP 23 / 6 79 / 21 6 / 1 86 / 14 NS Time to transplant, days, median (range) 395 (137-5645) 216 (92-604) NS Cord blood characteristics Age of cord blood, months, median (range) 31 (9-165) 116 (23-140) NS Matching cordon with patient NS 4/6 10 35 3 43 5/6 19 65 3 43 6/6 0 0 1 14 Number of total nucleated cell 10^8/kg before and after thawing, respectively, median (range) 0,28 (0,16-0,455) ; 0,248 (0,157-0,406) 0,222 (0,135-0,492) ; 0,22 (0,11-0,392) NS Number of CD34+ cell 10^6/kg before and after thawing, respectively, median (range) 0,066 (0,022-0,215) ; 0,043 (0,02-0,2) 0,078 (0,031-0,427) ; 0,041 (0,019-0,259) NS Mismatch between cord blood and patient Sex 14 48 3 43 NS Serology CMV 13 45 3 43 NS ABO 16 55 2 28 NS Rhesus 22 76 6 86 NS Graft Neutrophil count recovery 〉0.5 G/L, days, median (range) 17 (6-32) 11 (7-20) NS Platellet recovery 〉20G/L, days, median (range) 41 (0-164) 31 (0-67) NS Acute GVHD (grade II-IV / grade III-IV) 19 (12 / 6) 65 (41 / 21) 4 (3 / 1) 57 (43 / 14) NS Chronic GVHD (Limited / Extensive) 11 (8 / 3) 38 (28 / 10) 3 (2 / 1) 43 (28 / 14) NS Chimerism Rate, %, median (range) 100 (96-100) 82 (14-94)

Beschreibung: Introduction Invasive fungal infections (IFI) due to Candida and Aspergillus species remain a major complication of allo-SCT. In the myeloablative setting, previous studies have demonstrated that fluconazole, administered for 75 days after transplant (400 mg/d), in a prophylaxis setting, can allow for a decreased risk of gut GVHD and disseminated candida infections or candidiasis-related death, resulting in an overall survival benefit (Marr et al., Blood 2000). However, to our knowledge, there is currently no study, addressing the potential benefit of fluconazole prophylaxis in the setting of reduced-intensity conditioning (RIC) allo-SCT. Methods This retrospective study included 105 patients with acute leukemia (AML, n=55, ALL, n=11) or myelodysplastic/myeloproliferative disorders (MDS, n=24; myeloproliferative disorder n=15) who received an allo-SCT between January 2000 and December 2011. In this series, patients received one (n=105) or two (n=4) RIC allo-SCT and PBSC as stem cell source for all. Among these 109 procedures, we compared those cases receiving (n=53) or not (n=56) fluconazole prophylaxis after transplant. The post-transplant fluconazole prescription or not was at the discretion of the attending physician and was homogeneous for each physician. There were not significant differences between both groups in terms of gender, median age (fluco: 55 vs 57 years), median follow-up (fluco: 42 months (range: 19-76) vs 37 months (range: 11-124)), median year of transplant (fluco: 2008 (range: 2003-2011) vs 2009 (range: 2000-2011)), type of disease and disease status at time of transplant or type of donor. Results The median time of fluconazole administration (400mg/day) after transplant was 88 days (range: 7-324). Fluconazole was stopped only in 2 patients because of (reversible) liver cytolysis. Before day +100, only 2 Aspergillus infections were documented in the fluconazole group vs 4 in the non-fluconazole group (P=NS). No Candida infections (septicemia or cutaneous candidiasis) developed in the fluconazole group compared to 2 in the non-fluconazole group (P=NS). After day +100, Aspergillus infections were documented in 5 patients in the fluconazole group versus 3 in the non-fluconazole group (P=NS). The number of patients receiving pre-emptive or curative antifungal treatment (voriconazole, caspofungin or ambisome) after transplant was higher in the non-fluconazole group (52% of cases vs 34%, P=0.09). 3-year OS, DFS and NRM were similar between both groups (fluco: 42% vs 51%, P=0.42, fluco: 38% vs 46%, P=0.62, and fluco: 28% vs 23%, p=0.67). Also, there were no significant differences in term of cumulative incidences of acute grade II-IV GVHD (fluco: 27% vs 36%, P=0.29), acute grade III-IV GVHD (fluco: 21% vs 18%, P=0.42) or chronic GVHD (fluco: 47% vs 33%, P=0.67). Conclusion This is the first series reporting the comparison of the use or not of fluconazole as prophylaxis after RIC allo-SCT. Our results showed that the use of fluconazole has no impact in term of fungal infections or overall outcomes after RIC allo-SCT, suggesting that fluconazole is not required after RIC allo-SCT. Large prospective studies are warranted to further confirm this important therapeutic issue. Disclosures: Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Mohty:Novartis: Honoraria, Research Support Other.

Beschreibung: Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients〉 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with 〉 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p

Beschreibung: Introduction : TP53 mutated (TP53m) MDS and AML have very poor outcome irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months (Bejar, Blood 2014). APR-246 is a prodrug spontaneously converted to methylene quinuclidinone (MQ), a Michael acceptor that binds covalently to cysteines in mutant p53, leading to protein reconformation that reactivates its pro apoptotic and cell cycle arrest functions. The combination of AZA and APR 246 showed promising results in a phase Ib study in TP53m MDS (Sallman, ASH 2018). We report interim results of a GFM phase 2 study of AZA+ APR-246 in TP53m MDS and AML, conducted in parallel with a similar US MDS consortium study. Patients and Methods : The study included hypomethylating agent (HMA) naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV /d (6 hour infusions) (days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles, and treatment with reduced APR 246 and AZA doses could be continued after allo-SCT. Results : 53 patients were enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 73 years (range 44-87), and M/F: 28/25. 34 patients had MDS (including 74% very high IPSS-R) and 19 had AML. IPSS-R cytogenetic risk was very poor in 30/34 MDS, and unfavorable in 18/19 AML, complex in 89% of the patients. Median baseline mutated TP53 VAF was 21% (range 3-76). Nineteen of the 53 patients had been included at least 7 months before date of analysis (25 July 2019), had received protocol treatment and were thus potentially evaluable for response after 6 treatment cycles (ITT population). One of them died after only one cycle from an unrelated cause (cerebral ischemic stroke), and 2 during the third cycle (from bleeding and sepsis, respectively). In the remaining 16 patients (evaluable population per protocol), the response rate was 75% including 9 (56%) CR, 3 (19%) marrow CR or stable disease with hematological improvement (HI), and 4 treatment resistance. In the ITT population, the response rate was 63%, including 47% CR, and 16% stable or marrow CR+ HI. Among CR patients, complete cytogenetic CR and negative NGS for TP53 mutation (VAF cutoff of 2%) were achieved in 7/9 (78%) and 8/8 (100%), respectively. So far, 1 patient has undergone allo-SCT. All 53 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of the patients. The latter, reviewed with a neurological team, were mainly grade 1 or 2 and consisted of ataxia (n=13), sometimes associated with cognitive impairment (n=4), suggesting a cerebellar origin. Other patients experienced acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1). Neurological AEs reached grade III in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p

Beschreibung: Introduction: Despite therapeutic advances in recent years, disease relapse is still observed in up to 50-60% of the patients (pts) receiving allogeneic transplantation for high risk AML and MDS. In an initial Phase II trial of 30 pts treated with prophylactic low-dose AZA and escalated doses of DLI to prevent relapse, we reported that such prophylactic treatment can be safely administered and compared favorably to patients receiving no post-transplant maintenance. We here update 16 pts from our center, included in that protocol, as well as a larger cohort of additional patients treated with combined epigenetic and cellular therapy and the resultant effect on their event-free survival and their overall survival. Patients and methods: Fifty-nine pts (median age 59 yrs (range, 37-70); 30 M/29 F), comprising 40 pts with AML and 19 pts with MDS, were treated. Among the AML pts (ELN classification FAV n=2, INT n=17, ADV n=21), high risk criteria were as follows: 15 had complex karyotypes, 7 Flt3-ITD, 1 MECOM (EVI1) rearr., 3 monosomies, 2 t(9;11), and 1 t(11;19)); 9 were in CR≥2, 4 were refractory, and 13 had 2ary AML to MDS/chemotherapy/or MPS. Among the MDS pts, high risk criteria included 6 pts with complex caryotypes, 2 monosomies, 1 MECOM (EVI1) rearr., and 4 had 2ary MDS. IPSS-R median was 5.5 (3 - 7.5). MDS pre-transplant status included 7 CR1, 1 CR2, 5 PR, 1 relapse, 4 upfront, and 1 refractory. The therapeutic protocol administered to the initial 16 pts consisted of AZA, starting between d56 and d100 post-transplant, at a dose of 32 mg/m²/d SC, for 5 consecutive days, every 28 days, for up to a total of 12 cycles followed by DLI commencing after 3 cycles of AZA and 4 weeks following discontinuation of immunosuppressive prophylaxis. Two additional DLI were scheduled every 8 weeks following the 1st DLI. The doses of DLI 1, 2 and 3 were, respectively, 5x106, 1x107, and 5x107 CD3+ cells/kg for matched related donor (MRD), and 1x106, 5x106, and 1x107 CD3+ cells/kg for unrelated donor (UD). In the extended patient cohort, presented here, we slightly modified the schedule: DLI could be given earlier (after one or two cycles of AZA) and haploidentical pts could receive AZA/DLI as well, with DLI at the escalated doses of 1x105, 5x105, and 1x106 CD3+ cells/kg. Immunosuppression included cyclosporine A (CsA) in case of MRD, CsA and mycophenolate mofetil (MMF) in case of UD or haplo. MMF was progressively reduced during the first 2 months. CsA was tapered starting at day 60-100 post-transplant. Patients could start AZA while they were still receiving CsA. The conditioning regimens consisted of MAC for 5 pts, RIC for 46 pts and sequential for 8 pts. Donors were MRD, MUD, UD 9/10, and haplo for 20, 30, 1 and 8 pts respectively. Results: The median number of cycles AZA was 7 (range 1-12), 17 pts received 12 cycles of AZA, while 42 pts (71%) received at least one DLI. The median number of DLI was 1 (range 0-4), 15 pts received ≥ 3 DLI. The median time for the first post-transplant AZA injection was 83 days (range 56-145 d) and the median time post-transplant for those pts who received a first DLI was 148 days (range 78-245 d). The median pt-follow-up was 17 months (range 2-83). Eight pts (13%) relapsed (7 AML and 1 MDS). The cumulative incidence of relapse and NRM at 1 year was 12% and 11.5% respectively. Fifteen pts (25%) died. Causes of death included relapse in 6 pts, infection in 7 pts, myocardial infarction in 1 pt, and GvHD in 1 pt. Overall survival and event free survival for the entire group at 2 years was 71% (95% CI 54-82%) and 67% (95% CI 50-80%) respectively. The cumulative incidence of acute GvHD grade 1-4 and chronic GvHD were 32% (95% CI 16-49%) and 39% (95% CI 20-58%). Among the 8 pts who developed grade 3 acute GvHD, 4 occurred in pts who had received DLI. One pt died from grade 4 digestive GvHD post-AZA alone. Conclusion: We conclude that, despite their very high risk disease, prophylactic/preemptive low-dose AZA and DLI can be readily and safely administered with an acceptable incidence of subsequent GvHD to the AML and MDS pts described here. Significantly, in the poor-prognosis pts under study, the incidence of relapse is lower than expected. Furthermore, considering the immune escape mechanisms prophylactic or pre-emptive either AZA or DLI might be associated to additive non-cross reactive interventions, such as checkpoint inhibitors, in order to further decrease disease relapse and increase overall survival. Disclosures Peterlin: Jazz Pharma: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy; AbbVie Inc: Consultancy. Orvain:Novartis: Honoraria; Incyte: Honoraria. Chevallier:Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria.

Beschreibung: 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.

Beschreibung: Background: Pre-transplant pulmonary function testing (PFT) is required in all patients eligible for allogeneic stem cell transplantation (allo-SCT). Diffusion lung capacity for carbon monoxide (DLCO) is the main parameter taken into account but the overall impact of this factor is debated. Diffusion lung capacity for nitric oxide (DLNO) may be of higher interest to predict pulmonary complications, because radiotherapy and chemotherapy used to treat patients with haematological diseases affect mostly the alveolar-capillary membrane, which destruction is more appreciate by DLNO than DLCO measure. Also, DLNO/DLCO ratio represents a new index of gas exchange and an alternative way of investigating the alveolar membrane and the blood reacting with the gas. Methods: We considered all patients who received an allo-SCT for hematological malignancies between March 2012 and January 2014 in our department and for whom a pre-transplant PFT, including DLCO and DLNO measures, was validated. Factors influencing pre-transplant DLCO, DLNO and DLNO/DLCO ratio were analyzed as well as impact of those 3 diffusion lung parameters on general outcomes and pulmonary complications (severe pulmonary complications (SPC) defined as any pulmonary complication responsible for hospitalization, pulmonary related mortality (PRM), acute respiratory distress syndrome (ARDS). Results: We included 103 patients (male: n=68, median age at transplant: 58 years) in this study. Majority of them had a myeloid disease (n=67), and were in complete (n=56) or partial (n=23) remission at transplant. Type of donor was: matched related donor (N=35), haploidentical related donor (n=5), matched unrelated donor (n=43), mismatched unrelated donor (n=9) and umbilical cord blood (n=10). First stem cell source used was peripheral blood stem cell (n=83). Eight five percent of patient received a reduced intensity regimen. With a median follow up of 21.5 months (range: 3.8-34.7), 2 year cumulative incidence of overall survival, Disease free survival, relapse incidence, non-relapse mortality, SPC, ARDS and PRM were respectively 65.4% ( 55.2-73.6), 52.5% (42.7-62.2), 31.8% (22.3-41.7), 15.8% (9.4-23.5), 25.4% (17-34), 7.8% (4-14), and 4.9% (1.8-10.4). Normal DLCO and DLNO percentages of predicted normal value (〉80%) were documented in 48 and 44 patients, respectively but median percentages for the all cohort were under the normal at transplant: DLCO: 78.9%, DLNO: 78.1%. Median DLNO/DLCO ratio was 5.3 (range: 2.7-8.6). Regarding factors influencing pre-transplant PFT results, DLCO was significantly decreased in patients with respiratory history (72.3% versus 81.5%, p=0.001), in patients having received therapeutic with cardiac or pulmonary toxicities (74.2% versus 80.6%, p=0.02) and in patients over 58 years (81.0% versus 75.4%, p=0.05). Similarly, DLNO was significantly decreased in patients with respiratory history (74.3% versus 80.9%, p=0.03) and in patients' smokers or with history of smoking (75.3% versus 81.8%, p=0.03). Finally, patients' age was the only parameter with a significant impact on DLNO/DLCO (5.5 in patients 〉58 years versus 5.2 in patients ≤58years, p=0.04). In univariate analysis, a DLNO value

Beschreibung: Introduction: Allogeneic stem cell transplantations (allo-SCT) using alternative donors are increasingly used in patients lacking suitable matched sibling or unrelated donor. Recently, the use of post-transplant cyclophosphamide (CY) has allowed to re-consider first-generation relatives (brother, sister, father, mother, son or daughter) as haplo-identical donors for allo-SCT. Indeed, the incidence of severe acute GVHD is lowered by post-transplant administration of CY, due to the early destruction of putative alloreactive T cells. Still, some patients may not have a suitable relative donor for various reasons such as older age of the parents, no siblings nor children, no cord blood available, or because use of a graft from a first-generation haplo-identical relatives is contra-indicated. The probability of having a haplo-identical donor among siblings is 50% while it is almost 100% when considering both biological parents and offspring. When considering as a potential donor the child of a matched or haplo-identical sibling, the probabilities for the donor to be haplo-identical with the recipient remain 50% and 25%, respectively. Thus, second-generation relative donor (i.e. nephew or niece) may be finally considered as a source of stem cell graft. Methods: Here we report the case of a 61-year old man who received a T-replete haplo-identical allo-SCT with high-dose post-transplant CY from his second-generation relative nephew. In 2010, the patient was diagnosed with ALK- CD30+ anaplastic T-cell lymphoma and received 8 cycles of CHOD allowing to obtain morphologic and metabolic partial response. The patient received an allo-SCT from a sibling matched donor (brother) on November 2010 after an FB2A2 reduced-intensity conditioning regimen but secondary graft failure was rapidly documented in spite of donor lymphocyte infusions. Relapse occurred in September 2014 and brentuximab vedotin was administered each 21 days for seven cycles allowing to obtain a complete morphologic and metabolic response. It was decided to perform a second allograft using a different donor. The patient was childless and no unrelated donor or cord blood units were available. It was thus chosen to ask for donor the son of the matched brother, who was haplo-identical and had no antibodies directed against the patient's HLA specificities. This nephew had a O- blood group and negative CMV serology while the recipient was O+ and CMV+. Results: The second allograft was performed on April 2nd 2015 using the Baltimore (Luznik, BBMT 2008) conditioning regimen with 2 days of post-transplant CY. A megadose of peripheral blood stem cell was administered (14.16x106 CD34+ cells/Kg) at day 0. Neutrophils and platelets recovery (〉50 Giga/L) were achieved as early as days +18 and +33, respectively, with full donor whole blood chimerism (99.8%) at day +30, persisting on day +60 and +100 (both whole blood 99.9%, CD3+ T cells: 99.9%).Grade 2 acute cutaneous GVHD occurred at day +21. The evolution was favorable after initiating corticosteroids at 2 mg/kg/day with tapering thereafter. Not surprisingly, CMV reactivation was documented at day+22, controlled by ganciclovir treatment. Immune reconstitution evaluated at days +30, +60 and +100 showed normal monocyte counts while B lymphocytes were undetectable. NK cells increased from 42/mm3 at day+30 to 453/mm3 at day +60 and 665/mm3 at day +100. Interestingly, after profound lymphopenia within the first 100 days post-transplant, CD8+ T large granular lymphocytes expansion was documented at day + 110. At four months post-transplant, the patient is alive in persistent metabolic remission with no active acute or chronic GVHD nor active infection. His outcomes will be updated for the meeting. Conclusion: T-replete haplo-identical allo-SCT with high-dose post-transplant CY using a second-generation relative donor was feasible allowing for full engraftment and moderate acute GVHD in our patient. This result expands the possibility to find a donor for a selected patient, meanwhile paving the way for using unrelated haplo-identical donor, which could be of interest when considering solid transplantation. Indeed, combining solid organ transplantation and allo-SCT from the same haplo-identical donor may open the door to withdraw immunosuppression in this particular setting, because stable tolerance may be induced, as it has been already reported for kidney transplant (Kawai, NEJM 2013). Disclosures Moreau: Celgene: Honoraria, Other: Adboard; Amgen: Other: Adboard; Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard.

Beschreibung: Introduction: Recently, theuse of high-dose post-transplant cyclophosphamide (PTCY) has contributed to reconsider T-replete haplo-identical allo-SCT because of the lower incidence of severe graft-versus-host disease (GVHD) observed in patients. However, the influence of PTCY on early outcomes has been poorly studied so far, especially in comparison to the standard use of anti-thymoglobulin (ATG) as GVHD prophylaxis. Patients and Methods: This retrospective study was conducted at the University Hospital of Nantes with the aim to compare the incidence of early outcomes (engraftment, neutrophils and platelets recovery, viral infections (HHV-6, CMV, EBV, BKv, ADV), acute GVHD, relapse or deaths and day+100 non-relapse mortality (NRM)) between patients receiving either PTCY (n=30) or ATG (n=46) as part of GVHD prophylaxis for a RIC allo-SCT. In the PTCY group, RIC was the Baltimore regimen (Luznic, BBMT 2008) in 17 patients while 9 patients received clofarabine instead of fludarabine because of a myeloid malignancy and 4 patients a sequential approach. In this group, 6 and 24 patients received 1 or 2 days of PTCY, respectively, while donors were matched (sibling n=2, unrelated n=5) in 7 cases and haplo-identical in 23, respectively. All patients received cyclosporine + MMF with PTCY as GVHD prophylaxis. In the ATG group (2 days of ATG for siblings and 10/10, 3 days for 9/10), 13, 11 and 22 patients received respectively a FB2, FB3 or CloB2 RIC regimen (Chevallier, Haematologica, 2014). Donors were siblings in 18, matched unrelated in 23 and mismatched unrelated (9/10) in 5. GVHD prophylaxis was cyclosporine alone in case of sibling donors and cyclosporine +MMF for all other cases. The characteristics of both groups (PTCY vs ATG) were similar in terms of gender (male: 63% vs 54%), type of disease (myeloid: 67% vs 63%) and disease status at transplant (complete remission: 43% vs 67%). PTCY patients were significantly younger (median age: 55.5 vs 63 years, p=0.01) and had been previously allografted in a significantly higher proportion (40% vs 4%, p=0.003). Patients were transplanted between March 2012 and April 2015 and were considered up to day+100 post-transplant. All patients received peripheral blood stem cells as stem cell source except one patient in the PTCY group who received bone marrow. Results: All patients engrafted except one in the ATG group. The median time of neutrophils recovery was similar between both groups (PTCY 18 days vs ATG 19 days, p=0.9). Conversely, median time of platelets recovery was significant higher for the PTCY group (27 vs 13 days, p