ALBERT

Description: Introduction: Allogeneic stem cell transplantation is a potentially curative treatment for patients with high-risk non-Hodgkin lymphoma (NHL). Fludarabine/busulfan based conditioning regimens are widely used in Europe for this purpose. Busulfan dose intensity discriminates between reduced intensity (FB2, 2 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) and reduced-toxicity myeloablative (FB3/FB4, 3 or 4 days of busulfan at 4 mg/Kg/d per os or 3.2 mg/kg/d iv) conditioning regimens (Bacigalupo, 2009). While some data have been recently published showing some advantages of higher busulfan dose intensity for myeloid malignancies, there is no such data available in the lymphoid setting. Methods: This was a large retrospective study conducted on behalf of the SFGM-TC including all adults allografted in France between January 2004 and December 2014 for NHL (n=378). Clinical data were obtained through ProMISe (Project Manager Internet Server), an internet-based system shared by all French transplantation centers. We aim to compare various outcomes (overall (OS) and lymphoma free (LFS) survivals, relapse incidence (RI), non-relapse mortality (NRM), acute and chronic GVHD) between those who received FB2 (n=277) or FB3/FB4 (n=101) as conditioning regimens. GVHD free relapse free survival (GRFS) was also studied (defined as alive with no previous grade III-IV aGvHD, no moderate or severe chronic GvHD (cGvHD) and no relapse). Results: Both groups were comparable for the following variables: median follow-up (FB2: 24.9 vs FB3/4: 23 months), gender (male 61% vs 53%), disease type (low-grade lymphoma 25% vs 21%, mantle-cell lymphoma 17% vs 13%, high-grade lymphoma 25% vs 21%, T cell lymphoma 32% vs 45%), disease status at transplant (complete remission/very good partial response 64% vs 62%, partial response 28% vs 31%, active disease 8% vs 7%), donor type (sibling 43% vs 49.5%, matched unrelated 56% vs 47), median number of previous courses of treatment (2 vs 2, p=0.44), stem cell source (peripheral blood 96% vs 95%). FB2 patients were significantly older (median 57.3 vs 53.1 years, p=0.07), have been transplanted more recently (median year of transplant: 2011 vs 2010, p=0.001) and have been more previously autografted (69% vs 50.5%, p=0.001). FB3/4 patients have been allotransplanted earlier during the evolution of their disease (median time between diagnosis and allograft 18.2 vs 33.8 months, p=30 months), there were also no significant differences between both groups in terms of OS, LFS, RI or NRM. In multivariate analysis there was a trend for worse outcome using FB3/FB4 regimens (OS: HR 1.46, 95%CI: 0.96-2.23, p=0.07; LFS: HR: 1.43, 95%CI: 0.99-2.06, p=0.05; RI: HR 1.54; 95%CI: 0.95-2.48, p=0.07). These results were also confirmed using a propensity score-matching strategy including 184 FB2 and 98 FB3/4 patients. Conclusion: This large retrospective study showed that reduced toxicity myeloablative fludarabine/busulfan regimens did not improve outcomes of adults allografted for NHL. FB2 conditioning regimen still should be considered as the standard of care conditioning regimen in this setting. To validate these results, prospective studies are needed, like the French prospective trial currently ongoing for myeloid diseases (NCT01985061). Also, new conditioning regimens and post-allograft strategies should be tested to improve outcomes of patients. Disclosures Peffault De Latour: NOVARTIS: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding.

Description: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of a variety of hematologic diseases. However, allo-HSCT can be associated with many complications, including poor graft function early after transplant requiring long-lasting supportive care. In the literature, the incidence of poor graft function post allo-HSCT has been reported to range from 4 to 27%. Here, we retrospectively studied 10 patients (male/female: 4/6, median age: 45 years, range 19 to 67) who received a boost of CD34+ selected cells for poor graft function after allo-HSCT (of whom 4 cases of haplo-identical allo-HSCT with post-Cy prophylaxis), between January 2014 and January 2016. Patients' disease and transplant characteristics are summarized in the below table. Patients were selected for the CD34+ cells "boost" therapy after eliminating other causes that could explain a poor graft function (eg. drug toxicity, infections, disease relapse, etc.) The same original allo-HSCT donor was used to collect the CD34+ cells after mobilization with G-CSF and positive selection. The patients did not receive any prior conditioning therapy prior to CD34+ cells boost infusion. At time of the boost, all patients were in full donor chimerism. The number of infused CD34+ cells differed from one patient to another ranging from 2.91 to 7.99 x106 cells/kg recipient body weight. The median day of infusion post- allo-HSCT was 120 (range, 76-352). Among these 10 patients, 7 patients had full counts recovery at a median of 15 days (range, 7-30) post-infusion, while 3 patients had an incomplete response with persistent anemia and/or thrombocytopenia. None of the patients experienced clinically significant GVHD symptoms after the boost. At last follow-up, 7 patients were alive whereas 3 patients died of severe infections after 1, 6 and 13 months post-boost. Based on these results, we concluded that boost therapy can be used in the treatment of poor graft function post-allogeneic HSCT, including in those patients who received a haplo-transplant. Disclosures No relevant conflicts of interest to declare.

Description: AN and MM are co-senior authors. Background. Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). Patients and Methods. In the current survey, we compared transplantation outcomes in a cohort of 394 acute myeloid leukemia (AML) patients given grafts from HLA-identical siblings after FB (n=218; with a total busulfan dose ranging between 7.1 and 8.9 mg/kg p.o., or between 6.0 and 6.9 mg/kg i.v.) or FM (n=176; with a total melphalan dose ranging between 130 and 150 mg/m2). Patients given manipulated grafts and those given T cell depleting agents (ATG or alemtuzumab) were not included. At time of transplantation, 266 patients (68%) were in first complete remission (CR1), 69 (18%) in later CR, while 59 patients (15%) had advanced diseases. Three-hundreds and fifty-two patients (89%) received peripheral blood stem cells while the remaining 42 patients received bone marrows as stem cell source. Results. Three FB patients but no FM patients failed to engraft. Median time for reaching 500 neutrophils was 17 (1-50) days in FB patients versus 14 (9-43) days in FM patients (P

Description: 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

Description: Background The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is rapidly increasing. The safety and efficacy of myeloablative conditioning (MAC) in haplo-HCT has been reported in patients with acute leukemia. However, optimal MAC in haplo-HCT setting is unknown. We studied the outcomes of total body irradiation (TBI) vs. chemotherapy (CT) based MAC regimens in acute myelogenous leukemia (AML) patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 1008 AML patients (secondary AML=149, 15%) who underwent haplo-HCT with PTCy during the years 2010-2018, following TBI (n=89, 9%) or CT (n=919, 91%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose

Description: 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)

Description: Patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) usually have a very poor prognosis and an expected survival of less than 6 months.The complete remission (CR) rates in the setting of the first salvage chemotherapy are about 30% to 46% and these rates drop sharply to 18% to 25% after the second salvage chemotherapy. Chimeric antigen receptor T cells (CAR-T) can induce high CR rates of 70-95% (MRD negative CR rates of 60-90%) among patients with R/R ALL. Howeve, relapse after CAR-T treatment is supposed a main obstacle for long-term outcome. Some reports have described relapse rates of 20-70% when the follow-up was long enough. It remains controversial whether these patients should receive allo-HSCT after CAR-T treatment or not. We designed a multi-center retrospective study to assess the efficacy and safety profiles of CAR-T therapy followed by haplo-HSCT. A total of 31 patients treated with CAR-T therapy followed by haplo-HSCT were included. Eleven patients who progressed to MRD positive or relapse subsequently underwent haplo-HSCT (MRD positive or relapse group) and the rest 20 patients with MRD negativity received haplo-HSCT (MRD negative group). The median time from CAR-T infusion to haplo-HSCT was 83 (range 62-114) days. After a median follow-up period of 288 (range 189-554) days post-transplantation, the 100-day cumulative incidence (CI) of grade III~IV aGVHD was 0% and 10.5% in the MRD positive or relapse group and MRD negative group, respectively (P〉0.05)(Figure 1a). One and 2-year CIs of cGVHD requiring systemic steroid therapy were 52.3% and 31.1% (P〉0.05), 52.3% and 39.7% (P〉0.05) in the MRD positive or relapse group and MRD negative group, respectively(Figure 1b).The 1-year cumulative incidence of CMV viremia was 90.9%, 68.4% and 77.8% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P〉0.05). The 2-year cumulative incidence of CMV viremia was 90.9%, 78.9% and 85.2% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P〉0.05). The 1-year cumulative incidence of EBV viremia was 90.9%, 79.6% and 84.2% in the MRD positive or relapse group, MRD negative group and the whole population, respectively (P〉0.05). And the 2-year cumulative incidence of EBV viremia was 90.9%, 89.8% and 89.5% in the MRD negative or relapse group, MRD negative group and the whole population, respectively (P〉0.05). Onset of CMV and EBV viremia occurred in 33.5 (26.3-50.0) days and 44.0 (28.5-57.0) days after transplantation in 24 and 25 patients, respectively. Median peak CMV DNA and EBV DNA load were 1.5X104 (2.6X103-3.4X104) copies/ml and 2.2X104 (1.1X104, 4.1X104) copies/ml, respectively. One and 2-year CIs of relapse were 84.8% and 6.7% (p

Description: Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was 〉90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p

Description: Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a standard of care for patients with acute myeloid leukemia (AML) being at high risk of relapse. However, the procedure using conventional myeloablative conditioning regimens based on either busulphan (Bu) or total body irradiation (TBI) in combination with cyclophosphamide is associated with significant risk of non-relapse mortality (NRM). The use of reduced-intensity or non-myeloablative conditioning regimens results in improved tolerance but increased incidence of disease recurrence. In order to reduce toxicity while maintaining the efficacy, alternative approaches have been proposed including the use of moderately reduced doses of Bu or TBI in combination with fludarabine (Flu). The goal of this retrospective study to compare BuFlu and TBI/Flu reduced-toxicity regimens. Patients and methods: Adult patients with AML treated in CR1 with alloHSCT from either HLA-matched sibling or unrelated donor between January 2006 and June 2018 were included in the analysis. The following conditioning regimens have been selected for the comparison: intravenous Bu at a total dose 9.6 mg/kg (3 days) + Flu (Bu3Flu, N=350) or TBI at a total dose of 8 Gy + Flu (TBI8Flu, N=168). In both groups the proportion of patients with intermediate risk karyotype was 74% while high risk - 24%. The proportion of patients with secondary AML was also the same (14%). Patients in the Bu3Flu group were significantly older, were treated more frequently with alloHSCT from unrelated donors and were treated in more recent period. Results: The engraftment rate was 99% for both regimens. In a univariate analysis the use of TBI8Flu was associated with reduced incidence of relapse (20% vs. 30% at 2 years, p=0.01) and tendency to increased leukemia-free survival (LFS; 66% vs. 60%, p=0.15) and overall survival (OS; 74% vs. 58%, p=0.051) as well as reduced incidence of grade III-IV acute graft-versus-host disease (GVHD, 4% vs. 9%, p=0.03). The effects on non-relapse mortality (NRM), grade II-IV acute GVHD and chronic GVHD were not significant. In a multivariate analysis a chance of LFS was reduced for patients with high risk karyotype and secondary AML, with no effect of donor type. Due to significant interaction between type of conditioning and age, further analyses were performed stratifying patients above or below 50 years. For patients ≤50 y.o. the use of TBI8Gy was associated with reduced incidence of relapse (21% vs. 35%; Cox model: HR=0.49, p=0.049), tendency to improved NRM (4% vs. 7%,; HR=0.17; p=0.1), significantly improved LFS (75% vs. 58%, p=0.02; HR=0.45, p=0.02), improved OS (84% vs. 60%; HR=0.29, p=0.002) improved survival free from both GVHD and relapse (GRFS; 56% vs. 46%; HR=0.53, p=0.02) and reduced incidence of grade II-IV acute GVHD (15% vs. 26%; HR=0.53, p=0.02). For patients 〉50 y.o. the effect of TBI8Flu on relapse was not statistically significant (19% vs. 29%; HR=0.64, p=0.21) while this regimen was associated with increased risk of NRM (26% vs. 11%; HR=3.98, p=0.0006) leading to a tendency to decreased OS (59% vs. 63%; HR=1.53, p=0.1). Conclusion: Reduced-toxicity regimens using either TBI8Flu or Bu3Flu for patients with AML in CR1 are associated with relatively low risk of relapse and NRM leading to enhancing survival rates after alloHSCT. The use of TBI8Flu appears more effective compared to Bu3Flu and may be advised in younger patients where reduced risk of relapse translates into improved survival. In older individuals it should be used with caution due to increased risk of NRM. Prospective studies are needed to verify our findings. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.