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Summary Background Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. Methods This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. Findings 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0–7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1–27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3–4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3–4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37–4·57]), bacterial infection (2·12 [1·11–4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05–3·10]). Interpretation Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Funding Groupe de Recherche Respiratoire en Reanimation Onco-Hematologique.

We report on 59 Hodgkin lymphoma patients undergoing haploidentical stem cell transplantation (SCT; haplo-SCT) with posttransplant cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis, comparing outcomes based on pretransplant exposure to checkpoint inhibitors (CPIs). Considering pretransplant characteristics, the 2 cohorts (CPI = 29 patients vs no-CPI = 30 patients) were similar, except for the number of prior lines of therapy (6 vs 4; P < .001). With a median follow-up of 26 months (range, 7.5-55 months), by univariate analysis, the 100-day cumulative incidence of grade 2-4 acute GVHD was 41% in the CPI group vs 33% in the no-CPI group (P = .456), whereas the 1-year cumulative incidence of moderate to severe chronic GVHD was 7% vs 8%, respectively (P = .673). In the CPI cohort, the 2-year cumulative incidence of relapse appeared lower compared with the no-CPI cohort (0 vs 20%; P = .054). No differences were observed in terms of overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) (at 2 years, 77% vs 71% [P = .599], 78% vs 53% [P = .066], and 15% vs 21% [P = .578], respectively). By multivariable analysis, CPI before SCT was an independent protective factor for PFS (hazard ratio [HR], 0.32; P = .037). Stable disease (SD)/progressive disease (PD) was an independent negative prognostic factor for both OS and PFS (HR, 14.3; P < .001 and HR, 14.1; P < .001, respectively) . In conclusion, CPI as a bridge to haplo-SCT seems to improve PFS, with no impact on toxicity profile.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing chronic lymphocytic leukemia (CLL). Minimal residual disease (MRD) assessment at 12 months (M12) post-HSCT is predictive of relapse. This phase II study aimed to achieve M12 MRD negativity (MRDneg) using an MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed in case of failure by donor lymphocytes infusions. Patients had high-risk CLL according to the 2006 European Society for Blood and Marrow Transplantation consensus, in complete or partial response with lymphadenopathy

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.

While bone marrow (BM) grafts were initially used for T-replete HLA-haploidentical related donors transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), the use of peripheral blood stem cell (PBSC) remains debated. We thus conducted a detailed analysis evaluating the incidence, risk factors, and prevalence of GVHD after PBSC Haplo-SCT with PT-Cy. One hundred and eighty-one patients with hematological diseases were included. Median time for neutrophil and platelet recovery was 21 and 30 days, respectively. The cumulative incidence of grade 3-4 acute GVHD and severe chronic GVHD were 8% and 4%, respectively, approaching what was observed after BM Haplo-SCT. NRM at 2 years was 21%, and 41% of the non-relapse deaths were caused by GVHD. The cumulative incidence of relapse at 2 years was 17% in the whole cohort, and 13% among AML patients (n = 54), suggesting a high GVL effect. As surrogate markers for good quality of life, we observed a 2-year GVHD-relapse-free survival probability of 50% and found that 6% and 2% of disease-free patients at 2 years were still living with GVHD and immunosuppressive treatments, respectively. Haplo-SCT with PT-Cy using PBSC grafts results in low incidence GVHD and promising disease control, making PBSCs a valuable alternative to BM graft in this setting.

We propose to test whether the new refined Minnesota risk score, which represents a new tool for acute Graft-versus-Host-Disease (aGVHD) grading, may be useful to predict the final outcome of patients with aGVHD after haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy). Hundred consecutive patients with grade 2–4 aGVHD were included. Twenty-two percent of the patients had high-risk (HR) aGVHD and had a lower chance to respond at day 28: 41% of non-responders (NR) were in the HR vs 13% in the standard-risk (SR) group (p = 0.003). By multivariate analysis, grade 3–4 aGVHD according to the traditional Keystone classification was the main independent predictor of non-response to front-line treatment at day 28, while HR aGVHD by the new refined Minnesota score remained the main independent variable associated with adverse NRM and OS. The new Minnesota refined risk score is a useful tool to predict the outcome of patients with aGVHD after Haplo-SCT with PT-Cy. Due to the few patients exchanging between categories in the two classifications, it is not possible to discriminate which system better predicts the outcome of patients with aGVHD in the setting of Haplo-SCT. Extending these preliminary observations to a larger cohort is warranted.

Posttransplant cyclophosphamide (PT-Cy) is an efficient GVHD prophylaxis but has not been extensively evaluated in mismatched unrelated donor (MMUD) allo-HSCT, for which antithymocyte globulin (ATG) is still considered as a standard. Thus, we evaluated the outcome of MMUD allo-HSCT with PT-Cy (n = 22) and performed a historical comparison with a control group receiving ATG (n = 40) in a single center experience. Compared with the ATG group, the risk of grade 2–4 acute GVHD was significantly lower in the PT-Cy group (HR = 0.12, 95% CI = [0.03–0.48], p = 0.002). No difference was observed in the cumulative incidence of chronic GVHD. The risk of both NRM and relapse was significantly lower in the PT-Cy group (NRM: HR = 0.05, 95% CI = [0.00–0.63], p = 0.021; relapse: HR = 0.31; 95% CI = [0.09–1.10], p = 0.07). Thus, we observed significantly better PFS (HR = 0.22, 95% CI = (0.07–0.65); p = 0.006), OS (HR = 0.24, 95% CI = (0.07–0.84); p = 0.026), and GRFS (HR = 0.37, 95% CI = (0.17–0.80); p = 0.011) in the PT-Cy group. We conclude that PT-Cy is an effective GVHD prophylaxis in the setting of MMUD allo-HSCT, resulting in a better outcome compared with standard prophylaxis using ATG. This suggests that as it was shown in the setting of haploidentical allo-HSCT, the use of PT-Cy can overcome the impact of HLA disparity, leading to promising survivals that approach those observed after HLA matched allo-HSCT.

Introduction Failure to respond to steroid therapy for intestinal acute graft-versus-host disease (aGvHD) is associated with limited further therapeutic options. Fecal microbiotherapy is defined as the perfusion of treated stool from one or several healthy donors via the upper or lower gastrointestinal (GI) route aiming at improving microbial diversity and functionality. Here we report clinical outcomes from a 76-patient cohort with steroid refractory (SR) GI-aGvHD treated with the pooled allogenic fecal microbiotherapeutic MaaT013. Twenty-four patients were treated in the prospective, single-arm, phase IIa, HERACLES study (NCT03359980) while 52 patients were treated in an expanded access program (EAP). Patients and methods For HERACLES, 24 patients with grade III-IV SR-GI-aGvHD were treated with MaaT013 in 26 European sites, as a 2 nd line therapy after SR diagnosis and evaluable for treatment response. In EAP, 52 patients with steroid-dependent or SR-GI-aGvHD (classical n=41, late onset n=3, overlap syndrome n=8) were treated. These patients had previously received and failed 1 to 6 lines (median 3; 40/52 received ruxolitinib) of GvHD systemic treatments. GI-GvHD response was evaluated weekly and 28 days after day (D) 0 (inclusion for HERACLES or 1st dose for EAP). For all patients, GI-overall response rate (ORR) at D28 was defined as the proportion of patients achieving complete response (CR), very good partial response (VGPR) or partial response (PR), compared to D0, without the use of additional systemic therapy. Other endpoints included the best overall response (BOR) achieved at any time, and overall survival (OS). Prepared under GMP, MaaT013 is characterized by a highly consistent richness of 455 ±3% OTUs and an Inverse Simpson index > 20. Treatment comprised 3 MaaT013 doses, each composed of 30 g of feces in 150 mL volume of inoculum (total 90 g of feces from 4 to 8 healthy donors) administered by enema (except for 2 EAP patients by nasogastric tube). All patients received at least 1 MaaT013 dose, 92% (HERACLES) and 87% (EAP) at least 2 doses, and 50% (HERACLES) and 71% (EAP) the full treatment course. In HERACLES, the reasons for not applying the 3 rd dose were death (n=5), physician decision to introduce salvage therapy (n=5), and ICU hospitalization (n=2)). Results In HERACLES, the GI-ORR was 38% including 5 CR, 2 VGPR and 2 PR. In EAP, positive GI-response was achieved in 31/52 patients (60% with 16 CR, 11 VGPR and 4 PR). Considering the GI-BOR, 13/24 (54%) and 35/52 (67%) achieved at least a PR in HERACLES and EAP respectively. In HERACLES, OS was 29% at month (M) 6 and 25% at M12. OS was significantly higher in responding (R) patients (achieving at least PR at D28) compared to non-responding (NR) (44% vs 20% at M6 and 44% vs 13% at M12, logrank p=0.047). In EAP, OS was 48% at M6 and 37% at M12, and significantly higher in R patients compared to NR (71% vs 17% at M6 and 62% vs 6% at M12, logrank p In HERACLES, treatment with MaaT013 was characterized by excellent tolerance: 252 Treatment-Emergent Adverse Events (TEAE) were reported for the 24 patients, the majority being infections (79%) and GI disorders (62%), as expected in GvHD patients. Of these 252 TEAE, only 2% (5 serious events in 2 patients) could not reasonably be excluded from being related to MaaT013 by the investigators. Shotgun sequencing in these 5 TEAE revealed that the causative infectious agents could not be detected in the administered MaaT013. In EAP, the safety profile of MaaT013 was considered satisfactory for all patients. 16S microbiome analyses were performed in the HERACLES population and showed that MaaT013 produced an early increase in α-diversity at genus level with a significant increase in Richness index at all evaluated timepoints (p Conclusion We herein report the treatment of 76 SR-GI-aGvHD patients using a full ecosystem, pooled-donor, high-richness biotherapeutic. The D28 GI-ORR was 38% and 60% in HERACLES and EAP respectively and this clinical benefit positively and significantly impacted OS (44% and 62% M12 in HERACLES and EAP R patients respectively). MaaT013 was shown to be safe and effective in these heavily immunocompromised patients, warranting further exploration of this approach. Figure 1 Figure 1. Disclosures Malard: JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Astellas: Honoraria; Biocodex: Honoraria; Therakos/Mallinckrodt: Honoraria; Janssen: Honoraria. Loschi: CELGENE/BMS: Honoraria; AbbVie: Ended employment in the past 24 months, Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Cluzeau: Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Takeda: Other: travel, accommodations, expenses. Huynh: Jazz Pharmaceuticals: Honoraria. Holler: MaaT Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Vehreschild: SocraTec R&D GmbH: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Takeda Pharmaceutical: Research Funding; Seres Therapeutics: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; 3M: Research Funding. Gasc: MaaT Pharma: Current Employment. Plantamura: MaaT Pharma: Current Employment. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP. Seven patients developed acute graft-versus-host disease (GVHD), with 15% grade ≥ II cumulative incidence at day 100. The cumulative incidence of chronic GVHD at 2 years was 22%. The 2 years probability of overall survival (OS) and progression-free survival (PFS) were 84 and 74%, respectively. This study shows encouraging results with low acute and chronic GVHD incidence and no interference with graft-versus-leukemia (GVL) effect.

Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia due to a constitutional genetic defect.1 To date, these diseases have not been considered to be frequently associated with malignant solid tumors, unlike the risk of secondary myelodysplastic syndrome leukemia, which is well-known in CN. Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993. Solid tumors, identified during routine patient follow-up, were classified according to WHO criteria. We included localized lymphoma in the spectrum of malignant solid tumors. We calculated the incidence of malignant solid tumors in a cohort of CN patients. Results: Among 868 patients with various CN subtypes followed for a total of 16617 person-years, 24 patients who developed a malignant solid tumor were identified. Those cancers are described in Table 1, including the CN genetic anomaly. Cancers were almost always diagnosed in adulthood, with median age at diagnosis of 38.1 (range 10-72) years; only 3 cancers were diagnosed before age of 20 years. The cancer rate was 1.2% at 30 years of age, 7% at 40 years and 24% at 50 years (Fig. 1A). The risk-of-cancer percentages depended mainly on the associated genetic deficiency. Solid tumors were roughly distributed as follows: 33% among WHIM (CXCR4) patients, 5.3% among GATA2 patients, 2.7% among ELANE patients, 1.9 % among SBDS patients and 0.8% among for all other subtypes combined (Fig. 1B). Human papillomavirus (HPV) was the cause of cancer for 2/5 in WHIM patients and 2/6 in GATA2 patients. Three Lymphoma were identified, one in GATA2 patient and 2 in WHIM patients. Notably, our cohort's follow-up is skewed to the right, with less efficient monitoring of adults, with still limited long-term follow-up beyond 40 years. Therefore, we probably underestimated the solid-tumor risk in CN patients, as many patients, if alive, are no longer followed in hematology centers. Among 103 patients who underwent hematopoietic stem-cell transplantation (HSCT), 76 were long-term survivors. None of them developed solid tumors, which differs strikingly from the high malignancy risk associated with Fanconi anemia post-HSCT. Lastly, the FSCNR also includes and follows patients with idiopathic neutropenia. Among the 232 idiopathic neutropenia patients, followed for a total of 2866 person-years, no malignancy has been observed so far. Conclusion: Our data lead us to advance that CN patients should be considered at risk of developing solid cancers, especially after the age of 30 years. This risk, at first glance, depended on the CN-associated genetic anomaly, with CXCR4 mutation, GATA2, SBDS and ELANE being the most frequent. HSCT was not associated with a higher risk and may, in contrast, be protective. These findings warrant confirmation but represent a compelling reason to prolong follow-up into adulthood of CN patients diagnosed during childhood. No indication was found of a specific high solid-tumor risk associated with idiopathic neutropenia. Reference Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574. Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support. Disclosures Hermine: Roche: Consultancy; Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Novartis: Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant:X4 Pharmaceuticals, Inc.: Current Employment.

Introduction Intestinal graft-versus-host disease (GvHD), following allogeneic hematopoietic stem cell transplantation (allo-HSCT), has a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with limited further therapeutic options, thereby representing an unmet medical need. Aiming at restoring microbiome functions, fecal microbiota transfer (FMT) has proved to be a promising treatment modality in this challenging clinical setting, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of a next-gen FMT product "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 29 patients with intestinal aGvHD as part of a compassionate use/expanded access treatment program. Patients and methods Twenty-nine allo-HSCT recipients with steroid-dependent or SR intestinal GvHD (classical aGVHD n=22, late-onset aGVHD n=2; aGvHD with overlap syndrome n=5) were treated with MaaT013 biotherapeutic as part of a compassionate use/expanded access treatment program of the developer MaaT Pharma. These patients had previously received and failed 1 to 5 lines (median 3; 22/29 received ruxolitinib) of GvHD systemic treatments. Each patient received 1 to 3 doses (median: 3; total doses administered: 71) of MaaT013, a 150 mL bag, by enema (n=28) or nasogastric tube (n=1). GI-GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 ±3% Operational Taxonomic Units and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing and proportion of proinflammatory species), ensuring the desired consistency across batches. Results We observed a GI overall response rate of 59% (17/29) at day 28 after first dosing, including 9 complete response (CR), 6 very good partial response (VGPR), and 2 partial response (PR). Considering the best GI response achieved, 20/29 patients (69%) achieved at least a PR, with 9 CR, 8 VGPR and 3 PR. Among the 29 treated patients, 16 were still alive at last follow-up (median follow-up (FU): 131.5 days; range [28; 413]) and 6 months overall survival was 54%. Among the 9 patients achieving CR, all were still alive at last follow-up (median FU: 197 days; [49; 301]) and were able to taper or stop steroids and immunosuppressants. Among these 9 patients, three patients presented GI symptom recurrence between 2 and 3 months after dosing. In 2 patients, this recurrence occurred after heavy antibiotic treatment, one of them received an additional MaaT013 dose and achieved a second CR. Of note, among these 9 patients, mild chronic mucosal GvHD symptoms persisted in one patient, and molecular relapse of hematologic malignancy was observed in another. The safety of the MaaT013 microbiota biotherapeutic was satisfactory for all patients. One patient developed "possibly related" sepsis one day after the third dosing but no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Another patient developed C. difficile diarrhea 24 hours post-administration. This was not causally related to MaaT013, as C. difficile testing was negative in the MaaT013 lot. Nosocomial transmission was suspected as the cause as several patients with C. difficile infection were hospitalized in the same unit during this period. Conclusions We herein report for the first time the treatment of 29 patients with steroid-dependent or SR intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. The overall response rate was 59% with the off-the-shelf MaaT013 product, which was shown to be safe and effective in these heavily pre-treated and immunocompromised patients, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Astellas: Honoraria; JAZZ pharmaceutical: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Keocyt: Honoraria; Theralos/Mallinckrodt: Honoraria; Biocodex: Honoraria. Plantamura:MaaT Pharma: Current Employment. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Advanced hematologic malignancies have a higher incidence in older patients and very often lack effective treatments. Allo-HSCT represents the only potential curative option for most of hematologic malignancies. However, 2 main limitations limited this development for a long period of time in older patients. High rates of fatal non-relapse morbidities have been progressively decreased using reduced toxicity conditioning approaches. This allowed pushing up the age limit of patients considered for transplant. The search for a donor has been also a high limitation in older population, due to the lower incidence of matched sibling donors in this population. The development of allo-HSCT from a familial Haplo donor after a reduced intensity (RIC) or non-myeloablative conditioning (NMAC) has allowed for the recent development of allo-HSCT in older population. Here we analyzed a cohort of 111 consecutive patients aged of 65 years or older transplanted from a haplo donor in a single institution from 2013 to 2018. During this period of time, the search for a one-mismatch haplotype donor (Haplo) has been progressively introduced in our program, the upper limit age for transplant progressively increased and more advanced diseases. Patient characteristics: Median age: 69,3 (65-78) years; Male patients: 64%; Acute leukemia (AL): 34%; Myelodysplastic/myeloproliferative syndromes (MDS/MPS): 45%; Chronic Leukemia: 2%; Lymphoma: 18%; others: 3%. High or very high risk disease index (DRI): 44%. Donor characteristics: median age: 39,2 (22-68); Male gender: 61%; sibling donor: 17%; offspring donor: 83%. Non Myeloablative/ Reduced toxicity conditioning: 51%/49%; All patients received PTCY. PT Immunosuppression included CSA and MMF. Median follow-up: 20 (3-78) months; ANC recovery in 96%: 19 (10-44) days; untransfused platelet recovery above 20 in 75%: 17 (7-56) days. In evaluable patients for aGVHD: No: 59%; Grade 1: 7%; Grade 2: 16%; Grade 3: 11%; Grade 4: 5%; 85% patients were evaluable for cGVHD: No: 62%; limited: 13%; Moderate/severe:25%; 32 patients (25%) patients died from non-relapse mortality at a median of 116 days (13-1373); 16 patients relapsed/progressed at a median of 5,6 (1-63) months. Two year overall and disease-free survivals are respectively of 58% (95% CI: 6.35-7.04) and 54% (95% CI: 7.17-7.55). the only predictive factor was disease risk. Overall these data show that allo haplo HSCT is a valid option in older patients with high-risk malignancies. To improve results we performed from 2015 in patients older than 65 years systematic and combined evaluation of comorbidities score, performance status and geriatric assessment (instrumental activity of daily living (AIDL); vulnerability assessment) that will be presented in the meeting for this population.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by availability of HLA-matched sibling donors (MSDs). The alternative use of unrelated donors (UDs) is currently challenged by haploidentical-related donors (HRDs). We retrospectively analyzed 209 consecutive patients younger than 60 years undergoing allo-HSCT from UDs (n = 128) or HRDs (n = 81). Cumulative incidences of grade 3–4 acute (17 vs. 2%, p = 0.003) and 2-year moderate and severe chronic (20 vs. 2%, p

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged >= 60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged >= 60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML. (C) 2018 American Society for Blood and Marrow Transplantation.

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m2). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 107/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (

International audience; Little data have been published concerning invasive fungal infections during treatment of acute lymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the multicenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed for the occurrence of IFI using the EORTC modified criteria. These patients did not routinely receive antifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developed IFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candidiasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosis was 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serum was tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median time between induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes. Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortality after diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33. The median delay between induction chemotherapy initiation and attributable death related to IC was 15 days. These findings may help to optimize the future management of ALL patients, and as in AML advocate systematic monitoring and the development of prophylactic or preemptive antifungal treatments.

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 consecutive patients who underwent allo-SCT for progressive MDS between October 1999 and December 2009, 93 received ATG (ATG group) at the median dose of 5 mg/kg, whereas 149 patients did not (no-ATG group). Donors were sibling (n = 153) or HLA-matched unrelated (n = 89). Patients received blood (n = 90) or marrow (n = 152) grafts after either myeloablative (n = 109) or reduced-intensity (n = 133) conditioning. Three-year overall and event-free survival, nonrelapse mortality, relapse, and chronic graft-versus-host disease (GVHD) development were not significantly different between the 2 groups. In contrast, acute grade II to IV GVHD occurred more often in the no-ATG group (55% of the patients) than in the ATG group (27%, P

Advanced hematologic malignancies in older patients are unmet medical needs due to increased incidence in the aging population and the lack of effective treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only potential curative option for most of hematologic malignancies. However, two main limitations limited this development for a long period of time. High rates of fatal non-relapse morbidities have been progressively addressed using reduced toxicity conditioning approaches and pushing up the age limit of patients considered for transplant. The search for a donor has been also a high limitation in older population, due to the lower incidence of matched sibling donors in this population. The development of allo-HSCT from a familial haplo mismatch donor (Haplo donor) after a reduced intensity (RIC) or non-myeloablative conditioning (NMAC) has allowed for the recent development of allo-HSCT in older population. Here we analyzed a cohort of 252 consecutive patients aged of 65 years or older treated in a single institution. Patients were selected on the following parameters: age of 65 or older on the day of transplant, first allogeneic transplant, no unrelated cord blood HSCT, hematologic malignancies, transplant between 01/01/2004 and 31/12/2018. During this period of time, the search for a one-mismatch haplotype donor (Haplo) has been introduced, the upper limit age for transplant progressively increased, more advanced diseases were considered and patients have gradually benefit from improvement in transplant care. Patient characteristics: Median age: 67,9 (65-77) years; Male patients: 61 %; CMV Positive (70%); Acute leukemia (AL): 43%; Myelodysplastic/myeloproliferative syndromes (MDS/MPS): 35%; Chronic Leukemia: 5%; Lymphoma: 11%; Plasma cell disorders (PCD): 6%. Complete remission (CR) or Chronic phase: 155 (62%) (of whom 81 CR1 AL) Donor characteristics: median age: 62,45 (19-77); Male patients: 63 %; Matched sibling donor (MSD) (24%): 60: Unrelated donor: 75 (29%); Haplo Donor: 118 (47%). Transplant characteristics: % patients per period of time: year range: 2004-2010: 12% (Median age: 67; % Haplo D: 0; No CR/CP: 23%); 2011-2015: 40% (Median age: 68; % Haplo D: 35%; No CR/CP: 39%); 2016-2018: 48% (Median age: 69; % Haplo D: 69%; No CR/CP: 42%); PBSC: 97%; Non Myeloablative/ Reduced toxicity conditioning: 35%/65%; All patients received Post-Transplant (PostT) CSA; PT Cyclophosphamide: 49%; Pre-Transplant ATG: 47%. Median follow-up: 17 (3-112) months; ANC recovery in 96%: 19 (10-44) days; untransfused platelet recovery above 20 in 75%: 17 (7-56) days. In evaluable patients for aGVHD: No: 58%; Grade 1: 13%; Grade 2: 14%; Grade 3: 10%; Grade 4: 4%; 85% patients were evaluable for cGVHD: No: 68%; limited: 17%; extensive:16%; 64 patients (25%) patients died from non-relapse mortality at a median of 122 days (13-3934): 2004-2010: 10/30 (33%); 2011-2015: 36/101 (25%); 2016-2018: 28/121 (23%); 53 patients relapsed/progressed at a median of 252 (30-2764) days. Three year overall and disease-free survivals are respectively of 56% (95% CI: 6.35-7.04) and 47% (95% CI: 7.17-7.55) without any difference according to age or donor type but with an impact of disease status (EFS: CR/CP 51% (95% CI: 8.7-9.5) vs others 38% ((95% CI: 11.9-12.0)) Overall these data show that allo HSCT is a valid option in older patients with high-risk malignancies. They show also that over a long period of time patient typology (more advanced diseases, older patients) and transplant practice (lower number of MSD) show a regular evolution making transplant realization more challenging. This field needs specific approach taking into account comorbidities, performance status and geriatric evaluation, to adapt treatment to every given patient. In this perspective we performed from 2015 in patients older than 65 years systematic and combined evaluation of comorbidities score, performance status and geriatric assessment (instrumental activity of daily living (AIDL); vulnerability assessment). Disclosures Chabannon: Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria.

BACKGROUND Reduced intensity conditioning (RIC) combining fludarabine, busulfan and ATG is commonly used in patients with advanced age and/or comorbid conditions, thus deemed unfit for standard myeloablative conditioning (MAC) regimens (i.e. BuCy or CyTBI12). Although non-relapse mortality (NRM) is dramatically reduced with RIC, relapse remains a major concern. In younger patients, myeloablative doses of busulfan in combination with fludarabine (i.e. myeloablative reduced toxicity conditioning [MA-RTC] regimen) produce similar antitumor effect compared with standard MAC while keeping low NRM. The feasibility of such an approach for older patients is not known. We hypothesized that a pharmacokinetics (PK) guided strategy could improve the safety of busulfan administration, allowing the use of myeloablative doses in older patients. STUDY DESIGN AND METHODS We compared the outcome of patients older than 55 years with hematological malignancies included in a prospective monocentric single arm trial (BxPK: NCT02483325) evaluating the feasibility of PK-guided busulfan doses in myeloablative conditioning regimen (BxPK group: fludarabine 150 mg/m² + IV busulfan targeted AUC 5300 x 4 days + ATG 5 mg/kg) before matched sibling (MSD) or unrelated (URD) donor AlloSCT, with a retrospectively enrolled control cohort of patients with same inclusion criteria, treated during the same period but receiving fixed busulfan dose RIC regimen including fludarabine (150 mg/m²), IV busulfan (260 mg/m²) and ATG (5 mg/kg) [Bx2 group]. The primary objective was 2-year progression-free survival (PFS). Hazard ratio of BxPK vs. Bx2 were adjusted by age, disease risk index (DRI), donor type and hematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS We analyzed 83 consecutive patients (BxPK: n=27; Bx2: n=56) without significant difference in baseline characteristics between both conditioning groups. In the BxPK and Bx2 groups: median age was 65 (range: 57-70) and 63 (range: 55-70) years, respectively (p = 0.552); 10/10 URDs were used for 15 (56%) and 37 (66%) patients, respectively (p = 0.493); HCT-CI was ≥ 3 in 18 (67%) and 28 (50%) patients , respectively (p = 0.232); and DRI was high in 5 (19%) and 5 (9%) patients, respectively (p = 0.369). Based on PK data from day-6 busulfan administration, 22 (81%) patients had dose adjustment (increased and decreased dose in 12 and 10 patients, respectively) in the BxPK group. Median busulfan AUC on day-2 (post adjustment) was 5287 µmol.min (range: 3326-7556). Four patients had AUC > 6000 µmol.min on day-2. Grade 3-4 mucositis (BxPK vs Bx2: 52% vs. 11%, p < 0.001) and nausea (BxPK vs Bx2: 11% vs 0%, p = 0.050) were more frequently observed in the BxPk group. No difference was observed between BxPK and Bx2 patients in grade 3-4 liver (BxPK vs Bx2: 15% vs 11%, p = 0.810), renal (BxPK vs Bx2: 0% vs 1.8%, p = 1) and gastrointestinal tract (BxPK vs Bx2: 11% vs 0%, p = 0.450) toxicities. There was a trend to higher cumulative incidence of grades 2-4 acute graft-versus-host disease (GVHD) at 100 days in the BxPK group (BxPK vs Bx2: 41% vs 29%, p = 0.058) while no difference was observed in 2-year chronic GVHD (BxPK vs Bx2: 41% vs. 36%, p = 0.547). Those trends were confirmed by multivariate analyses (acute GVHD: HR 2.22, 95Cl [1.10-4.48], p = 0.026; chronic GVHD: HR 1.30, 95Cl [0.60-2.80], p=0.502) With a median follow up of 33 months (range: 9-60), 2-year NRM was 19% and 18% (p=0.960) in the BxPK and Bx2 group, respectively. Multivariate analysis confirmed the absence of significant increase in the risk of NRM in the BxPK group (HR 1.11, 95CI [0.36-3.45], p = 0.859). The 2-year cumulative incidence of relapse was 19% and 31% (p=0.269) in the BxPK and Bx2 group, respectively (HR 0.55, 95IC [0.20-1.56], p = 0.264). No significant difference in 2-year PFS (BxPK vs Bx2: 62% vs. 51%, p = 0.391) and OS (BxPK vs Bx2: 70% vs. 61%, p = 0.667) was observed. CONCLUSION In patients older than 55 years who are usually candidates for RIC regimen, the use of PK-guided busulfan myeloablative dose allows delivering higher antitumor intensity without increasing NRM. Beyond the feasibility, we observed low incidence of relapse (19%) and promising OS (70%) suggesting that conditioning intensification may lead to long term disease control. These trends need to be confirmed in a larger comparative study for validating the optimal conditioning intensity in older and/or unfit patients. Disclosures Stoppa: takeda: Other: travel fees; celgene: Other: travel fees, lecture fees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Chabannon:Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Sanofi SA: Other: research support, speaker's fees, hospitalities; Gilead: Other: speaker's fees, hospitalities; EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees. Blaise:Pierre Fabre medicaments: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria.

Introduction Intestinal Graft-versus-Host Disease (GvHD), following allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), comes with a high mortality rate and a reduced life-expectancy. In this context, failure to respond to steroid therapy is associated with an absence of further therapeutic options, thereby representing an unmet medical need. A marked reduction in gut microbiota diversity leading to loss of functions was strongly associated with reduced overall survival in GvHD, while a high gut microbiota diversity appears to be protective. Aiming at restoring microbiome functions, Fecal Microbiota Transfer proved to be a promising treatment modality in this challenging clinical situation, with recent studies reporting favorable results in steroid refractory-acute GVHD (SR-aGvHD) patients. Here we report on the use of "MaaT013", a standardized, pooled-donor, high-richness microbiota biotherapeutic, used to treat 8 patients with intestinal-predominant aGvHD. Patients and methods Eight allo-HSCT recipients with steroid-dependent or steroid-refractory gastrointestinal GvHD (classical aGVHD n=3, late-onset aGVHD n=2; aGvHD with overlap syndrome n=3) were treated with the MaaT013 biotherapeutic as part of a compassionate use program. These patients had previously received and failed 1 to 5 lines (median 2.5) of GvHD systemic treatments. MaaT013 microbiota biotherapeutics were provided as a pharmaceutical preparation to hospitals by the developer, "MaaT Pharma". Each patient received 1 to 3 doses (median: 3; total doses administered: 21) of MaaT013, a 150 mL bag, by enema (n=7) or nasogastric tube (n=1). GvHD response was evaluated 7 days after each administration and 28 days after the first dose. Prepared under Good Manufacturing Practices, MaaT013 biotherapeutics are characterized by a highly consistent richness of 455 +/- 3% Operational Taxonomic Units (OTUs) and an Inverse Simpson index greater than 20. Batch release specifications are based on potency (viability), identity (diversity), and purity (microbiological safety testing following regulatory guidelines and proportion of proinflammatory species), ensuring the desired consistency between batches. Results We observed 6/8 positive responses at D28 after first dosing, including 3 Complete Responses (CR), one Very Good Partial Response (VGPR), and 2 Partial Responses (PR). Considering the best GI response achieved, all (8/8) patients experienced at least a PR, with 3 CRs, 2 VGPRs and 3 PRs. The 3 patients with CR were still alive at last follow-up (60 to 192 days after last dosing; median: 115 days) and were able to taper and stop steroids and immunosuppressants without relapse of GI symptoms. Of note, among these 3 patients, mild mouth chronic GvHD symptoms persisted in one patient, and relapse of hematologic malignancy was observed in another patient. Among the 8 treated patients, 5 were still alive at last follow-up (60 to 232 days after last dosing; median: 125 days). The safety of the MaaT013 microbiota biotherapeutic was satisfactory in all patients. One patient developed a possibly related sepsis one day after the third MaaT013 administration. In the latter case, no pathogen was identified in blood cultures, and the patient recovered after a course of antibiotics. Conclusions We herein report for the first time the treatment of 8 patients with steroid-dependent or steroid-refractory intestinal aGvHD using a full ecosystem, standardized, pooled-donor, high-richness biotherapeutic. Overall, 3/8 patients attained a complete response following treatment with the off-the-shelf MaaT013 product, shown to be safe and effective in these immunocompromised patients with severe conditions, warranting further exploration of the full ecosystem microbiota restoration approach. Disclosures Malard: Sanofi: Honoraria; JAZZ pharmaceutical: Honoraria; Astellas: Honoraria; Therakos/Mallinckrodt: Honoraria; Keocyte: Honoraria; Janssen: Honoraria. Plantamura:MaaT Pharma: Employment. Carter:MaaT Pharma: Employment. Chevallier:Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Introduction: allogeneic transplantation (allo-HSCT) is a curative treatment for patients with advanced lymphoma. Haploidentical (haplo-SCT) transplantation extended the accessibility to allo-HSCT, overcoming the issue of donor availability. However, alternative donor allo-HSCT is still considered at higher risk of non-relapse mortality due to the HLA disparity and thus an anticipated higher incidence of GVHD. In this context, the use of a non myeloablative conditioning (NMAC) regimen combined with post transplantation cyclophosphamide (PT-Cy) based GVHD prophylaxis may reduce procedure related toxicity. The aim was to evaluate the toxicity and efficacy of haplo-SCT using NMAC with PT-Cy in advanced lymphoma patients. Methods: We here report the retrospective experience of a bicentric transplantation program. We analyzed a cohort of lymphoma patients undergoing Haplo-SCT and homogeneously receiving NMAC and PT-Cy. Inclusion criteria were: 1) first allo-HSCT for advanced lymphoma between 2009 and 2018; 2) haploidentical donor; 3) NMAC (fludarabine cyclophosphamide and 2 gray TBI GVHD prophylaxis consisted of PT-Cy day+3 and +4 , cyclosporine A and MMF starting from day +5. Multivariate analyses included age, disease type (NHL vs HL), HCT-CI (< vs ≥ 3), graft source (PBSC vs BM), disease status at haplo-SCT (CR vs other). Results: One hundred forty seven patients (73 NHL; 74 HL) with a median age of 46 years (range: 19-71) were included. PBSC (peripheral blood stem cell) was used as graft source in 96 patients (65%). Patients received a median number of 3 conventional chemotherapy lines before haplo-SCT (1-8). Sixty-five (44%) had relapse after Auto-HCT. At the time of haplo-SCT, 96 patients (66%) were in complete remission. The cumulative incidences of day+100 grade 2-4 and 3-4 acute GVHD were 30% and 3%, respectively. The cumulative incidences of 2-year chronic and moderate or severe chronic GVHD were 13% and 8%, respectively. With a median follow up of 39 months (6-114), 2-year NRM was 14%, with a trend for higher risk in patients with HCT-CI ≥ 3 (HR 0.39, 95CI [0.15-1.04] p = 0.061) while age was not associated with an increased risk of NRM (HR 1.01, 95CI [0.98-1.05], p = 0.450). Two-year cumulative incidence of relapse (CIR) was 21% and 18% in HL and NHL patients, respectively. Disease status at the time of haplo-SCT was strongly associated with relapse (HR 2.99, 95CI [1.41-6.35], p = 0.004) In HL patients, 2-year PFS, OS and GRFS were 65%, 77% and 57%, respectively, while corresponding values in NHL patients were 65%, 69% and 55%, respectively. Two-year PFS and GRFS were significantly higher in patients who underwent haplo-SCT in CR (PFS: CR vs. no CR: 72% vs. 55%, p=0.045; GRFS: CR vs. no CR: 63% vs. 42%, p=0.010). There was a trend for better 2-year OS in CR (OS: CR vs. no CR: 78% vs. 63%, p=0.063. Conclusion: We confirm the feasibility of haplo-SCT using NMAC and PT-Cy with low incidence of GVHD (notably severe forms) and NRM. In addition, we observed a relatively low incidence of relapse (19%) in this cohort of heavily pretreated patients, underlining a potent graft-versus-lymphoma effect after haplo-SCT, leading to promising survivals, including high rate of GRFS (>50%), suggesting a preserved long term quality of life in survivors. We conclude that NMAC haplo-SCT with PT-Cy should be considered as a valuable curative option for advanced lymphoma patients, with a favorable toxicity profile and promising long term survival. Figure Disclosures Stoppa: celgene: Other: travel fees, lecture fees; takeda: Other: travel fees. Carlo-Stella:MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Boehringer Ingelheim: Consultancy; Genenta Science sr: Consultancy; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Other: Travel, accommodations; Janssen Oncology: Honoraria; AstraZeneca: Honoraria. Chabannon:EBMT: Other: Working Party Chair, Board member; Fresenius Kabi: Other: research support; Miltenyi Biotech: Other: research support; Terumo BCT: Other: speaker's fees; Celgene: Other: speaker's fees; Novartis: Other: speaker's fees; Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities. Santoro:Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; BMS: Consultancy. Blaise:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria.

The PICALM-MLLT10 fusion gene, generated by the t(10;11)(p12-13;q14-21) translocation, is a rare but recurrent event in acute leukemias. In this study, we assessed the characteristics and outcome of 18 PICALM-MLLT10 AML patients. As compared with non PICALM-MLLT10 patients (n=72), PICALM-MLLT10 AML were characterized by more frequent extramedullary diseases, CD7 expression and higher platelet counts. Three out of four therapy-related PICALM-MLLT10 AMLs had been previously treated for diffuse large B-cell lymphoma. The complete response rate was 71% after intensive chemotherapy. PICALM-MLLT10 patients had a shorter median overall survival than patients with favorable cytogenetics (12 months vs. not reached, p=0.07) but not significantly different from those of intermediate (26 months, p=0.32) or unfavorable cytogenetic groups (8 months, p=0.13). Long term responses were achieved in a subset of patients after allogeneic stem-cell transplantation but also after high-dose cytarabine.

β-D-(1,3)-glucan (BG) is a component of the cell walls of many fungal organisms. Our aims were to investigate the feasibility of the BG assay and its contribution to early diagnosis of different types of invasive fungal infections (IFI) commonly diagnosed in a tertiary care centre. The BG serum levels of 28 patients diagnosed with six IFI [13 probable invasive aspergillosis (IA), 2 proven IA, 2 zygomycosis, 3 fusariosis, 3 cryptococcosis, 3 candidaemia and 2 pneumocystosis] were retrospectively evaluated. The kinetic variations in BG serum levels from the 15 patients diagnosed with IA were compared with those of the galactomannan antigen (GM). In 5/15 cases of IA, BG was positive earlier than GM (time lapse from 4 to 30 days), in 8/15 cases, BG was positive at the same time as GM and, in 2/15 cases, BG was positive after GM. For the five other fungal diseases, BG was highly positive at the period of diagnosis except for the two cases of zygomycosis and one of the three cases of fusariosis. This study, which reflects the common activity of a tertiary care centre, confirms that BG detection could be of interest for IFI screening in patients with haematological malignancies.

l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .

Allogeneic Hematopoietic Cell Transplantation (allo-HCT) currently represents the only potentially curative therapy for patients affected by advanced Mantle Cell Lymphoma (MCL). Haploidentical HCT (haplo-HCT) allows virtually all patients to proceed to allo-HCT. We analyzed survival outcomes of 20 MCL patients who received haplo-HCT at Humanitas Cancer Center and Institut Paoli Calmettes between 2012 and 2017. Median age of patients at transplant was 64 years (range, 35-71). Ten of them (50%) relapsed after autologous transplantation, one patient relapsed after allo-HCT (HLA identical sibling), while 9 underwent directly haplo-HCT due to the high risk of relapse (primary refractory disease). All patients except one had chemosensitive disease at transplant (75% complete response, 20% partial response, 5% progressive disease). In 10 patients, novel drugs were used as bridge to transplant to obtain response (8 patients were treated with ibrutinib, one with lenalidomide and one with bortezomib). The hematopoietic-cell-transplantation comorbidity index (HCT-CI) was 0-1 in 4 patients, 2-3 in 12 patients and 4-5 in 4 of them. In 5 patients bone marrow was used as the source of stem cells, while the other 15 received peripheral blood stem cells. Sixteen patients received a nonmyeloablative conditioning regimen while 4 patients underwent a reduced intensity conditioning regimen. In all patients, post-transplant cyclophosphamide (PT-Cy) was used as graft-versus-host-disease (GVHD) prophylaxis. Acute GVHD (aGVHD) was observed in 9 patients (grade I 2 patients, grade II 6 patients, grade III-IV 1 patient) at a median of 34 days from transplant (range, 21-80). The cumulative incidence of aGVHD grade 2-4 was 30% (95% CI, 12% to 51%) at 6 months. Three patients developed chronic GVHD (cGVHD) (1 mild, 1 moderate and 1 severe). The cumulative incidence at 2 years of moderate-severe cGVHD was 11% (95% CI, 2% to 30%). With a median follow-up of 22 months (range 5-73 months), relapse or progression were observed in 2 patients at a median of 6 months (range, 3-8 months) from haplo-HCT with a cumulative incidence of disease relapse/progression of 11% (95% CI, 2% to 29%) at 3 years. The GVHD-free/relapse-free survival (GRFS) at 1 year was 68% (95% CI, 42% to 84%). Three deaths were attributed to toxicity and occurred at a median of 123 days (range, 17-274 days) after transplant. The specific causes of death were: aGVHD, 1; infection, 1; cGVHD 1. The cumulative incidence of NRM was 16% (95% CI, 4% to 36%) at 3 years. The 3-years progression-free survival (PFS) and overall survival (OS) were 73% (95% CI, 47% to 88%) and 71% (95% CI, 43% to 77%), respectively. Comparing this cohort with a similar cohort of 20 MCL patients who underwent allo-HCT from HLA identical sibling or unrelated donors in the same centers during the same time frame, the clinical outcomes (GRFS, NRM, PFS and OS) were not statistically different, even if there was a trend for better outcomes using haploidentical donor. In conclusion, our study suggests that haplo-HCT with PT-Cy in MCL patients is feasible and is associated with a low relapse rate and NRM, even in the era of new drugs. Figure. Figure. Disclosures Carlo-Stella: Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; Genenta Science: Speakers Bureau; MSD Italia: Speakers Bureau; Janssen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Boehringher Ingelheim Italia: Consultancy; Rhizen Pharmaceuticals: Research Funding.

To the editor: We describe a successful salvage treatment with intensive chemotherapy and stem cell transplantation for a relapse of Hodgkin lymphoma (HL) after single umbilical cord blood transplantation with a reduced intensity-conditioning regimen (RIC).[1][1],[2][2] The originality of this

Purpose Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. Patients and Methods In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non–mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC). Results Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response. Conclusion AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

Adenovirus infection remains an important cause of mortality after bone marrow transplantation (BMT). Currently no efficient antiviral treatment is known. Thus, testing new modalities of early diagnosis and treatment is a crucial objective. Adenovirus infection is defined by the combination of symptoms and the isolation of virus from the source of clinical symptoms. The involvement of two or more organs and the presence of virus in blood cultures define disseminated disease. Seven children with a median age of 7 years received bone marrow transplantation for leukemia. All received an unrelated graft without T cell depletion. Adenovirus was sought in blood, urine and biopsy specimens using PCR and culture. Analysis of biopsy specimens included systematic immunohistochemistry. Cidofovir treatment was initiated as soon as biopsy revealed the histopathological signs of adenovirus. Cidofovir was given at 5 mg/kg once weekly for 3 weeks then every 2 weeks. Six patients had diarrhoea and one patient had cystitis. Adenovirus infection and disseminated disease were diagnosed in four cases and three cases, respectively. In six cases, serotype A31 was isolated from gastrointestinal biopsy and in two cases serotypes B2 and C6 were detected in blood and urine. Cidofovir treatment was associated with clinical improvement of diarrhoea, cystitis and fever in five patients, in whom the virus became undetectable in cultures and PCR analyses despite the persistence of immunodeficiency. The median follow-up was 360 days after BMT (240-570). One child died of invasive aspergillosis and another of disseminated adenovirus after interruption of cidofovir therapy. Further studies in immunocompromised patients will be needed to extend these promising results concerning the role of cidofovir in adenovirus infection.

Background: While therapeutic outcomes in patients (pts) with acquired severe aplastic anemia (SAA) has greatly improved in recent years, results remain poor for pts who are refractory to first-line immunosuppressive therapy (IST) and lack a matched unrelated donor. We conducted a prospective multi-center phase II uncontrolled trial to assess the efficacy and safety of cord blood transplantation (CBT) in refractory SAA pts (NCT 01343953). Patients and methods: Pts with SAA refractory to IST with anti-thymocyte globuline (ATG) and ciclosporin (CsA) were eligible in case of no existing matched unrelated donor but available one or two unrelated CB units containing alone or both together more than 4 x 107/Kg frozen nucleated cells/Kg (no more than 2 out of 6 HLA mismatches allowed between each CB unit and the pts). Pts with isolated bone marrow cytogenetic abnormality (absence of morphologic evidence of myelodysplastic syndrome) were also eligible. The conditioning regimen consisted of fludarabine 30mg/m2 (D-6 to D-3), cyclophosphamide 30mg/kg (D-6 to D-3), ATG (thymoglobulin) 2.5mg/kg at D-3 and D-2 (5mg/Kg total dose) and total body irradiation (2 Gray) on D-2. All pts received one injection of anti-CD20 (150 mg/m2) to prevent EBV reactivation (D+5). CsA was given alone as prophylaxis for graft versus host disease (GVHD). The trial used the Fleming's Single Stage Phase II Design, with sample size computed to demonstrate an improved overall survival (OS) rate at one year from 20% up to 50%, with type I and type II error rates set at 0.05. A minimum sample of 25 pts was required, with a minimum number of 9 pts alive at one year needed to indicate treatment efficacy. Secondary endpoints included cumulative incidences (CumI) of engraftment, acute and chronic GVHD (aGVHD and cGVHD), infections, relapse and late cause of death. Results: 29 pts were included between June 2011 and October 2015. One pt was diagnosed with dyskeratosis congenita and a matched unrelated donor was identified for another pt between inclusion and anticipated date of CBT (exclusion criteria). One pt died before CBT due to a septic shock (D+4 after inclusion). Analyses were conducted in the remaining 26 pts. Median time between SAA diagnosis and CBT was 12 months (interquartile range (IQR) 8.7 to 17.8). All pts received at least one course of IST before CBT (2 courses, n=8). Twenty-three pts received 20 or more transfusions before CBT. BM karyotyping showed 2 pts respectively with monosomy 7 in 4 and 15 mitoses as well as one pt with trisomy 8 in 4 mitoses before CBT. Eight pts (31%) have a PNH clone (median 4.5% [IQR: 3.1-9.7]). Median age at time of CBT was 16 years (IQR 8.25 to 23) and median follow-up is 13.2 months (IQR 4.1 - 23.5). Three out of 26 pts incorrectly received twice the dose of ATG (10mg/Kg total dose) due to protocol violation. Sixteen pts received one CB and 10 received two CB units. Median number of nucleated cells infused was 3.7 x 107/Kg (IQR, 3-4.9) and CD34+ cells infused was 1.4 x 105/Kg (IQR, 1.0-1.9). Myeloid engraftment occurred in 23 pts, with a 60 day-CumI of neutrophil engraftment of 88.5% with full chimerism for all of them. Three pts did not engraft (2 deaths at D71 and D92 and one successful second HSCT). The 100 day-CumI of grade II-IV acute GVHD was 40% (95% CI, 20-60) (8 grade II; 0 grade III; 2 grade IV). Among the 23 pts alive at day 100, five developed cGVHD leading to a one-year CumI of cGVHD at 27% (95% CI, 7-47) (severe cGvHD in 2 pts). During follow-up, 8 pts experienced a total of 18 grade III infections with a 6-month CumI of 32% (95% CI, 13-51). None of the pts presented post-transplant EBV-related lymphoproliferative disorder. Immune reconstitution is shown in Figure 1. Three pts died before 1 year due to non-engraftment (n=2) and infection (n=1, one of those who received twice the dose of ATG). With 23 pts alive at 1 year, the primary objective of the study was thus reached. The one-year treatment related mortality (TRM) was 15% (95%CI, 4-35). One additional pt who had also received twice the dose of ATG died (severe cGvHD) after one year (at 13.6 months), resulting in a 14-month OS of 81% (95%CI, 66-100) (Figure 2). Conclusion: CBT with at least 4 x 107/Kg frozen nucleated cells/Kg after a FLU-CY-TBI-ATG conditioning regimen gave rise to very encouraging results in this particular high risk SAA refractory population. Pediatric and young adult SAA pts who are refractory to first-line IST should now be considered either way for matched unrelated donor or CBT. Disclosures Peffault de Latour: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Background Although allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative option to treat hematologic malignancies, disease recurrence remains a concern in the setting of high risk diseases. Thus, post alloSCT therapeutic strategies are needed to treat and/or prevent disease progression. In this setting, donor lymphocytes infusion (DLI) is an option as post alloSCT immunotherapy aiming to enhance graft versus leukemia (GVL) effect. Although DLI may induce persistent remission, graft versus host disease (GVHD) is a potential complication following DLI. Because of the suspected higher incidence of GVHD in the presence of HLA mismatches, few series focused on DLI following haploidentical stem cell transplantation (HaploSCT) so far. We therefore report our experience of DLI following HaploSCT using post-transplantation cyclophosphamide (PT-Cy) platform. Methods: We included in this single center study all consecutive adult patients with hematological malignancies who received DLI after HaploSCT with PT-Cy as part of GVHD prophylaxis from 2013 to 2016 (n=21). Conditioning regimens were non-myeloablative (low dose TBI-based) or with reduced toxicity (various dose of busulfan according to disease and patient characteristics). Ciclosporine A and mycophenolate mofetil were given as additional GVHD prophylaxis in all cases. DLI were given at escalating doses, expressed as CD3+cells/kg, without GVHD prophylaxis, and ranged from 1x105 to 5x107 cells/kg. Results: Eleven patients (52%) were transplanted for high risk disease according to the disease risk index (DRI, Armand et al., blood 2015). Twelve patients (57 %) received haploSCT in complete remission,.18 patients received first transplant and 3 patients their second transplant. After HaploSCT, 21 patients (median age: 56 years [range: 23-73]) received either therapeutic (treatment of hematological post transplantation relapse, n=6) or prophylactic (n=15) DLI. The median interval from HaploSCT to the first DLI was 128 days (range: 79-1011). The average number of DLI per patient was 1.8 (range, 1-3). Clinical characteristics are outlined in Table 1. Patients with AML and MDS received DLI alone (n = 13) or in association with azacytidine (n = 2). Patients with MM received DLI in association with Revlimid (n=3). Chimerism before first DLI was complete in 19 patients. 6 patients (33%) developed post DLI GVHD in a median time of 42 days (range: 30-210) with exclusively chronic features. 2 patients (9 %) had severe forms of chronic GVHD. GVHD-related death occurred in 1 patient No response was achieved when DLI were given as therapeutic and 4 of 6 patients died from disease progression. Otherwise, only 3 of 16 patients who received prophylactic DLI experienced relapse. With a median follow up of 129 days, overall survival was 63%. Conclusion Our study suggests that DLI following HaploSCT with PT-Cy is feasible. GVHD is frequent but with a relatively low incidence of severe forms. No response rate was achieved in the context of hematological relapse, underlining that preemptive or prophylactic strategy might be preferred. Indeed, the overall good outcome in patients receiving prophylactic DLI is promising taking into account the poor prognostic of the diseases indicated for alternative donor transplantation. Further prospective studies are needed in specific disease settings to assess the benefit for using such post alloHSCT immune-intervention. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

T-replete Haplo-HSCT is presently a major evolution in the field of allo-HSCT. Despite we miss prospective evaluation, we are faced to a high pace of diffusion worldwide. We however need to collect informations on many aspects. In this abstract we report an analysis of the early events and organ toxicities in the first patients transplanted in our program. Between 2011 and 2015, 117 patients treated for hematologic malignancy, receiving a Haplo-HSCT and post-transplant high dose cyclophosphamide (PT-HDCY) with a minimal follow-up of 100 days were analyzed. All organ toxicities were graded according to WHO scale and only grade 3-4 toxicities were analyzed: impact of age, Hematopoietic transplant comorbidity index (HCT-CI) and conditioning regimen were analyzed in this first step evaluation. Median age was 56 (19-73) and 58% were males (M/M: 35%; M/F: 21%; F/M: 23%; F/F: 21%; Donor origin: Sibling: 43%; offspring: 45%; Mother: 9%; Father: 3%). Patients were transplanted for: Acute Leukemia (AL): 32%; Non-AL myeloid malignancies: 19%; Lymphoma: 36%; Non-lymphoma Lymphoid malignancies: 13%. Patients were at high risk of both relapse (48% of active disease at the time of Haplo-HSCT, Disease risk index: low: 8%; Intermediate: 59%; high/very high: 33%) and non-relapse mortality [NRM] (65% had HCT-CI of 3 or more). Conditioning regimens were non-myeloablative TBI-based (NMAC), busulfan-based reduced intensity (RIC) and busulfan-based myeloablative conditioning (MAC) in 68%, 10% and 22%, respectively. PBSC were infused in 89% of the patients. Graft CD34/CD3 cells: 5.2 (0,8-14,8) / 261 (27-629) x 10e6/kg. Seventeen (15%) pts received a previous allo-HSCT and 7 (6%) pts with AL were included in a sequential debulking-transplant strategy. One-year overall survival, PFS and GRFS were 85%, 78% and 55%. Graft failure occurred in 3 pts (all with positive donor specific antibodies). Others reached ANC>0.5 G/L and platelet count>20G/L in a median time of 20 (14-38) and 31 (10-395) days post Haplo-HSCT. Day-100 cumulative incidence of grade 2-4 and 3-4 acute GVHD were 24% and 7%, respectively. Grade 3-4 WHO toxicities within 100 days: Pulmonary: 31%; Cardiac: 23%; Liver: 20%; Cystitis: 14%; mucositis: 12%; renal: 8%. 14 patients (12%) died within 100 days at a median of 40 (2-84) days (9 (9%) of the 100 patients with first and 5 (29%) of 17 patients with previous allo-HSCT). Causes of NRM were (n patients): infection: 6; Cardiac: 4; GVHD: 2; Neurologic: 2. In a multivariate analysis, grade 3-4 3-4 OMS cardiac toxicity occurred more frequently in pts older than 60 (HR: 0.42 (0.17-1.0), p=0.05, Figure 1A) and both oral mucositis (HR: 0.22 (0.06-0.72), p=0.01) and liver toxicity (HR: 0.32 (0.12-0.89), p=0.03) in patients treated with busulfan-based conditioning (Figure 1B). Seventy-nine (68%) patients experienced bacterial infection, 56 (48%) viral reactivation and 14 (12%) fungal infections. Pts older than 60 experienced more frequent bacterial infection than others (82% vs 58%: p=0.01, Figure 1A). In conclusion, this retrospective analysis suggests a higher incidence of peculiar organ toxicity as cardiac and bladder deserving further analysis. It also suggests that in a high-risk population (second allo-HSCT:15%; patients over 60 years: 38%; HCT-CI≥3: 65%; High/Very high DRI: 33%; transplanted with active disease: 48%early NRM is somehow limited allowing further development at the condition to take into account the main factors leading to these toxicities and to develop adapted care. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Allogenic hematopoietic stem cell transplantation (SCT) is often the only curative treatment for a part of patients with malignant or benign hematological disorders. The availability of a HLA matched related or unrelated donor remains a major obstacle which can be resolved by the presence of alternative donors, like umbilical cord blood, partially matched unrelated or haploidentical family donors. T cell repleted SCT using haploidentical donors (H-SCT) has considerably improved over the last years due to better control of Graft Versus Host Disease (GVHD) using post-transplantation cyclophosphamide (PTCY). Our study aims to shed light on the interest of chimerism evaluation after H-SCT and to elucidate the cause of graft failure (GF) in our H-SCT recipients. Patients and methods: We conducted a retrospective study of 179 patients (pts) who received a H-SCT in our center from august 2009 to march 2016. The pts characteristics are reported in Table 1 and 2. One hundred sixty pts received a Reduced Intensity (RIC) and 19 pts a MyeloAblative Conditioning (MAC) regimen. Twenty-eight pts had refractory or relapsed acute myeloid leukemia. All pts received PTCY on days 3 and 4 and Ciclosporine A and mycophenolate of mofetil since day 5 for GVHD prophylaxis. Twenty pts received H-SCT for relapse after a first SCT with a HLA identical donor. Stem cell sources were bone marrow (BM) for 19 pts, peripheral blood stem cells (PBSC) for 157 pts and BM+PBSC for 3 pts. The donors were children (79 daughters sons), parents (4 fathers, 14 mothers), family members (75 siblings, 1 cousin, 1 nephew) and 5 unknown. Chimerism analysis: The peripheral blood CD3 positive cells were selected using the kit Human CD3 Positive selection (Stemcell) and genotyping was performed with the PowerPlex 18D System (Promega), a multiplex STR system allowing the co-amplification of 18 loci. DSAs (donor-specific anti-HLA antibodies): The DSAs were identified with the use of highly sensitive solid-phase immunoassays. Desensitization therapy with Bortezomib, Rituxan and plasmapheresis was performed in two patients with a high level of DSAs. Results: Chimerism could be evaluated in 167 patients, where 162 had ≥ 98% of donor cells at a median time of 35 d post-transplant (range 15-170) without secondary GF. One patient suffering from sickle disease had stable mixed chimerism (82% donor). Only 4 pts had primary GF (2%), all of donor-recipient pairs were ABO compatible, all of them received a Baltimore conditioning whereas 2 pts had BM as SC source. Recipients with PBSC as SC source had poor CD34+ cells infused (1,2 and 2,3 x 106/kg). One of the 4 pts had a high level of DSAs. A patient with mycosis fungoide had secondary GF after relapse (PBSC/DSAs negative). One patient with a high level of DSAs (78%) had a primary graft failure. Two pts with a high level of DSAs who were desensitized by the described procedure. Forty-five patients had a positive anti-HLA antibody no specific to donor with a median level of 3% (range: 1-45%) with no impact on engraftment (Anti-HLA antibody class I in 30 pts, class II in 11 pts and mixed in 4 pts). The median number of CD34+ cell count was 5,2x 106/kg (range: 1,3-17) in 160 pts who had PBCS as SC source. With a median follow up of 532 d (range: 164-1587d), 123 pts are alive and 116 of them are in CR. Conclusion: Full donor chimerism is obtained in almost all pts after T cell repleted H-SCT with PTCY. Primary graft failure occurred principally in pts with high levels of DSAs and poor graft CD34+ cells. Chimerism analysis post H-SCT is not crucial and might focus on a small group of high-risk pts. Detection of DSAs is crucial in HLA mismatched transplants not only to select the most appropriate donor but also to include a pre-transplantation strategy of desensitization to minimize the risk of graft failure. Disclosures No relevant conflicts of interest to declare.

Introduction Allogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform. Methods This retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia. Results One hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT. At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC. With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC Discussion We found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Background: Since the first publication at the John Hopkins Hospital, (Luznik et al. BBMT 2008), Haploidentical T-cell replete Stem Cell Transplantation (HaploSCT) with post transplantation cyclophosphamide (PT-Cy) has become a reproducible and feasibility therapeutic option for many patients (pts) with hematologic malignancies , notably because of the low incidence of GVHD and infections, without increased graft failure. Initially, bone marrow (BM) was considered as the favorite source of hematopoietic stem cells in order to minimize the risk of GVHD. In a retrospective study, we previously showed no difference in terms of increased events (GVHD, NRM), regardless of the hematopoietic stem cell source (PBSC or BM) (Castagna et al. BMT 2014). Some recent publication seems to confirm this observation (Sugita J. BBMT 2015 , Solomon R. Adv in Hem. 2016), although no randomized study so far has been conducted. Here, we retrospectively analyze the incidence and the characteristics of GVHD in the setting of HaploSCT using PT-Cy, after infusion of PBSC. Methods: Inclusion criteria were: adult pts with hematologic malignancies receiving a PBSC HaploSCT from 2012 to 2015 in 4 centers (3 in France and 1 in Italy) with PT-Cy as part of the GVHD prophylaxis. PBSC infusion at day 0 was followed by PT-Cy 50 mg/kg on days +3 and +4 in association with calcineurin inhibitors (cyclosporine A or Tacrolimus) and mycophenolate mofetil (MMF), started at day +5. All patients received G-CSF support from day+5 until neutrophil recovery. Study end points were the cumulative incidences of acute (a) and chronic (c) GVHD, with a specific organ grading evaluation, non-relapse mortality (NRM), relapse (CIR) as well as progression free (PFS) and overall survival (OS). Additionally, we analyzed the composite endpoint "GVHD and relapse free survival" (GFRS) for which the occurrence of relapse, death or severe chronic GVHD was considered as relevant events. Correlation between CD 34+ and CD 3+ and the incidence of aGVHD and cGVHD was studied by a linear continuous variable. Results: Between March 2012 and December 2015, 192 pts with a median age of 57 years (range: 16-73) received T-cell replete PBSC HaploSCT for hematologic malignancies (myeloid: n= 55%; lymphoid: n=45%) in 4 centers. Patient's characteristics are shown in table 1. Pts received non myeloablative (according to Baltimore regimen) or busulfan-based reduced intensity conditioning, in 56% and 44% of cases, respectively. All, but 3 pts, engrafted, with a median time of 19 days (range, 14-47) to neutrophil recovery (ANC >500 x106/L) and 22 days (range, 14-252) to platelet recovery (PLT > 20 G x 109/L). The median CD34+ x 106/Kg and CD3+ x 106/Kg cells infused were 5.5 (range, 1.5-14.8) and 404 (range, 38-704), respectively. No relevant correlation was observed between the CD34+ and CD3+ infused cells and the incidence of GVHD, studied by linear continues variable. We noted only a trend to develop severe cGVHD with an increasing number of CD3+ cells infused. This result has to be considered with caution, because of the small events (6 pts affected by severe cGVHD). Complete donor T cell chimerisme was evaluable in 162 pts (83%) and achieved by day +30. The incidence of aGVHD was 38% at 100 days (all grades), whereas grade II-IV and III-IV were 24% and 10%, respectively. Concerning patients with aGVHD grade 2-4, the most affected organ was skin (19%), followed by gut (9%) and liver (2%). The incidence of 3-year cGVHD according to NIH classification was 15% (all grades). Three percent of pts developed severe cGVHD (lung n=1; liver, n=1). The most frequent involved organs were skin and mucosae (70%). No patient showed gut cGVHD. Finally, in univariate analysis, busulfan-based conditioning seems to negatively impact on severe cGVHD (p = 0.03; HR=3.37 [1.09 -10.46]) After a median follow up of 20 (range, 4 - 52) months, NRM at 100 days and 1 year was 10% and 20%, respectively. Three-year OS, PFS, CIR and GRFS were 63%, 55%, 25% and 49%, respectively. Conclusion: This retrospective study shows a very low incidence of severe cGVHD after HaploSCT even with PBSC as stem cell source, suggesting that the use of PT-Cy may overcome the anticipated increased incidence of cGVHD, contrary to as previously reported in the HLA identical setting (Mohty et al. Leukemia 2003). Similar to HLA identical sibling and unrelated donor transplantation, the most frequent organs involved are skin and mucosae Disclosures No relevant conflicts of interest to declare.

Background : Bacterial infections (BI) are a major cause of morbidity and mortality in patients treated for hematological malignancies, especially those with acute myeloblastic leukemia or receiving allogeneic hematopoietic stem cell transplantation. Despite severe neutropenia and prolonged treatment with corticosteroids, there are little published data on BI during induction chemotherapy in adults with acute lymphoblastic leukemia (ALL). Between 2006 and 2014, 787 adult patients were included in the GRAALL-2005 study, a prospective, randomized and multicenter phase III trial for patients newly diagnosed patients with Philadelphia chromosome-negative B-cell precursor (BCP) or T-cell ALL. We retrospectively reviewed the occurrence of BI during induction treatment in these patients. Patients and Methods: The GRAALL-2005 study evaluated the value of hyperfractionated cyclophosphamide in the whole study population and of rituximab in patients with CD20+ BCP-ALL. All patients received a 5-drug induction therapy with corticosteroids (prednisone) for 21 days, associated with vincristine, daunorubicin, cyclophosphamide and L-asparaginase. A broad-spectrum antibiotic treatment effective on Gram-negative and positive germs was recommended when the neutrophil count was less than 0.5 G/L. Pneumocystis prophylaxis was made by trimethoprim/sulfamethoxazole or pentamidine. Results: During induction chemotherapy, 270 of the 787 patients (34.3%) experienced a total of 376 BI episodes (1.4 BI episodes per patient). The BI incidence rate was higher in the subgroup of patients combining hyperfractionated cyclophosphamide and rituximab as compared to those who received standard-dose cyclophosphamide and no rituximab (40.7% versus 29.5%; p=0.098). The median time from the first day of induction therapy to BI diagnosis was 10 days (range, 7-14). The infection was considered as serious in 58 patients, with a diagnosis of septic shocks in 57. Forty-one patients were transferred in intensive care unit. At 50 days after induction initiation, 22 patients had died from BI: 8.1% of patients with BI and 2.8% of all patients. Bloodstream was the most common site (82.7%), followed by gastrointestinal tract (6.5%) and lungs (6.5%). In less than 2% of cases, skin and soft tissues, central venous catheter, or urinary tract was concerned. Infections with Gram-positive cocci predominated as the etiology of microbiologically documented infections (46.9%), more specifically coagulase-negative Staphylococci. E. coli and Pseudomonas species were the most common Gram-negative organisms (40.5%). The patients received a median number of 3 antibiotics. The first-line was a monotherapy in 57% of cases, with the predominant use of betalactam. In one-third of the cases, it was betalactam in combination with aminoglycoside or glycopeptide. More than 2 antibiotics were prescribed in 12% of cases. Conclusion: Induction chemotherapy in adults with ALL is associated with a high incidence of bacterial infections and a significant related mortality. To our knowledge, this report is the only large adult ALL study dealing with bacterial infectious complications during induction chemotherapy. Despite an intensely myelosuppressive chemotherapy regimen, the infection-related mortality seems to be lower than that reported during induction in acute myeloid leukemia. Predictive risk factors for bacterial infections have to be analyzed, as well as prophylactic/empirical antibiotic strategies in order to improve care for this subset of patients. Disclosures No relevant conflicts of interest to declare.

INTRODUCTION: Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a major therapeutic challenge: outcome is very poor, without curative option in most cases. Second alloHSCT may be considered in few selected patients because of anticipated limitations: 1) donor availability; 2) high toxicity due to previous treatments; 3) low efficacy considering the very advanced disease situation. We hypothesized that the use of post transplantation Cyclophosphamide (pCY) haplo-SCT may be an interesting alternative to overcome these limitations. In particular, the presence of full haplotype HLA mismatch could provide a decisive antileukemic effect relative to alloreactivity. In absence of large series in this setting, we report here the outcome after HaploSCT for patients who relapse after a first alloHSCT. METHODS: We retrospectively studied adult patients, who received a second pCy Haplo-SCT for hematological malignancies. Patients were treated between 2009 and 2016. The objective was to assess both the feasibility and the efficacy of HaploSCT in this setting. RESULTS: Twenty seven patients were included: median time between first alloHSCT and relapse was 11 months (range: 1-82). Median age at second transplantation was 49 years old (range: 21-61). Most of patients had acute myeloid leukemia (n=12, 44%) or Hodgkin lymphoma (n=6 patients, 22%). Fifteen patients (55%) were in complete remission at the time of pCY Haplo-SCT. Hematopoietic cell transplantation-comorbidity index was ≥ 3 in 20 patients (74%). Thirteen patients (48 %) received non-myeloablative conditioning regimen (as Baltimore schema, Luznik et al. BBMT 2008) prior to HaploSCT while remaining patients received busulfan-based regimen. Day+100 cumulative incidence of grade 2 to 4 and 3 to 4 acute GVHD was 15% and 7%. 2-year cumulative incidence of chronic GVHD was 12%. The cumulative incidence of non-relapse mortality and relapse at 2 years were 38% and 27%, respectively. With a median follow up of 25 months (range: 4-63), 2-year progression-free and overall survivals were 36% and 39%, respectively. Disease status at the time of HaploSCT was a major determinant for outcome. Indeed, 2-year NRM and OS were 58% and 25% in patients transplanted with active disease, respectively, while corresponding values in patients transplanted in CR were 21% (p=0.036) and 49% (p=0.041), respectively (Figure 1A and 1B). CONCLUSION: We can conclude that in selected patients who could be candidate for second transplantation, HaploSCT is feasible and may represent a curative option. The overall incidence of relapse of 27% is promising in this situation for which no alternative for cure is available, with relatively good survival in patients transplanted in CR. However, the very high NRM (58%) in refractory patients should make us consider second transplant with caution in this setting. For these patients, specific developments are needed to avoid procedure-related toxicity. Disclosures No relevant conflicts of interest to declare.

International audience; Digestive cryptosporidiosis (DC) can mimic GVHD after allogeneic haematopoietic stem cell transplantation (HSCT), thus requiring a reduction of immunosuppressive drugs and a specific therapy, whereas GVHD requires an intensification of immunosuppression. We systematically searched for cryptosporidiosis by light microscopy, immunochromatography and PCR in HSCT recipients who presented with at least one episode of diarrhoea. Of 115 consecutive patients allografted between July 2006 and November 2008, we analysed stools in 52 of 56 patients meeting these criteria. We identified Cryptosporidium parvum in 5 of the 52 patients (9.6%) at a median of 503 days (range 20-790) after HSCT. In those five patients, the median CD4+ cell and B lymphocyte counts were 60/mm3 (0-234) and 0/mm3 (0-96), respectively. Two patients died of invasive fungal infections. In the other three patients, diarrhoea disappeared after a median of 5 weeks following onset of bitherapy with azithromycine and nitazoxanide; they were still alive 433, 380 and 1179 days after the DC diagnosis. DC is probably under diagnosed after HSCT because it is difficult to detect during the asymptomatic phase. Early bitherapy and reduction of immunosuppression seem efficacious. In our series, DC has a seasonal pattern and is promoted by profound T lymphopenia.

The aim of the present study was to assess the diagnostic efficacy of a combination of two quantitative Aspergillus PCR assays, targeting a mitochondrial and a ribosomal target, in patients with risk factors for invasive aspergillosis (IA) and positive galactomannan (GM) antigen. Forty-four patients with hematological malignancies and risk factors for IA according to revised European Organization for Research on Treatment of Cancer and the Mycoses Study Group criteria (EORTC/MSG) criteria and presenting at least two sequential GM-positive sera were included in the study. Mitochondrial PCR was carried out prospectively on all GM-positive serum samples. Ribosomal PCR was carried out retrospectively on frozen stored sera. The sensitivities of mitochondrial and ribosomal PCRs were 58% and 50%, respectively. The diagnostic test performance was improved by using a combination of both PCR assays and by considering a patient PCR positive when at least two positive results were obtained. The sensitivity, specificity, and positive and negative likelihood ratios were 65%, 94%, and 11.8 and 0.37, respectively. A significant association between fatal outcome at 90 days and positive results of ribosomal PCR assays was observed (adjusted hazard ratio = 8.2; 95% confidence interval [CI] = 1.0 to 65.8; P = 0.048). Our results showed that the combination of two PCR assays targeting mitochondrial and ribosomal Aspergillus DNA improves the sensitivity of PCR in the diagnosis of IA in hematological patients with risk factors and positive GM results. This study also confirms that a positive PCR result is associated with a poor prognosis in these patients and should lead to specific antifungal therapy being introduced immediately.

Early immune reconstitution and efficient graft vs tumor effect after unrelated partially matched double cord blood transplantation in refractory 8p11 syndrome

International audience; BACKGROUND: Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy. OBJECTIVE: Our objective was to document the efficacy and tolerance of corticosteroid therapy (CST) in patients with symptomatic CDC, including those who experienced fever and abdominal pain despite ongoing antifungal therapy. METHODS: We performed a retrospective, multicenter study involving 10 pediatric and adult patients who experienced ongoing symptomatic CDC despite receipt of appropriate antifungal therapy for whom adjuvant oral CST was initiated. RESULTS: All cases of CDC were proven or probable, as determined on the basis of the European Organization for Research and Treatment of Cancer-Mycosis Study Group definition criteria, and occurred in patients with leukemia. CDC-attributable clinical symptoms resolved with CST, which was started a mean of 33.8 days after antifungal therapy had been initiated. Fever and abdominal pain disappeared a median of 4-5 days, and serum fibrinogen and C-reactive protein levels returned to normal values within 14-30 days. The median duration of hospitalization after CST initiation was 8.8 days. Hepatosplenic microabscesses decreased or disappeared within a mean period of 107 days (range, 30-210 days). No relapses of CDC were observed during a median duration of follow-up of 6.5 years (range, 4-9 years). CONCLUSIONS: In children and adults who experience persistently symptomatic CDC despite ongoing receipt of antifungal therapy, CST involving a prednisone equivalent at a dosage of > or =0.5 mg/kg per day for at least 3 weeks is associated with a prompt resolution of symptoms and of inflammatory response. These findings support the pathophysiological hypothesis that CDC belongs to the spectrum of fungus-related immune reconstitution inflammatory syndrome.

Purpose: The FB2A2 (fludarabine, intermediate doses of busulfan and ATG) reduced-intensity conditioning (RIC) regimen is considered as a standard RIC regimen in many centers worldwide. Recently, we have reported the prospective good results of a clofarabine-busulfan containing RIC regimen (CloB2A2) in adults with high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in complete remission (CR) at time of transplant (Chevallier et al, Haematologica, 2014). Thus, this regimen may prove to be superior to the FB2A2 regimen in patients with AML/MDS. Patients and Methods: The aim of this study was to compare outcomes between adult AML/MDS patients who have received, between 2009 and 2015, in 26 French centers, either a FB2A2 RIC regimen (n=170, male 61%, median age: 58 years, AML 86%, CR1 79%) or the CloB2A2 RIC regimen (n=39, including the 16 cases treated within the prospective trial mentioned above, male 62%, median age: 61 years, AML 62%, CR1 64%). The FB2A2 and CloB2A2 regimens consisted of either 30 mg/m²/day Fludarabine for 5 days or 30mg/m²/day Clofarabine for 4 or 5 days, each combined with 3.2 mg/kg/day Busulfan for 2 days and 2.5 mg/kg/day Anti-thymocyte globulin (ATG, Thymoglobuline) for 2 days. As GVHD prophylaxis, cyclosporine (CsA) alone was used in case of related donor in both groups, and for the 16 CloB2A2 patients treated within the prospective trial, while CsA+ MMF were used in case of unrelated donors. The two groups were not statistically different in term of gender, median age and performans status at transplant, median white blood count at diagnosis, median time between diagnosis and transplant, type of donors or cytogenetics for AML patients. Conversely, there were more AML patients (86% vs 62%, p=0.0004) and more patients in CR1 (79% vs 64%, p=0.04) in the FB2A2 group. Also, CloB2A2 patients were transplanted more recently (median year of transplant: 2014 vs 2011, p Results: All patients engrafted, except one in the FB2A2 group. Median time of neutrophils recovery was similar between both groups (FB2A2: 17 days vs CloB2A2: 18 days, p=0.10). With a median follow-up of 28 and 14 months in the FB2A2 and the CloB2A2 groups, respectively, 2-year overall survival (OS) were 59% (51.4-66.7) for the former vs 77% (62.8-91.1) for the latter, p=0.07, 2-year leukemia-free survival (LFS) were 52.7% (44.9-60.4) vs 64% (48.1-79.9), p=0.23, 2-year relapse incidence were 31.1% (24.2-38.4) vs 27.5% (14-42.9), p=0.58, 2-year non relapse mortality were 16.2% (5.8-31.3) vs 8.5% (2.1-20.7), p=0.26 and 2-year chronic GVHD were 13.8% (8.3-20.5) vs 23.9% (8.1-44.2), p=0.12. Incidences of grade 2-4 or grade 3-4 acute GVHD were similar between both groups: FB2A2 22% vs CloB2A2 23%, p=0.86,and 8% vs 3%, p= 0.31. In multivariate analysis, FB2A2 RIC regimen was significantly associated with lower OS and LFS (HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and HR: 2.32; 95%CI: 1.12-4.79, p=0.02) contrary to CR1 status which was associated with significant higher survivals (HR: 0.48; 95%CI: 0.28-0.83, p=0.008 and HR: 0.42; 95%CI: 0.25-0.70, p=0.001). MDS (HR: 1.88; 95%CI: 1.03-3.43, p=0.03) and higher WBC at diagnosis (>median) (HR: 1.76; 95%CI: 1.10-2.82, p=0.01) were also significantly associated with lower LFS. However, when considering AML and MDS patients separately, benefit of CLOB2A2 RIC regimen appears to be restricted to AML patients (2-year OS FB2A2: 58.1% vs CloB2A2: 80.2%; HR: 2.45; 95%CI: 1.08-5.55, p=0.03; and 2-year LFS FB2A2: 53.6%, vs CloB2A2: 76.9%; HR: 2.32; 95%CI: 1.12-4.79, p=0.02). Conclusion: Thisretrospective comparison suggests thattheCloB2A2 RIC regimen can likely provide a higher survival compared to the use of a FB2A2 RIC regimen for AML patients. A prospective phase 3 randomized study is warranted. Disclosures Deconinck: JANSSEN: Other: Travel for international congress; NOVARTIS: Other: Travel for international congress; ALEXION: Other: Travel for international congress; ROCHE: Research Funding; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; LFB loboratory: Consultancy. Mohty:Janssen: Honoraria; Celgene: Honoraria.

Up to now allo-HSCT is the only curative treatment for patients with myelofibrosis (MF) (Ballen, et al, Guardiola, et al 1999, Kroger, et al 2007, Robin, et al 2011). The engraftment rate ranges from 70% to 95% and is influenced by spleen size (delayed in patients with splenomegaly and faster in patients splenectomized prior to allo-HSCT). JAK1/JAK2 inhibitor Ruxolitinib is reported to decrease spleen size and constitutional symptoms. These effects could also be benefit for patients eligible for transplantation, by reducing their splenomegaly and improving their performance status, factors known to impact the results of allo-HSCT. The present study analyzes outcome of patients with MF who have been reported to the SFGM-TC registry. From 2008 to 2013, 11 patients with primary MF (n=7), MF secondary to PV or ET (n=3) or acute myeloid leukemia secondary to MF (n=1) were treated with Ruxolitinib before allo-HSCT. Median age at allo-HSCT was 54 years (range: 44-66); there were 9 men and 2 women. Nine patients had the JAK2V617F mutation. At Ruxolitinib initiation, median white blood cells were 4.4G/L (3.5–13.7), hemoglobin was 10g/dL (7.5-13.3) and platelets were 99G/L (41-290); all patients had palpable splenomegaly and 8 had constitutional symptoms. Lille score was low in 4, intermediate in 2 and high in 4 patients, respectively. Cytogenetics were favorable in 2, unfavorable in 3 (complex karyotype) and not done or failure in 6 patients, respectively. The median time between diagnosis and treatment with Ruxolitinib was 353 days (16-2687) and median time from diagnosis to allo-HSCT was 433 days (199–2793). Ruxolitinib was progressively tapered in 3 patients (with steroids for 2 of them) and discontinued without tapering in 4 (missing data for 3). Median time between Ruxolitinib withdrawal and allo-HSCT was 10.5 days (4-66). All patients received reduced intensity conditioning regimen based on Fludarabine and a graft-versus-host disease (GVHD) prophylaxis including ciclosporine. Donors were: HLA matched sibling in 4, matched unrelated donor in 3 and mismatched unrelated donor in 4 patients. All but one patients received peripheral stem cell transplantation (one patients received bone marrow). Before allo-HSCT, 7 patients were in partial response and 4 were stable. After Ruxolitinib treatment, 8 patients had an estimated reduction of spleen size > 25% and 2 underwent splenectomy. There was no progressive disease on therapy and only one patient experienced a grade III-IV hematological toxicity. All patients had neutrophil engraftment (>0.5G/L) in median on day +17 and 10/11 patients had platelet engraftment (> 20G/L) in median on day +21. Chimerism was full donor in 8, mixed in 1 (who relapsed at day 178), and not available in 2 patients, respectively. One patient who was 100% donor chimerism remains pancytopenic and transfused 90 days after allo-HSCT. Three patients experienced grade II and 2 grade IV acute GVHD after a median time of 18 days after allo-HSCT. Acute GVHD was refractory to corticosteroids in 2 patients and was the cause of death in 1 patient. Only 2 patients had chronic GVHD. Median time from Ruxolitinib initiation to last follow-up was 339 days (166 – 1928), 6 (54%) patients were assumed in complete remission (blood cell count normal and 100% donor chimerism) and 9 (80%) were alive. Two patients relapsed on days 77 and 148 and one of them received a second allo-HSCT. In this retrospective study, Ruxolitinib before allo-HSCT seems to be well tolerated with excellent engraftment rate. A prospective study (JAK-ALLO) is ongoing in France on behalf of SFGM-TC to precisely analyze the role of Ruxolitinib before allo-HSCT. Disclosures: Kiladjian: Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Mohty:Novartis: Honoraria, Research Support Other. Robin:Novartis: Research Funding.

Background Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative option for patients (pts) with myelofibrosis (MF). Patients with MF transformed to Acute Myeloid Leukemia (AML) have a very short life expectancy without transplantation (< 4 months). Umbilical cord blood transplantation (UCBT) from unrelated donor is a valid alternative to conventional allogeneic HSCT for pts with hematologic malignancies who do not have an HLA matched donor. Delayed engraftment and graft failure are the limitations of this procedure and represent a major issue for MF. Patients and Methods We analyzed 42 adults (28 males and 14 females) who underwent a single (n=15) or double (n=27) HLA mismatched UCBT between 2005 and 2012 in 26 EBMT centers reported to Eurocord. At diagnosis, 21 had primary MF (PMF), 5 polycythemia vera (PV), and 16 essential thrombocytemia (ET). Twelve patients transformed to acute myeloid leukemia (AML) before UCBT. Among pts with pre-transplant information available, 13/25 had severe marrow fibrosis; 8/16 had a high Lille score at diagnosis and 13/27 had JAK2 V617F mutation; 13/35 underwent splenectomy and 16/30 had an abnormal karyotype. The median time from diagnosis to transplant was 80 months (range 5-316), while in the subgroup of pts with transformation to AML, it was 119 months (range 5-246). Five pts had a prior transplant (1 autologous, 3 allogeneic and 1 had 2 consecutive allogeneic transplants). The median age at UCBT was 54 years (range 28-69). Conditioning regimens were reduced intensity (RIC) (n= 29) or myeloablative (MAC) (n=13). The most common conditioning in both MAC (n=5) and RIC (n=16) was Cyclophosphamide and Fludarabine associated with total body irradiation (TBI). Overall, 27 pts received TBI with a dose of 12-14 Gy in MAC (n=6) and 2-4 Gy in RIC (n=21); 20 pts received anti-thymoglobulin (ATG) in the conditioning regimen. The median infused total nucleated and CD34+ cells were 3,4x107/Kg (range 0,3-6,8) and 1,3x105/Kg (range 0,04-3,8),respectively. Results Median follow-up for survivors was 25 months (range 6 -72). The cumulative incidence (CI) of neutrophil engraftment was 64% (28 pts) with a median time of 29 days, and among the 12 pts transformed to AML, 10 engrafted in a median time of 30 days, while 18 of 30 pts without transformation engrafted in a median time of 28 days. Of the 14 pts who did not reach neutrophil engraftment, 7 had no hematological recovery, 6 of them died after a median of 3 months and 1 pt is alive at 14 months post UCBT. The remaining 7 pts had an autologous reconstitution, and 4 of them are alive with progressive disease at a median time of 42 months. Pts who received RIC conditioning had better engraftment (79% versus 36%, p=0.02). Twelve pts developed acute GvHD of grades II-IV; 7 pts had limited chronic GvHD with a median time of onset of 144 days. Overall, 17 pts relapsed (6 had transformed into AML before transplantation) at a median time of 5 months. The CI of relapse at 2 years was 29%±2%. The CI of transplant-related mortality at 1 year was 33%±2%. Causes of death were relapse (n=9), post-transplant lymphoproliferative disease (n=3), GvHD (n=3), multiorgan failure (n=1), bacterial infection (n=3), acute respiratory distress syndrome (n=2), infection of unknown origin (n=3), cardiac toxicity (n=1) and fungal infection (n=1). OS at 2 years was 44±8%: 80%, 21% and 52% for pts transplanted respectively for MF secondary to PV, ET and PMF (p=0.07). No difference in OS was seen in the subgroup of pts with JAK2 mutation. OS was 51% versus 29% for pts receiving double or single UCBT (p=0.15), and it was 37% for AML-transformed pts. Pts who did not receive ATG, had an OS of 59% versus 24% for those who received ATG (p=0.01). Among pts who underwent RIC (n=29), 13 had a TBI based conditioning without ATG, and 7 are alive. Failure-engraftment free survival at 2 years was 29±7%, better in pts receiving double UCBT as compared with single (40% versus 8% , p=0,01), and in pts receiving TBI (43% versus 7%, p=0,03). Conclusion Graft failure was a major concern for these pts. Despite a limited number of patients, our results indicate that life expectancy can be increased with UCBT particularly for patients with advanced stage MF. Furthermore, the use of RIC TBI based regimen without ATG and double CB might improve outcomes. Disclosures: Gluckman: Cord use: Honoraria; gamida: Honoraria.

Background IA is a major cause of morbidity and mortality for patients with hematological malignancies and has been mainly reported in patients with acute myeloblastic leukemia (AML) and stem cell transplantation. Much less is known about the role of IA during the treatment of lymphoproliferative diseases like ALL. Here, we retrospectively evaluated the characteristics of patients and the incidence of IA occurring during the induction course in adult ALL patients enrolled in the GRAALL-2005 trial. Methods We collected the data of 36 patients with IA during induction chemotherapy. All were included between May 2006 and October 2012 in the multicentric GRAALL-2005 phase III trial. According to ALL characteristics, these patients were treated in 3 different substudies: GRAALL, GRAALL-Rituximab (GRAALL-R) for CD20+ ALL, GRAAPH for Philadelphia (Ph) chromosome-positive ALL. IA was defined retrospectively using the EORTC modified criteria (De Pauw, CID 2008). Results Among the 969 patients enrolled, 36 (3.7%) developed IA during induction therapy. The median age was 30 years for all patients receiving induction and 47 years (range, 18 to 59) for patients with IA. We observed 18 IA (3%) by the GRAALL protocol (593 patients enrolled), 16 (8.3%) by the GRAALL-R protocol (191 patients enrolled), and 2 (0.7%) by the GRAAPH protocol (270 patients enrolled). In the GRAALL-R protocol, IA was diagnosed in 6 patients randomly assigned to receive rituximab and in 10 patients treated in the control group. The median time between first day of induction therapy and IA diagnosis was 20 days (range, -2 to 71). The median time between the first day of neutropenia and IA diagnosis was 18 days (range, 0 to 76). At the time of IA diagnosis, 13 patients were hospitalized in laminar airflow rooms, 10 patients in rooms with overpressure, 1 patient in a room with high-efficiency particulate filter, 5 patients in conventional rooms, 1 patient received home care and the type of hospitalization was unknown for the 6 remaining patients. Four patients with IA (11%) had received antifungal drug for invasive fungal infection (IFI) prophylaxis: one patient received fluconazole, one received caspofungin, and two received liposomal amphotericin B. All patients with IA presented pulmonary symptoms associated with a sinusal or cutaneous localization in 1 and 2 patients respectively. The diagnosis of IA was classified as possible in 7 episodes (19 %), probable in 22 episodes (61%), proven in 4 episodes (11%), and indeterminate in the remaining 3 episodes. Detection of Aspergillus antigen in serum by latex agglutination was positive in 24 cases (67%). Chest CT scans were taken for 33 patients (92%): nodules were found in 19 patients, halo sign in 20 patients, and “air crescent sign” in 1 patient. Bronchoalveolar lavage was performed in 11 patients (31%): culture was positive in 7 of them and Aspergillus antigen was positive in 2 of them. Biopsies where positive in 4 cases: in pulmonary biopsy in 3 patients and in cutaneous biopsy in 1 patient. Of all the Aspergillus isolates identified to the species level, Aspergillus fumigatus was isolated from 4 patients and Aspergillus flavus from 1 patient. Overall and IA-attributable 12-week mortality was 8 (0.8%) and 6 (16.7%) patients respectively. Conclusion IA is less frequently observed during induction therapy in adult ALL as compared to adult AML patients. However, the attributable mortality appears to be high in these patients. They are as at risk patients for IA and should be included in prophylactic and empirical antifungal clinical trials. Disclosures: No relevant conflicts of interest to declare.

Abstract 2813 Background: Myelodysplastic syndroms (MDS) are an heterogenous diseases. In order to define prognosis of differents subgroups, several scoring are elaborated. The most used was IPSS score including pourcentage of blasts, number of cytopenia and cytogenetics. Recently, IPSS was revised. IPSS-R includes new cytogenetics subgroups, anemia, thrombocytopenia, neutropenia and pourcentage of blasts. These score were defined in untreated MDS and Acute Myeloid Leukemia (AML) with less 30% of blasts patients. IPSS-R score was evaluated in MDS untreated population included AML with 20–29% of blasts. Only 16% of patients were higher-risk IPSS MDS in this study (Greenberg et al., Blood 2012). Azacitidine (AZA) prolongs survival when used as first line treatment of higher-risk MDS and AML with 20–29% bone marrow (BM) blasts (Fenaux et al., Lancet Oncology 2009). The aim of this study is to evaluate efficacy of AZA in higher IPSS-R MDS and AML with 20–99% BM blasts. Methods: We analyzed retrospectively MDS and AML patients treated by AZA in 6 centers. Patients having received ≥ 1 cycle of AZA and who had BM evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered évaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. Results: The study population included 149 patients: F/M: 65/84; median age 70 (range 35–88). Median number of cycle of AZA treatment was 6 (range 1–42). Diagnosis at AZA was (RAEB-1 n=1, RAEB-2 n=69, AML n=79). Median overall survival (OS) was 11 months. For MDS population excluding AML with 20–29% of blasts, IPSS score was intermediate-1 in 16 patients, intermediate-2 in 29 patients and high in 25 patients. In using IPSS-R score, we observed IPSS-R good in 2 patients, IPSS-R intermediate in 20 patients, IPSS-R poor in 29 patients and IPSS-R very poor in 19 patients. If we applied IPSS-R score in WHO-AML population, we observed IPSS-R intermediate in 11 patients, IPSS-R poor in 39 patients and IPSS-R very poor in 29 patients. In all cohort population, we observed a significant difference in median OS between « intermediate + poor » group versus very poor group (12 months vs 9 months respectively, p=0.01). In MDS sub group analysis excluding AML with 20–30% of blasts, we observed no significant difference in median OS between these 2 groups (13 months vs 9 mois respectively, p=0.39). Nevertheless, we still observed a significant difference in median OS between these 2 groups in AML population (12 months vs 6 months respectively, p=0.02). Conclusion: Our results suggest that AZA cancels prognostic impact of IPSS-R score in MDS patients treated by AZA. IPSS-R score could be applied in AML population and keep his prognostic impact in AML patients treated by AZA. IPSS-R score should be evaluated in larger cohort of MDS and AML patients treated by AZA in order to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Abstract 4936 Background: Azacitidine (AZA) has changed the outcome of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia with multi-lineage dysplasia (AML-MLD) unfit for intensive chemotherapy. AZA is a hypomethylating agent providing about 50% of responses in MDS and AML with low blast count (Fenaux et al., Lancet Oncol 2009, JCO 2010). IPSS-R scoring was evaluated in MDS and AML with 20–29% of blasts untreated patients. Conventional cytogenetic have major prognostic interest in this score (Schanz et al., JCO 2012). To date, SNP array analysis are not included in scoring system and no markers of AZA response have been identified with this analysis. Methods: This analysis included MDS and WHO-AML-MLD (>30% blasts) patients treated by AZA in 6 centers. Genomewide single nucleotide polymorphism (SNP) analysis using SNP 6. 0 arrays (Affymetrix, High Wycombe, U. K) was performed on bone marrow (BM) samples. Patients having received ≥ 1 cycle of AZA and who had bone marrow evaluation after ≥ 4 cycles, or who died or progressed before completion of 4 cycles were considered evaluable (the last 2 groups were considered as treatment failures). Responses were scored according to IWG 2006 criteria for MDS and to Cheson et al. (JCO 2003) for AML. DNAs were extracted for hybridization according to the manufacturers' recommendations (Qiagen). Affymetrix CEL files for each sample were analyzed using the Genotyping Console software (v3. 0. 2). Genotyping was performed using Birdseed V2 algorithm. Unpaired Copy Number and LOH analysis was performed with Regional GC correction. For each patient, size of all deletions (loss) find with GC was added to have a total deletion size. The same was performed for total gain size. Results: The study population included 51 patients: F/M: 23/28; median age 73 (range 42–88). Diagnosis at AZA onset was RAEB-2 in 19 patients (IPSS int-1 in 4, int-2 in 10, high in 5) and WHO-AML-MLD in 32 patients. Cytogenetic according to IPSS-R was good in 23, intermediate in 9, poor in 7 and very poor in 12. IPSS-R score was good in 1 patient, intermediate in 4 patients, poor in 25 patients and very poor in 21 patients. Median number of cycles was 7 (range 1–42). All patients received the approved (75mg/m2 for 7 days every 4 weeks) or a reduced AZA schedule (75 mg/m2 for 5 days every 4 weeks). Median overall survival (OS) of our cohort was 11 months. DNA samples from all patients were available for SNP analysis. In using smoothing spline Cox model analysis, we observed that relative risk (RR) of worse OS increased above 4 megabases (Mb) of total chromosomal loss size detected with SNP array. Increase of RR was found in IPSS-R intermediate, poor and very poor. OS of patients treated by AZA with more than 4 Mb of genomic loss detected by SNP array was significantly different of OS of patients with less than 4 Mb (6 months vs 14 months respectively, p=0. 0012). Negative effect of genomic loss above 4 Mb was mainly observed in IPSS-R very poor group. In IPSS-R very poor subgroup, we observed significant difference in OS between patients with more than 4 Mb of genomic loss versus patients with less than 4Mb (3 months vs 10 months respectively, p=0. 01). In our cohort, total genomic gain has no impact on OS. Conclusion: New tools such as SNP array are not used in current practice. Therefore, prognostic impact of molecular karyotype is unclear in MDS/AML treated by AZA; our data suggest that total genomic loss superior to 4 Mb could be a worse prognosis, mainly in IPSS-R very poor patients. Impact of SNP array should be studied in larger cohort of patients treated by AZA in order to validate these results. Starczynowski et al. (Blood 2008) showed that total genomic alterations superior to 3Mb were associated with a poor OS in low-risk MDS. Taken together, these data are in favor of the use of SNP array's parameters in future prognosis scoring system. Disclosures: No relevant conflicts of interest to declare.

Abstract 593 Background: Treatment of patients with myelodysplastic syndrome (MDS) relapsing after allo-SCT remains disappointing and prognostic factors for outcome are still unclear. Several therapeutic approaches are offered to those patients including: palliative and supportive care, intensive chemotherapy (ICT), demethylating agents (DMA) and immunotherapy with either donor lymphocyte infusion (DLI) or second allo-SCT. The aim of this study was to identify predictive factors for outcome and to investigate the impact of different treatment groups on survival. Methods: We report a retrospective study on 137 consecutive MDS patients who relapsed after allo-SCT between Jul 1999 and March 2011 in 19 French and Belgian centers. Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. HLA matching was double-checked by the French Bone Marrow Donor Registry. Results: At diagnosis, 61 patients presented RA/RARS/RCMD, 27 RAEB1 and 49 RAEB2 according the WHO classification. Cytogenetic was unfavorable in 47 patients (35%) while 76 patients (57%) had IPSS Int-2 or High and 52 (39%) had progressed to a more advanced disease before allo-SCT. At transplant, 62 patients (47%) were considered responders (in CR or PR), while 70 were transplanted with progressive disease (untreated, stable without hematological improvement, relapsed or refractory disease). Patients received either myeloablative (MAC) (n=38) or nonmyeloablative (RIC) (n=99) conditioning. Source of stem cells was BM (n=40) or PBSC (n=97) from sibling (n=89) or allele well-matched unrelated (10/10) (n=48) donors. Median age at relapse was 57 years (range, 19–70). Patients aged Post-transplant relapse occurred after a median time of 6 months (range, 0.8–102). Of the 109 evaluable patients 62 (57%) had >= 10% of marrow blasts, of whom 38 had >= 20%. At the time of relapse, 61 patients were still under immunosuppressive treatment which was quickly stopped in all of them. For the analysis, patients were divided into three groups according to ultimate salvage received treatment as follows: palliative and supportive care (PSC-group) (n=42, 31%), cytoreductive treatment alone (CRT-group) [DMA (n=18, 13%) and ICT (n= 11, 8%)] and immunotherapy preceded or not by a CRT (IT-group) [DLI (n=48, 35%) and second allo-SCT (n=18, 13%)]. With a median follow-up of 33 months from the relapse, estimated 2-year overall survival was 2.4%, 6.7% and 30.3% for the PSC-group, CRT-group and IT-group, respectively (p= 10%, HR=2.56 [95% IC= 1.55–4.22, p Conclusion: This study shows that salvage immunotherapy (DLI or second allo-SCT) provides the best results and should, whenever possible, be offered to patients with MDS who relapse after allo-SCT especially those with low tumor burden. Patients who received cytoreductive treatment alone (be it chemotherapy or DMA) had less satisfactory outcome. Our results emphasize the need to perform prospective protocols combining cytoreductive treatments and immunotherapy. Disclosures: No relevant conflicts of interest to declare.