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BackgroundDonor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT.MethodsPatients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies.ResultsWe identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with > 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with > 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with > 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%.ConclusionsDespite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.

Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007–2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed (“discovery cohort”). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs.14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the “validation cohort.” These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis.

Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched (“haploidentical”) hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9–3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3–1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality.

Introduction. The boundaries between MDS and AML are still a matter of debate. In the 2001 WHO Classification, the myeloblast count distinguishing AML and MDS was lowered from 30% to 20% of the bone marrow (BM) cells or peripheral blood (PB) leukocytes. It was justified on the basis that treating patients with 20-29% BM blasts with intensive chemotherapy showed a similar outcome to those with > 30% BM blasts. However, the better knowledge of the biology of both diseases is showing that in several cases AML and high risk MDS share identical genetic profiles, as it is well known in AML with myelodysplasia- related changes (AML-MRC). Currently there are new therapeutic options, less toxic, and suitable for elderly people.The threshold of 20% BM blast is artificial, but it is still the main criterion used in clinical trials and also in real life to discriminate patients that probably belong to the spectrum of the same biological entity. Treatment of patients with MDS or AML is widely based in this relatively arbitrary condition. Objective: To study if the threshold of 20% bone marrow blasts, distinguishing MDS with excess of blasts type 2 (MDS EB 2) and AML, is reproducible among different observers. Methods. 120 bone marrow samples from patients previously diagnosed with MDS-EB-2, AML or therapy-related myeloid neoplasms (t-MN) according to 2016 WHO classification were included. The diagnosis of MDS required cytogenetics and/or FISH, and the cases with AML should have been classified following the 2017 ELN recommendations, regarding immunophenotyping, cytogenetics and molecular biology. The design of the study was established to include cases with Results. Finally 116/120 samples were considered suitable for the study. Regarding 2016 WHO categories, 55 cases showed MDS EB-2, 44 AML-MRC, 8 t-MN, 4 AML- NOS, 2 NPM1-mutated AML, 2 RUNX1-RUNX1T1 AML, 1 BCR-ABL1+ AML. Next generation sequencing was performed in 79 cases. Discordance was observed in 34/116 cases (29.3%). 14 cases with MDS-EB2 (1 NPM1+) were classified as AML-MRC by the second observer, 16 AML cases as MDS EB-2, 3 MDS EB-2 as MDS- EB1 and 1 AML as MDS- EB1. The genetic and /or molecular profile of the discordant cases was heterogeneous. Regarding the threshold of 20% BM blasts, discrepancies were 31/116 (26.7%, I Kappa test = 0.46, moderate agreement). The agreement between MDS-EB-2 and AML-MRC, with discordance in 28/98 cases (28.6%), was moderate-fair (Kappa test= 0.42). Conclusion. The threshold of 20% BM blasts did not accurately separate AML from MDS EB-2. Particularly less concordance was seen for AML-MRC. Incorporation of genetic and molecular characteristics to the morphologic diagnosis is needed to optimize the definition of both entities. Acknowledgment: Angel Cedillo, Secretaría Técnica AMHH. Disclosures Font Lopez: GILEAD: Membership on an entity's Board of Directors or advisory committees; CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Loscertales: Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy; Janssen, Abbvie, Roche, Gilead: Speakers Bureau. Cedena: Janssen, Celgene and Abbvie: Honoraria.

Introduction: High-dose post transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplant (HSCT) and offer low rates of GVHD in the setting of HLA identical transplant. The objective of our study was to compare the outcomes of haplo vs HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. Patients and methods: We conducted a retrospective study of 229 patients undergoing a first HSCT for AML using PTCY, 130 from an haploidentical donor between 2013 and 2018 (median follow up 62.5 months) and 99 from a matched sibling (MSD) (n=38) or unrelated donor (MUD) (n=61) (median follow up 27 months) between 2013 and 2019, in 20 centers in Spain. Last update of the cohort was performed in March 2021. Results: Baseline characteristics are summarized in Table 1. There were more patients with active disease at transplant (5% MSD/MUD vs. 20% haplo, p=0.001), high/very high DRI (32% vs. 67%, p=0.000) and prior autologous HSCT (2% vs. 11%, p=0.010) in the haplo group. Mobilized peripheral blood stem cells was the most frequent stem cell source in both groups. Most patients received myeloablative conditioning (55% vs. 64%, p=0.170). All Patients in the haplo group received PTCY days +3+4 followed by a calcineurin inhibitor (CNI) and MMF from +5. In the MSD/MUD group, 37% received both CNI+MMF, 33% only CNI and 30% PTCY with sirolimus+MMF (this group included only MUD donors). None of the patients received ATG. Cumulative incidence of neutrophil recovery at day 28 was 97% in both groups, with a median of 16 and 17 days respectively (p=0.948). Both 2-year overall survival (OS) (72% vs. 62%, p=0.07) and event-free survival (EFS) (70% vs. 54%, p=0.055) were higher in the MSD/MUD group, but the difference was not statistically significant (Figure 1). Multivariate analysis only identified age and pre-transplant status as independent risk factors for OS, and pre-transplant status for EFS. No differences were found in the cumulative incidence of relapse at 2 years (19% vs. 25%, p=0.13) and non-relapse mortality (14% vs. 19%, p=0.145). Cumulative incidence of grade II-IV acute GVHD was lower in MSD/MUD (14% vs. 47%, p=0.000, Figure 2), while III-IV aGVHD was similar (4% vs. 9%, p=0.14). Cumulative incidence of chronic GVHD and moderate-severe cGVHD at 2 years was similar for both groups (42% vs. 33% (p=0.051); 22% vs. 19% (p=0.28)). No differences were found in GRFS (48% vs. 46% (p=0.506)). Most frequent cause of death in the early post-transplant period was non-GVHD related infection in both groups. Conclusions: in our experience, PTCY as GVHD prophylaxis in both MSD/MUD and Haplo transplant in AML using mostly PBSC effectively prevents GVHD and offers similar NRM, relapse and survival rates. Poor control of the disease before transplant was the only factor affecting OS and EFS in this setting. Prospective studies are needed to confirm our results. Figure 1 Figure 1. Disclosures Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Background. Donor specific antibodies (DSAs) are preformed IgG antibodies with specificity against HLA molecules not shared with the donor that can lead to graft failure (GF) in the setting of mismatched HSCT. The aim of this study is to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in patients with DSAs undergoing haplo-HSCT. Methods. Patients undergoing haplo-HSCT in centers from the GETH-TC from 2013 to 2021 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay (Luminex®); monitoring was performed prior to desensitization, prior to infusion and after infusion. Desensitization strategies used depended on center experience, immunofluorescence intensity, complement fixation and type of antibodies. Results. 59 haplo-HSCT with DSAs were performed in 57 patients in 13 centers. Characteristics of the population are shown in Table 1. 53 (93%) patients were female (91% with prior pregnancies). All patients lacked a suitable alternative donor. 51 (89%) received peripheral blood as stem cell source. Conditioning was myeloablative in 58% and all patients received post-transplant cyclophosphamide based GVHD prophylaxis; 3 (5%) patients received also ATG. 28 (49%) patients presented anti-HLA class I DSAs 22 of them with >5000MFI), 14 (25%) presented anti-HLA class II (6 with >5000MFI) and 15 (26%) presented both anti-HLA class I and II DSAs (13 with >5000MFI). Five patients did not receive desensitization treatment, 4 of them with After a median follow-up of 24 months, 2-year OS and EFS were 52% and 42%, respectively. 2-year cumulative incidence of relapse at was 14% and NRM was 41%. Cumulative incidence of grade II-IV aGVHD at day 180 was 13% and chronic GVHD was 25%. Conclusions. The use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor, including non-malignant disorders. Figure 1 Figure 1. Disclosures Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are the two autologous anti-CD19 chimeric antigen receptors T cells commercially approved in Europe for relapsed/refractory (R/R) DLBCL. We performed a retrospective study to evaluate patients characteristics, efficacy and safety for axi-cel and tisa-cel in a large cohort of patients within the GETH-TC (Spanish Group of Stem Transplantation and Cell Therapy)-GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation). Methods: Ten Spanish centers contributed data. Data were collected retrospectively from consecutive patients with DLBCL in whom apheresis was performed for axi-cel or tisa-cel treatment. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Patients included had at least 30 days of follow-up. Results: A total of 268 patients with R/R DLBCL underwent apheresis for axi-cel (n=123) and tisacel (n=145) from Nov-2018 to May-2021, of which 232 (86%) received CART-cell infusion (n=110, 89% and n=122, 84%, respectively). Reasons for not undergoing infusion were progression in 10 cases, tumor lysis syndrome in 1, infection in 1, and CR after bridging therapy in 1 for the axi-cel cohort, and progression in 21 (4 after manufacture failure), psychiatric disorder in 1, and post-apheresis cerebral hemorrhage in 1 case for the tisa-cel cohort. Time between apheresis and infusion was 41 days (IQR 40-56) and 49 days (IQR 46-62) (p=0.006), respectively. Characteristics at baseline, apheresis and at lymphodepletion are summarized in Tables 1 and 2. Median age was 60 (range 19-79), 61% of patients were male, most of them treated for DLBCL NOS (66%). There were no significant differences between patients intended to be treated with axi-cel and tisa-cel. 82% of the infused patients received bridging therapy. At apheresis and at lymphodepletion ECOG performance status score was 0-1 in 93% and 91%, and 7 and 32 patients were in response, respectively. The overall response rates (ORRs) at 1 month and 3 months were 65% and 56%, respectively, with 34% and 45% achieving a complete response (CR), respectively. In the intention-to-treat analysis, with a median follow-up of 9 months (IQR 5-15), EFS and OS at 9 months was 44% (95%CI 38-51)(Figure 1) and 59% (95%CI 53-66) with a median EFS and OS of 6 months and 11 months, respectively. At lymphodepletion, characteristics of infused patients and disease were not significantly different between axi-cel and tisa-cel cohorts. Rates of CRS, CRS grade 3-4, ICANS, ICANS grade 3-4 were 89% and 71% (p=0.001), 10% and 7% (p=0.34), 42% and 16% (p=0.001), 20% and 4% (p=0.001) for the axi-cel and tisa-cel cohorts, respectively. ICU admission was needed in 25% and 15% of patients (p=0.06), respectively. Non-relapse mortality at days 100 were 2.5% and 1.4%, and at day 180, 5.4% and 2.2% (p=0.08) for the axi-cel and tisa-cel groups, respectively. With a median follow-up of 8 months for patients who received infusion with axi-cel and 12 months for patients infused with tisa-cel, EFS and OS at 12 months were 48% and 33% (p=0.33), and 53% and 50% (p=0.27), respectively, with a median EFS of 11 and 6 months and a median OS of 13 and 12 months, respectively. In the multivariate analysis, the only factor associated with poor PFS was having ECOG-PS ≥2 at lymphodepletion (HR13, p=0.03). No factors were identified as associated independently to OS. Factors associated to CRS grade 3-4 were IPI score 4-5 at lymphodepletion (OR 1.4, p=0.03) and ECOG-PS ≥2 at apheresis (OR 1.5, p=0.03). For ICANS grade 3-4, factors associated were the use of axi-cel (OR 8, p=0.04) and diagnosis of HG double/triple hit lymphoma (OR 9, p=0.022). Conclusions:This multicentric analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe. Results are comparable to those from the pivotal studies and other large real-life experiences. Up to now, patients included for one or other product in Spain do not differ significantly in terms of baseline characteristics, and within this setting, results are comparable between both products in terms of efficacy. The use of axi-cel was associated to higher rates of CRS and especially, severe forms of ICANS. However, mortality associated to toxicity were low and not significantly different between both cohorts. Figure 1 Figure 1. Disclosures Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Caballero: Novartis, Gilead: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Sanchez: Janssen, Jazz Pharmaceuticals, Gilead, Novartis, Amgen: Consultancy. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Bastos-Oreiro: Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Kite: Speakers Bureau. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Mussetti: Gilead: Other: Unspecified, Research Funding; Novartis: Honoraria, Other: Unspecified; Takeda: Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Martin Garcia-Sancho: Takeda: Honoraria; Novartis: Consultancy; Incyte: Consultancy; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding.

Introduction: The severity of acute clinical outcomes and mortality in hematologic malignancy (HM) patients infected by SARS-CoV-2 was exhaustively documented in the first weeks of the pandemic. A consistent increased mortality compared to non-cancer patients was observed across studies. In this study we aimed to estimate survival in COVID-19 HM patients by type of malignancy, to describe acute and post-acute clinical outcomes, and to compare outcomes in early and later pandemic periods. Methods: In this population-based registry study sponsored by the Madrid Society of Hematology (Asociación Madrileña de Hematología y Hemoterapia), we collected de-identified data on clinical characteristics, treatment and acute and post-acute outcomes in adult patients with hematologic malignancies and confirmed SARS-CoV-2 infection within the Madrid region of Spain. Our case series included all eligible patients admitted to 26 regional health service hospitals and 5 private healthcare centers between February 28, 2020 and February 18, 2021 with a coverage of 98% on a population of 6.6 million inhabitants. The study outcomes were all-cause mortality, severity of disease (WHO), oxygen support, ICU admission, and follow-up symptoms and signs and complications. Survival probabilities were estimated with the actuarial method and reported overall and stratified by type of malignancy and for two study periods (early cohort,-COVID-19 diagnosis from February 28 to 31 May, 2020, and later cohort, up to February 18, 2021). Results: Of the 1408 patients reported to the HEMATO-MADRID COVID-19 registry, 1166 were included in the present analyses; 839 (72%) had a lymphoid malignancy, including 325 (28%) with non-Hodgkin lymphoma, 50 (4%) with Hodgkin lymphoma and 263 (23%) with multiple myeloma; and 327 (28%) had a myeloid malignancy, including 115 (10%) with myelodysplastic syndrome, 92 (8%) with acute myeloid leukemia (AML) and 87 (7%) with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Overall COVID-19 clinical severity was classified as critical in 19% of patients, severe in 36%, moderate in 22%, and mild in 22%; 10% were admitted to an ICU; 8% were on mechanical ventilation and 19% on noninvasive ventilation. Mild disease increased between early and later period from 15% to 38% of patients; severe disease decreased from 42% to 24%, p At follow-up, 22% reported persistent symptoms related to COVID-19 at 2 months, 16% at 4 months and 14% at 6 months. 381 of 1166 (33%) patients died. Overall 30-day survival was 68%; 2 and 3-month overall survival probabilities were 56% and 53%, respectively. Survival was more favorable for patients with myeloproliferative neoplasms (82%, 69% and 65% at 30-days, 2 and 3 months, respectively) than for those with lymphoid malignancies (68%, 56% and 54%) or myelodysplastic syndrome/acute myeloid leukemia (61%, 51%, 46%), p=001. 285 (37%) patients died in the early period vs 96 (24%) in the later, p Conclusions. A population-based registry in Spain provided strong evidence that although COVID-19 severity decreased over year 1 of the pandemic, mortality remained high, and survival was stable over time in the group of patients with hematological malignancy infected by SARS-Coc-2. A relevant proportion of the infected patients (1 in 6) referred persistent symptoms attributable to COVID-19. The improved clinical management of severe COVID-19 in non-cancer patients that followed the dissemination of evidence-based recommendations did not translate in more favorable survival in patients with hematological malignancies. Research is needed to address the specific characteristics and improve the clinical management of this vulnerable population. Disclosures Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Jiménez-Yuste: Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Kwon: Gilead: Honoraria.

Introduction: Chimeric antigen receptor (CAR) T-Cell therapy is approved for relapse/refractory diffuse large B cell lymphoma (DLBCL) patients after two lines of therapy. Although it is an effective treatment, approximately 20-30% of patients have an early relapse. In this context, biomarkers that helps to identify those patients who will be refractory to this therapy are relevant. Cell-free DNA (cfDNA) has emerged as a new tool for non-invasive monitoring of patients with lymphoma, therefore the aim of this study was to evaluate dynamic cfDNA concentration in addition to other biomarkers (LDH, CRP, ferritin) before CAR T-cell infusion to detect early progressors. Methods: We selected 44 r/r DLBCL patients treated with CAR T-cell in our centre. Plasma samples were collected pre-apheresis (PA) and pre-infusion (PI)(∆cfDNA). Other biomarkers (LDH, CRP, Ferritin) were studied PA, pre-lymphodepletion (PL) and PI, tumour volume metabolic (TMV) are also studied. CfDNA were obtained from plasma using QIAamp® Circulating Nucleic Acid (Qiagen) and quantified by QuantiFluor dsDNA System (Promega). The Mann-Whitney test was used to compare differences between two independent quantitative variables . ROC analysis was conducted to determine the cut-off value of biomarkers. Cumulative incidence of progression (1 and 3 months) was calculated from the date of CAR T-cell infusion. Data analysis was performed using Stata. Results: Cumulative incidence of relapse at 1 month and 3 months was 20% and 30% respectively. The correlation between the progression (1 month, 3 months) and the different biomarkers is shown in Table 1. The CRP PL, CRP PI, LDH PI and ∆cfDNA (PI-PA, median time 41.5 days [range:31-107]) was correlated with early progression (1 month). No differences were found with progression at 3 months. The different cut-off for the biomarkers selected was 9 ng/mL for ∆cfDNA, 225 U/L for LDH and 1.35 mg/dL for CRP. Cumulative incidence of progression at 1 month was calculated for these biomarkers (figure 1): ∆cfDNA, HR: 4.3 (1.05-17), p=0.042; CRP PL: HR: 6.9 (1.5-31.1), p=0.012; CRP PI, HR: 11.2 (1.5-83), p=0.019 and LDH PI, HR: 3.4 (1-17) p=0.11. It should be noted that 83.3% (10/12) of the patients who progressed during the first month had at least one of the above variables. Conclusions: Our results highlight that increase in cfDNA higher than 9 ng/mL, CRP PL and PI >1.35 mg/dL and LDH PI > 225 U/L before CAR T-cell therapy may detect early progressors within the first month after treatment. Therefore, ∆cfDNA, CRP and LDH could be useful to identify patients who highly probable will not benefit from the CAR T infusion, in which another prior strategy could be considered in an attempt to control the disease. These results need to be confirmed with a larger cohort. Figure 1 Figure 1. Disclosures Bailén: Pfizer: Honoraria; Kite-Gilead: Honoraria; Gilead: Honoraria. Kwon: Gilead: Honoraria.

Introduction: Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and reverses its anticoagulant activity. It has been available in Spain since June 2016 and is indicated for imminent surgery or invasive procedures and life-threatening bleeding. The aim of the study was to describe the actual experience with idarucizumab in different centers in Madrid. Methods: Patients with electronic prescription of idarucizumab between June 2016 and July 2021 were included. Demographic information, comorbidities, laboratory parameters, dabigatran indication, anticoagulation resumption, adverse events related to idarucizumab and death within 30 days were collected from medical records. Qualitative data are presented as frequencies and percentages. Quantitative data are presented as mean ± standard deviation (SD) or median (interquartile range -IQR-). Cumulative survival was calculated by dividing the number of patients alive by the number of patients in each indication category for idarucizumab in a 30-day post-infusion period. Results: A total of 69 patients from 8 hospitals in Madrid were included. Ninety-six percent received dabigatran for prevention of stroke and embolism in nonvalvular atrial fibrillation and 4% received it for the treatment of thromboembolic disease. The mean age was 73.5 ± 13.9 years, and 55.6% were men. Median aPTT was 45.6 seconds and was prolonged in 72.1% (49). Patient characteristics, concomitant conditions and laboratory parameters are reviewed in Table 1. The main indication for idarucizumab was reversal of anticoagulation for persistent bleeding (46.4%), followed by surgery (44.9%). Fibrinolysis due to ischemic stroke was performed in 3 patients (4.3%), dabigatran intoxication occurred in 3 patients due to acute renal failure (4.3%). Gastrointestinal bleeding was the most common type of bleeding. Two of the patients intoxicated with dabigatran also had gastrointestinal bleeding. Cardiac surgery was the most common type of intervention, with heart transplant being a common indication (9/13). Minor surgical procedures included 2 lumbar punctures and 1 central venous catheterization. In one case, the type of surgery was not available. Figure 1 A and B summarize the bleeding location and type of surgery. The median time between infusion of idarucizumab and cessation of bleeding or onset of surgery was 3 hours, however this information was only available in 43 patients. No reports of excessive bleeding during surgery or after fibrinolysis were noted. One patient with dabigatran intoxication was reported to have an episode of persistent melena in which the trough plasma level was 1178.1 ng/mL. This patient died of an aggressive lymphoproliferative disorder that couldn´t be biopsied due to altered coagulation. A case of auricular thrombosis occurred in a patient with a heart transplant due to hyperthophic cardiomiopathy and end-stage heart failure requiring thrombectomy. The patient required a biventricular assistance and died of myocardial infarction. Full 30-day follow-up was available for 68 patients, during this period 11 died. Five patients in the bleeding group died, 3 from hypovolemic shock, 1 from intraparenchymal hemorrhage and data were missing for 1. Two patients who received a heart transplant died, one as described previously 10 days after the transplant and the other 2 days after the transplant from hemorrhagic shock. Three patients who underwent abdominal surgery died of septic shock. One patient with dabigatran intoxication died. Cumulative survival after a follow-up period of 30 days was 86% (Figure 2). Seventy-seven percent (53) resumed anticoagulation after a median of 3 days (0-180), and 62.3% (33) were bridged with low molecular weight heparin (LMWH) at prophylactic doses. Finally, 75% (40) maintained LMWH (7) or restarted dabigatran or another direct oral anticoagulant (33). A total of 13 patients didn´t resume any anticoagulation. Conclusions: Idarucizumab is an effective drug for reversal of dabigatran anticoagulation in bleeding or imminent surgery/invasive procedures. In this cohort it was used safely in patients awaiting a heart transplant. No cases of bleeding after infusion or during surgery were reported, except for a single case of auricular thrombosis. Most patients resumed anticoagulation at discharge. The experience described confirms the safety of idarucizumab in daily clinical practice. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

BACKGROUND The revised genetic risk classification established by the European Leukemia Net (ELN) in 2017 stratifies patients diagnosed with acute myeloid leukemia (AML) into 3 prognostic categories (favourable, intermediate, and adverse) based on cytogenetic and molecular characteristics.The ELN classification is widely accepted in AML patients despite the fact that validation studies were performed in participants who received exclusively first-line treatment with intensive chemotherapy. For this reason, it is not well established whether the ELN risk groups are applicable to patients on non-intensive first-line treatment. OBJECTIVES - To describe and compare baseline characteristics at diagnosis between patients with AML treated with intensive and non-intensive therapy. - To assess whether the ELN prognostic classification is applicable in these subgroups of patients. METHODS We retrospectively analysed patients with newly diagnosed AML admitted to our center between 2007 and 2020. Patients with acute promyelocytic leukemia (M3), patients younger than 18 years old and/or patients who received exclusively supportive treatment were excluded. Demographic and clinical data, disease characteristics at diagnosis and first-line treatment were collected. Cytogenetic and molecular characteristics were used to classify patients in ELN risk groups. RESULTS Of the total of patients (n=218), one hundred and fifty-six (71.6%) received intensive chemotherapy treatment, while 62 (28.4%) were treated with non-intensive strategies. Idarubicin and cytarabine based schemes regimens (IA) were administered in most patients (98.6%) who received intensive treatment while the rest received fludarabine based regimens. One patient (0.6%) was treated with danurubicin and cytarabine liposome (CPX-351). Fifty-four (87%) patients treated with non-intensive regimens received hypomethylating agents, mostly azacitidine. Five patients (8%) were treated with venetoclax in combination with a hypomethylating agent. Table 1 shows the characteristics at diagnosis in both groups of patients. Patients who received intensive chemotherapy were younger and had higher leukocyte count, LDH values and a higher percentage of blasts in peripheral blood and bone marrow with a median of 40% and 62% blasts respectively. On the other hand, patients under non-intensive treatment more frequently presented a past history of hemopathy and a higher percentage of bone marrow dysplasia. Regarding ELN stratification significant differences were found between both groups. Patients who received aggressive chemotherapy vs patients who did not, were classified in low (28% vs. 7%), intermediate (36% vs. 58%) and high risk (36% vs. 35%) respectively (Figure 1). At the end of the follow-up, 41% of the patients who had received intensive therapy were alive while only 6.5% of the patients who had received non-intensive treatment were alive. Significant differences in survival were observed between both groups (p In the intensive chemotherapy group, significant differences in survival were observed according to ELN risk stratification (p However, in patients receiving non-intensive therapies, there were no significant differences in survival among different prognostic categories (p=0.06). In this group, 1-year OS was 25%, 57.6% and 40.7% and median OS was 2.1, 14.8 and 10.1 months for low, intermediate and high-risk groups respectively. See Figure 2. CONCLUSIONS: As validated in previous trials, ELN classification constitutes an adequate prognostic marker for patients with newly diagnosed AML treated with intensive chemotherapy. In our series, this classification does not appear to be a good predictor of survival for patients diagnosed with AML who initiated non-intensive treatments. Further validation in prospective studies are needed to better classify this growing subgroup of patients in clinical practice. Figure 1 Figure 1. Disclosures Martín-Rojas: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Font Lopez: Pfizer: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

INTRODUCTION Several studies have shown that morphological remission at day 14 is a predictor of post-induction response in patients with acute myeloid leukemia (AML) undergoing an intensive treatment. However, the role of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) at day 14 remains unknown. The aim of our study is to explore the role of MRD at day 14 and its association with outcomes of patients with AML undergoing an intensive treatment. METHODS We conducted a retrospective study in adult patients with newly a diagnosed AML in our center between 2007 and 2020. Adult patients who received intensive chemotherapy, excluding those with an acute promyelocytic leukemia, were included. Bone marrow aspiration was performed at day 14 after induction to assess morphological response and MRD by MFC. Early blast clearance (EBC) was defined as RESULTS A total of 131 patients were analyzed. Median age was 55.6 years (IQR 42.3-64.2). The most frequent AML subtype was AML with myelodysplasia-related changes (34.4%), followed by NPM1-mutated AML (32.1%). The most commonly used induction regimen was "7+3" (96.2%) (Table 1). On day 14 bone marrow aspiration, median cellularity was 0.5/5 (IQR 0.5-1). 107 patients (81.7%) showed a blast reduction >50% compared to diagnosis and 87 patients (66.4%) had less than 5% of blasts. In this latter group, 28.6% of patients had a positive MRD and 71.4% had a negative MRD. NPM1-mutated AML showed the highest EBC rates while AML with myelodysplasia-related changes had the lowest rates (83.3% versus 55.5%; p=0.04). Furthermore, there were statistically significant differences in EBC rates based on the 2017 European Leukemia Net risk stratification, with 80% of EBC in low risk, 66.6% in intermediate risk and 53.4% in high risk AML (p=0.038). No differences were observed in MRD at day 14 based on AML subtypes or risk stratification. We subsequently analyzed the negative (NPV) and positive predictive values (PPV) of day 14 bone marrow aspiration results by morphology and MFC to predict post-induction results. As a predictor of post-induction CR, day 14 EBC had a NPV of 82% and a PPV of 69%, while day 14 MRD had a NPV of 86% and a PPV of 49%. However, for predicting post-induction MRD, day 14 EBC had a NPV of 49% and a PPV of 15%, while day 14 MRD had a NPV of 71% and PPV of 74%. The correlation between day 14 and post-induction bone marrow aspiration is shown in Table 2. Bivariate analysis showed that achieving CR with negative MRD in post-induction bone marrow aspiration was associated with EBC (p CONCLUSION Patients showing EBC with negative MRD on day 14 bone marrow aspiration are more likely to achieve post-induction CR with negative MRD, with day 14 MRD by MFC being the only independent factor able to predict post-induction CR with negative MRD in our cohort. However, further prospective studies are needed to confirm our findings. Figure 1 Figure 1. Disclosures Martín-Rojas: Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

Author(s): Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang W; Al Malki, Monzr; Jacobsen, Eric; Steinberg, Amir; Hamerschlak, Nelson; Kharfan-Dabaja, Mohamed; Salit, Rachel; Ball, Edward; Bashir, Qaiser; Cashen, Amanda; Couriel, Daniel; Diez-Martin, Jose; Katsanis, Emmanuel; Linhares, Yulia; Mori, Shahram; Nash, Richard; Pawarode, Attaphol; Perales, Miguel-Angel; Phipps, Colin D; Richman, Carol; Savani, Bipin N; Shapira, Michael Y; Stiff, Patrick; Strair, Roger; Fenske, Timothy S; Smith, Sonali M; Sureda, Anna; Olteanu, Horatiu; Hamadani, Mehdi

BACKGROUND Development of de novo alloantibodies against recipient's red blood cell (RBC) antigens by engrafted donor's lymphocytes is a known phenomenon in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). This situation is usually clinically insignificant. We report a case of early clinically relevant hemolytic anemia in a blood group A1 D+ patient, due to a limited production of anti-D and anti-A1 produced by nonpreviously sensitized newly engrafted donor's immune system. CASE REPORT A 31-year-old Caucasian woman, blood group A1, D+, with Hodgkin's lymphoma, received an unmanipulated haploidentical allogeneic peripheral blood HSCT after a nonmyeloablative conditioning regimen. Donor blood group was A2B, D–. The patient had an uneventful course until Day +34, when she developed clinically significant hemolytic anemia with a positive direct antiglobulin test. Anti-D and anti-A1 produced by the donor-engrafted lymphocytes were detected both in serum and in eluate. The hemolysis produced an accelerated group change, turning the patient's ABO group into A2B 2 weeks after the detection of the alloantibodies. As the residual patient's RBCs progressively disappeared, anti-D and anti-A1 production decreased and were not detected in serum by Day +41. CONCLUSION This case illustrates that de novo alloantibody production against ABO and D antigens by the newly engrafted donor's lymphocytes can occasionally cause clinically significant anemia. To our knowledge, this is the first case reported of clinically significant hemolytic anemia due to a transient anti-D anti-A1 alloimmunization after T-cell-repleted haploidentical HSCT.

Background: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies. Methods: Six clinical centres entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with

Background: Prediction of patient outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) remains a tenacious problem. An important limitation of current prediction models is the heterogeneity in outcome even among similar cases. We introduce a novel approach to individualizing estimates of leukemia-free survival (LFS) in acute leukemia patients undergoing haploidentical (haplo) HSCT. Methods: Data were obtained from the registry of the European Society for Blood and Marrow Transplantation for all cases of haplo HSCT for acute leukemia performed between 2011 and 2017. Patients receiving ex-vivo T-cell depleted grafts were excluded. Acute myeloid leukemia patients were classified by clinical disease ontogeny (de novo vs. secondary), cytogenetics, and FLT3-ITD/NPM1mut status; acute lymphoblastic leukemia patients by disease status and the presence of the Philadelphia chromosome. Common patient and transplantation parameters including recipient age, Karnofsky performance status (KPS), time from diagnosis to transplantation, conditioning and graft-versus-host disease (GvHD) prophylaxis were included. Data were split into training and geographic validation sets. Results: A total of 2,001 patients was included in the training set and another 270 in the validation cohort. In the training set, the median age was 50 years; 68% of patients were in complete remission, and 69% had a KPS ≥ 90; 87% received post-transplant cyclophosphamide and 13% antithymocyte globulin for GvHD prophylaxis. To provide the clinician insight on outcomes of similar patients, we developed a descriptive tool to visually explore outcomes of cases with comparable features. We next generated 50 random survival forest models for the prediction of 1-year LFS. In contrast to single point-estimates, the ensemble of 50 models generates a prediction interval accounting for predictive uncertainty. There was heterogeneity of variable importance between models, with either disease status or KPS leading in all models (Figure A). The model was well calibrated (Figure B); the median c-statistic was 0.64 on the validation set. An online interface presents the individual outcomes of the fifteen patients most similar to the index case, the prediction interval, and a visualization of all 50 survival forest predictions. Predictions for a sample patient are shown in Figure (C). Conclusions: We present the first system for individualized prediction of leukemia-free survival following T-cell replete haplo transplantation. A key, novel component of the model, distinguishing it from standard risk scores, is that it provides a measure of predictive certainty. This is essential for judging the robustness of prediction. Our approach is applicable to other clinical settings and can be used for designing risk-guided interventions and for informing patients and clinicians. Figure Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Introduction. In the absence of an HLA-identical sibling or a matched unrelated donor, whether to prefer a Haploidentical (Haplo) or a one antigen mismatched unrelated donor (MMUD) for allogeneic hematopoietic cell transplantation (HCT) remains an unanswered question. Implementation of graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) was initially pioneered in the Haplo and then also extended to MMUD setting, resulting in low rates of GVHD. Methods. This was a retrospective study from the EBMT registry. Included were adults undergoing either Haplo- or MMUD-HCT for acute myeloid leukemia during the period 2010-2018 and who were in first or second complete remission at allo-HCT. Only patients receiving unmanipulated grafts with PTCY as GVHD prophylaxis were included. Ex vivo and in vivo T-cell depletion were exclusion criteria. Comparisons were made among three groups: MMUD-HCT with peripheral blood as stem cell source (PBSC; n=124); Haplo-HCT with bone marrow (Haplo-BM; n=560); Haplo-HCT with PBSC (Haplo-PB; n=769). Results. Patients in Haplo-PB were older (median age of 55 years versus (vs) 52 and 51 years in MMUD-HCT and Haplo-BM, respectively; p Conclusion. According to our results, use of MMUD is associated to significantly higher LFS. However, our results highlight that both MMUD- and Haplo-HCT are valid options for transplant candidates, with no differences in GRFS. On the other hand, when choosing Haplo over MMUD, one should consider BM as stem cell source in order to better prevent GVHD. Further strategies to better prevent NRM are needed, particularly in Haplo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

INTRODUCTION Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been established as a powerful treatment modality for patients with hematological malignancies. The graft-versus-leukemia effect, however, is strongly associated with the occurrence of graft-versus-host disease (GVHD) and subsequent transplant-related mortality (TRM). Several strategies are applied in order to prevent GVHD, the post-transplant cyclophosphamide (PT-Cy) is one of the most used in Haploidentical HSCT (Haplo-HSCT). Cyclophosphamide (CY) is an alkylating agent with antineoplastic and immunosuppressive activities. CY is metabolized by highly polymorphic enzymes to produce phosphoramide mustard which is a bifunctional DNA alkylating agent, is the therapeutically active metabolite. Thus, the aim of our study is to identity polymorphisms in the genes of the CY metabolism and correlated with complications post-HSCT (GVHD, TRM, veno-occlusive disease (VOD) or hemorrhagic cystitis (HC)). METHODS We selected 182 consecutive patients who received an Haplo-HSCT from 2007 to 2019. Eleven genes related to CY metabolism were analyzed (Table 1). The genotyping was performed in peripheral blood samples for recipient using an enrichment-capture custom gene panels (IDT probes) in a MiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with BaseSpace software (Illumina, USA). Variants located in coding region and splicing sites were analyzed. We selected polymorphisms corresponding to read depth ≥30X in the canonical isoform with an allele frequency ≥0.4 and represented in at least 5% in our cohort. The collected clinical variables were age/gender recipient and donor, pathology, pretransplant status, conditioning regimen, total body irradiation, basal ferritin and CMV reactivation. Fisher test was used to compare the differences among groups. Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of II-IV and III-IV grades at 100 days was 39% and 12% respectively. The cumulative incidence rates for cGVHD, moderate or severe cGVHD and TRM at 1000 days were 37%, 19% and 29%, respectively. Among the cases analyzed, 9% developed VOD and 25% HC. Patients who received ablative conditioning regimen presented a higher incidence of TRM (p=0.005). No other clinical data was associated with complications post HSCT. Forty polymorphisms were detected in 9 genes by bioinformatic analysis. The variants that presents some correlation (p Overall, polymorphisms related with decrease activity of enzymes that active cyclophosphamide (level lor active metabolite) were correlated with higher aGVHD, cGVHD, TRM and VOD (Table 1). On the other hand, polymorphisms associated with low activity in detoxification enzymes were correlated with higher toxicity (TRM). As described in bibliography, GSTM1 null allele were correlated with higher probability of developing VOD. CONCLUSIONS Genetic analysis of CY metabolism genes correlated with several post HSCT complications. The analyses of this variants before transplant could facilitate personalized risk and clinical management of patients undergoing Haplo HSCT. Results must validated in others cohorts of patients. Disclosures Kwon: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

Peter Paschka and Hartmut Döhner contributed equally. Background. SARS-CoV-2 infection (COVID-19) has had a great impact worldwide and its mortality has been reported to be higher in patients with haematological malignancies. However, description of its effects and outcomes among recipient of hematopoietic stem cell transplantation (HSCT) is scarce. Objectives. To describe the characteristics, treatment and outcome of COVID-19 in recipients of HSCT reported to the Madrid registry of COVID-19 ("HEMATO-MADRID COVID-19 registry"). Results. Data of 842 patients from 23 hospitals with haematological malignancies and COVID-19 infection were reported in the Madrid registry between March and June 2020. Among those, 87 (10.3%) patients were HSCT recipients: 58 auto-HSCT and 29 allo-HSCT (7 of them from matched related donor (MRD), 12 matched unrelated donor (MUD) and 10 haplo-HSCT). Characteristics of the population are described in Table 1. Median age at COVID-19 infection was 61 years (IQR, 53-67) and 35 patients (40%) were female. Recipients of auto-HSCT with COVID-19 were older and showed a trend towards a higher incidence of arterial hypertension (28% vs 10%, p=0.067) without statistical differences in other comorbidities; active disease requiring treatment at COVID-19 diagnosis was more frequent in auto-HSCT recipients (65% vs. 21%, p Conclusion. In our multicentric experience in a high COVID-19 impacted area, the median time of COVID-19 infection presentation was relatively late in transplanted patients, however shorter in allo-transplanted patients. COVID-19 related mortality was high in HSCT recipients, significantly higher in allo-transplanted patients. Factors associated to this higher mortality should be further investigated to promptly identify high-risk patients since the pandemic is still highly active worldwide. Disclosures Kwon: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Duarte:Incyte Corporation: Other: Has received speaker and advisor fees. Hernandez-Rivas:Rovi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell-replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

International audience; Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only medical intervention that has led to an HIV cure. Whereas the HIV reservoir sharply decreases after allo-HSCT, the dynamics of the T cell reconstitution has not been comprehensively described. We analyzed the activation and differentiation of CD4+ and CD8+ T cells, and the breadth and quality of HIV- and CMV-specific CD8+ T cell responses in 16 patients with HIV who underwent allo-HSCT (including five individuals who received cells from CCR5Δ32/Δ32 donors) to treat their underlying hematological malignancy and who remained on antiretroviral therapy (ART). We found that reconstitution of the T cell compartment after allo-HSCT was slow and heterogeneous with an initial expansion of activated CD4+ T cells that preceded the expansion of CD8+ T cells. Although HIV-specific CD8+ T cells disappeared immediately after allo-HSCT, weak HIV-specific CD8+ T cell responses were detectable several weeks after transplant and could still be detected at the time of full T cell chimerism, indicating that de novo priming, and hence antigen exposure, occurred during the time of T cell expansion. These HIV-specific T cells had limited functionality compared with CMV-specific CD8+ T cells and persisted years after allo-HSCT. In conclusion, immune reconstitution was slow, heterogeneous, and incomplete and coincided with de novo detection of weak HIV-specific T cell responses. The initial short phase of high T cell activation, in which HIV antigens were present, may constitute a window of vulnerability for the reseeding of viral reservoirs, emphasizing the importance of maintaining ART directly after allo-HSCT.

Allogeneic hematopoietic cell transplantation (allo-HCT) using siblings and matched donors has the potential for long-term disease control in a subset of high-risk patients with multiple myeloma (MM); however, the data on using haploidentical donors in this disease are limited. We conducted a retrospective analysis to examine the outcomes of patients with MM who underwent haploidentical allo-HCT within European Society for Blood and Marrow Transplantation/Center for International Blood and Marrow Transplant Research centers. A total of 96 patients underwent haploidentical allo-HCT between 2008 and 2016. With a median follow-up of 24.0 months (range, 13.2 to 24.9 months), 97% (95% confidence interval [CI], 93% to 100%) of patients had neutrophil engraftment by day 28, and 75% (95% CI, 66% to 84%) achieved platelet recovery by day 60. Two-year progression -free survival (PFS) was 17% (95% CI, 8% to 26%), and overall survival (OS) was 48% (95% CI, 36% to 59%). At 2 years, the cumulative risk of relapse/progression was 56% (95% CI, 45% to 67%), and 1-year nonrelapse mortality (NRM) was 21% (95% Cl, 13% to 29%). The incidences of acute graft-versus-host-disease (GVHD) grades ll-IV by 100 days and chronic GVHD at 2 years were 39% (95% CI, 28% to 49%) and 46% (95% CI, 34% to 59%), respectively. On univariate analysis, use of post-transplantation cyclophosphamide (PT-Cy) (54% [95% CI, 41% to 68%] versus 25% [95% CI, 1% to 48%]; P=.009) and use of bone marrow as source of stem cells (72% [95% CI, 55% to 89%] versus 31% [95% CI, 17% to 46%]; P=.001) were associated with improved OS at 2 years. Disease status, patient sex, intensity of conditioning regimen, recipient/donor sex mismatch, and cytomegalovirus serostatus had no impact on OS, PFS, or NRM. Haploidentical transplantation is feasible for patients with multiply relapsed or high-risk MM, with an encouraging 2-year OS of 48% and an NRM of 21% at 1 year, supporting further investigation of haploidentical allo-HCT in suitable candidates with MM. (C) 2018 American Society for Blood and Marrow Transplantation.

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PT-CY in HLA-identical donor is less explored. In this study, we analyzed the results of PT-CY for GVHD prophylaxis in matched unrelated donor (MUD) HSCT and compared them with those obtained after prophylaxis with anti-thymocyte globulin (ATG), methotrexate (MTX) and cyclosporine (CsA). Methods: 132 matched unrelated donor HSCT from 4 Spanish centers have been analyzed: 60 performed between 2010 and 2018 using ATG-MTX-CsA and 72 performed between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. Peripheral blood was used as graft source in 92% of the patients in the ATG group and in 78% in the PT-CY group. GVHD prophylaxis consisted in rabbit ATG either 2mg/kg days -4 to -2 (41 patients, 68%) or 0.5mg/m2 on day -3 followed by 1mg/kg days -2 and -3 (19 patients, 32%), MTX days +1, +3, +6 and +11, and CsA from day -1 in the ATG group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +4, followed by either CsA or tacrolimus plus mycophenolate mofetil (MMF) from day +5 in 30 patients (42%), or cyclophosphamide on days +3 and +5 combined with CsA or tacrolimus in 42 patients (58%; 16 out of them also received sirolimus due to 9/10 HLA-match). Cumulative incidence of grade II-IV (67% vs 46%, p=0.008) and III-IV (34% vs 3%, p=0.003) acute GVHD, were significantly higher in the ATG group (Figure 1). There were no differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (23% vs 24%, p=0.86). After a median follow-up of 78 months for the ATG group and 26 months for the PT-CY group, no differences were found in the 2-year overall survival (58% vs 60%, p=0.475), 2-year event-free survival (51% vs 50%, p=0.961) and the composite endpoint of GVHD-free and relapse-free survival (44% vs 40%, p=0.742). The 2-year cumulative incidence of relapse (22% vs 26%, p=0.67) and non-relapse mortality (NRM) (24% vs 22%, p=0.68) were also similar between both groups. However, NRM in the ATG group was due to GVHD in 9 out of 16 patients, while in the PT-CY group NRM was mostly due to infections and organ toxicity and only 3 out of 15 patients died due to GVHD. The incidence of sinusoidal obstruction syndrome was low in both groups (0% vs 4%, p=0.11). CMV reactivation rates were similar (40% vs 51%, p=0.191). However, both hemorrhagic cystitis and EBV reactivation were higher in the ATG group (56% vs 12%, p=0.00, and 5% vs 0%, p=0.05, respectively). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after MUD HSCT, using mostly peripheral blood as graft source, resulted in lower incidence of aGVHD compared to prophylaxis based on ATG-MTX-CsA. Although no impact on non-relapse mortality was observed, GVHD associated mortality was higher in the ATG group as well as cystitis and EBV reactivations. Prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Background The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) is rapidly increasing. The safety and efficacy of myeloablative conditioning (MAC) in haplo-HCT has been reported in patients with acute leukemia. However, optimal MAC in haplo-HCT setting is unknown. We studied the outcomes of total body irradiation (TBI) vs. chemotherapy (CT) based MAC regimens in acute myelogenous leukemia (AML) patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 1008 AML patients (secondary AML=149, 15%) who underwent haplo-HCT with PTCy during the years 2010-2018, following TBI (n=89, 9%) or CT (n=919, 91%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose Results In univariate analysis, day 100 incidence of acute GVHD (aGVHD) II-IV and III-VI was 22% vs. 27% (p-0.44) and 12% vs. 12% (p-0.92) in TBI and CT cohorts respectively. Two-year total and severe chronic GVHD (cGVHD) incidence was 42% vs. 27% (p No interaction was observed between the type of MAC and RI, NRM, LFS, OS and GRFS in a separate subgroup univariate analysis of patients Conclusions In this large cohort of AML patients who received first haplo-HCT with PTCy, TBI based MAC was associated with higher incidence of overall cGVHD without impacting other transplant outcomes compared to CT based MAC. In the absence of a prospective study, these findings may guide clinicians when choosing an optimal MAC in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

¶ Martin-Rojas RM and Oarbeascoa G contributed equally to this work. INTRODUCTION Relapse is the main cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). The evaluation of minimal residual disease (MRD) could provide a more accurate assessment of the depth of response, and therefore identify patients with higher risk of relapse. AIMS The aim of our study was to analyze the impact of pre-HSCT flow cytometry (FCM) and molecular MRD together with chimerism and MRD in the early post-HSCT period in patients with AML. METHODS We conducted a retrospective study in patients with complete remission AML who underwent a HSCT between 2008 and 2019 in our center. MRD was analyzed by flow cytometry in bone marrow aspirates and by quantitative RT-PCR (NMP1, RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3, WT1) in bone marrow aspirates and/or peripheral blood. MRD was determined within the 30 days preceding the HSCT and at day +30 and +90 post-HSCT. Bone marrow and selected CD34+ lineage chimerism was analyzed by STR (AmpFISTR SGM Plus, Thermo Fisher) at days +30 and +90 post-HSCT. This study was approved by our Institutional Ethics Committee. Data were analyzed using IBM SPSS Statistics version 24 and R version 3.5.1. RESULTS A total of 115 patients were analyzed. Pre-HSCT MRD was negative in 58 patients (50.4%) and positive in 57 patients (49.6%). We found no statistically significant differences in the characteristics between the two groups (Table 1). Median follow up was 39 months (IQR 10.4-55.8). 3-year overall survival (OS) for patients with pre-HSCT negative MRD was 72.5% versus 70.3% in patients with positive MRD (p=0.41), with an event free survival (EFS) of 66.9% versus 66.1 (p=0.48) respectively (Figure 1). Median time to the beginning of immunosuppression withdrawal was 82.5 days (IQR 59-93) for patients with negative MRD and 68 days (IQR 55.3-85.3) for patients with positive MRD (p Patients with negative MRD at day +30 showed a 2-year OS of 83.5% versus 58.1% in patients with positive MRD (p=0.03) and a EFS of 79.9% versus 48.6% (Figure 2). The cumulative incidence of relapse was more elevated in patients with positive MRD (29.8% versus 13.6%) at day +30. Patients with mixed chimerism (MC) at day +30 showed a significantly lower 3-year OS and EFS than patients with complete chimerism (CC). Likewise, the cumulative incidence of relapse was significantly higher in patients with MC, both if detected in bone marrow aspirate and in CD34+ cells. The multivariate analysis revealed that MRD status at day +30 post-HSCT was an independent prognostic factor for EFS (HR 3.74; 95% CI 1.38-10.1; p=0.009). CONCLUSIONS Patients with AML presenting a positive MRD in the early post-HSCT period and those who show a MC at day +30 post-HSCT have lower EFS, with positive MRD at day +30 being an independent prognostic factor for EFS. The evaluation of MRD and chimerism in the early post-HSCT period is useful to identify patients with higher risk of relapse, who may take advantage of preemptive measures. Disclosures Kwon: Gilead, Novartis, Pfizer, Jazz: Consultancy, Honoraria.

INTRODUCTION COVID-19 is associated with coagulopathy that correlates with poor prognosis. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, early reports suggested that it may be a form of disseminated intravascular coagulation (DIC). However, recent studies have highlighted the potential role of endothelial cell injury in its pathogenesis. AIMS The aims of our study were to analyze the coagulation parameters of critically and non-critically ill patients with COVID-19 pneumonia admitted to our hospital, determine if coagulation factors consumption occurs, identify potential prognostic biomarkers of this new disease and explore possible underlying mechanisms of COVID-19 coagulopathy. METHODS We conducted a retrospective cohort study performed at Gregorio Marañon Hospital in Madrid, Spain. Adult patients with a diagnosis of COVID-19 hospitalized in our center were recruited, including those admitted to the ICU and to general wards. Patients were randomly selected from blood samples that arrived at our Hemostasis laboratory during April 2020. For each patient, we conducted a complete analysis of coagulation parameters, including basic coagulation tests, quantification of coagulation factors and physiological inhibitor proteins, evaluation of the fibrinolytic system and determination of von Willebrand Factor (vWF) and ADAMTS13. Laboratory data were compared with clinical data and outcomes. Data were analyzed using IBM SPSS Statistics for Mac, version 24. This study was approved by our institutional Ethics Committee and it was executed along with the international ethics recommendations for conducting research in humans following the latest revision of Declaration of Helsinki. RESULTS A total of 62 patients (31 ICU, 31 non-ICU) were analyzed. Mean age of the sample was 61.8 (SD 15.2) years and 69.4% of the patients were male. The coagulation parameters assessment demonstrated normal median PT, INR and APTT in our cohort and all coagulation factors were within normal range. Factor VIII showed an increasing trend (194.5±71.9) which could be interpreted as an acute phase reactant, and it was significantly higher in non-survivors (p=0.003). Similarly, we did not observe consumption of physiological inhibitor proteins and platelet counts were also within the normal limits, despite being slightly lower in non-survivor patients (p=0.006) (Table 1). Von Willebrand Factor (vWF) was above the normal range (median 216%, IQR 196-439, normal range 62-175%) in our cohort and higher levels of vWF-antigen (p=0.001) and vWF-activity (p=0.02) were associated with poor prognosis. Likewise, a lower ADAMTS13 activity was observed in non-survivors (p=0.008). Regarding the fibrinolytic pathway, PAI levels were above the normal range (median 52.6ng/ml, IQR 37.2-85.7, normal range 4-40ng/ml), but we found no statistically significant differences based on survival. The remaining parameters of the fibrinolytic pathway (plasminogen and alpha-2 antiplasmin) were within normal range (Table 1). ICU-patients had a poorer prognosis, with a higher rate of mortality (p=0.003). Likewise, they showed more elevated acute phase reactants (p CONCLUSIONS COVID-19 infection is associated with coagulopathy that correlates with poor prognosis. However, coagulation factors, physiological inhibitory proteins and alpha-2-antplasmin levels were preserved in our study. Similarly, we did not observe platelets or fibrinogen consumption, which leads us to assume that COVID-19 coagulopathy is not a form of DIC. Increased vWF and decreased ADAMTS13 activity in our cohort could indicate that the underlying mechanism of this coagulopathy may reside in the endothelial cells and share a similar pathogenesis with thrombotic microangiopathy (TMA), as it has been recently suggested in some scientific reports. Disclosures No relevant conflicts of interest to declare.

[Background]: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies., [Methods]: Six clinical centers entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with, [Results]: An overall “very good” agreement on CD34+ cell count among participants (intraclass correlation coefficient = 0.720) was observed, but agreement was “low” in 22 files. No single parameter could fully explain all discrepancies, but 3 technical issues were identified as relevant: the use of the CD34/CD45/CD117/HLA-DR mAb combination, acquisition of ≥50,000 events and a low percentage of debris/aggregates. The frequency of discordant results increased with the accumulation of pitfalls (none, 16%; 1 pitfall, 40%; 2 pitfalls, 83%; P = 0.006). Finally, the use of a common gating strategy for analysis increased the percentage of files with “very good” agreement to 100%., [Conclusions]: Prevention of specific technical pitfalls is mandatory to reach a good reproducibility of CD34+ cell count among centers. These recommendations set the basis for laboratory standardization and enable the use of CD34+ cell enumeration as additional information in low-risk MDS patients. © 2017 International Clinical Cytometry Society

We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Espanol de Trasplante Hematopoyetico. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.

Background The impact of the use of anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation performed with HLA-identical sibling donors following fludarabine and 4 days intravenous busulfan myeloablative conditioning regimen has been poorly explored. Methods We retrospectively analyzed 566 patients who underwent a first HLA-identical allogeneic stem cell transplantation with this conditioning regimen for acute myeloid leukemia in first complete remission between 2006 and 2013 and compared the outcomes of 145 (25.6%) patients who received ATG (ATG group) to 421 (74.4%) who did not (no-ATG group). The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results Patients in the ATG group were older, received more frequently peripheral blood stem cell grafts from older donors, and were transplanted more recently. With a median follow-up of 19 months, patients in the ATG group had reduced 2-year cumulative incidence of chronic graft-versus-host disease (GVHD) (31 vs. 52%, p = 0.0002) and of its extensive form (8 vs. 26%, p

Introduction: Non-Hodgkin B lymphomas (NHL-B) are a large group of heterogeneous diseases, with well-defined, histological and clinical features. Currently, the lymph node biopsy is essential for diagnosis, often obtained from hard to reach areas. Our aims with this study was to analyze genetics variants at diagnosis trying to discriminate between different NHL-B histologic subtypes using formalin fixed paraffin embedded (FFPE) tissue sections and circulating tumor free DNA (ctDNA) samples. Material and Methods: This is a retrospective, cross-sectional, single-center study. Sixty patients were selected with a diagnosis of different NHL-B subtypes: Diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), marginal lymphoma (ML), mantle cell lymphoma (MCL) and plasmablastic lymphoma (PL). Sixty FFPE tissue samples and 23 ctDNA specimens obtained at diagnosis were selected. We performed an enrichment panel of 54 genes recurrently mutated in lymphomas (Lymphoma Solution; Sophia Genetics) by next generation sequencing (NGS; NextSeq; Illumina). The depth of 90% of the readings was greater than 2600x. Quantitative variables were expressed as median and range. Categorical variables were expressed as frequency and percentage. The Fisher exact test was used to compare the distribution of categorical variables. The Mann-Whitney test was used to compare differences between quantitative variables. Statistical significance was set at p < 0.05. Results: Our study shows that 97% (58/60) of patients presented any variant. The most frequently mutated genes were KMT2D, EP300 and SOCS1. Exclusive variants were detected in FL in the genes CCND1, PAX5, CREBBP, BCL2 and REL genes. In the same way, in DLCBL the variants detected in the BRAF, TCF3, XPO1, PIM1, CHD2, ID3 and BCL6 genes were exclusive of this subtype. Furthermore, the genes BCL2 (p=0.0021), CREBBP (p=0.0004), NOTCH2 (p=0.03), PAX5 (p=0.01) and TNFRSF14 (p=0.04) are more frequently altered in patients with FL, ATM (p=0.02) gene in MCL; NFKBIE (p=0.03), CIITA (p=0.02), MYC (p=0.009) and PIM1 (p=0.04) in DLCBL, among which it was found that high-grade lymphomas are more frequently associated with mutations in CHD2 (p=0.02), MYC (p=0.03) and MYD88 (p=0.02; data not shown). In the subgroup of 23 patients with paired samples (FFPE/ctDNA), 95% (22/23) of patients had mutations in any of the genes on the panel in FFPE tissue samples and 82% (19/23) in ctDNA specimens. The number of variants detected was different depending on the type of sample analysed, 52% of the variants were detected in both specimens, 39 only in FFPE tissue and 9% in ctDNA; Figure 1). In variants detected in both samples, the average value of the VAF was higher that when is detected only in one of the samples (FFPE: 28.1 vs 5.8 (p We did not find significant differences in the number of variants depending on the stage, classification, tumour burden or bulky mass (Table 1). Conclusion: In our study, we were able to identify genetic variables that could characterize different histological groups of NHL-B in FFPE tissue and ctDNA samples, by using a commercial gene panel of NGS. The mutational profile obtained from ctDNA and FFPE tissue is comparable in all histological subtypes, regardless tumour burden, aggressiveness or stage, throwing each one of them complemental information. These results support the hypothesis that could be possible to distinguish different histologies through non-invasive strategies, specially oriented to lesions where obtaining a tissue sample is difficult. We are working on the development of clinical-genetic algorithms that allow us to achieve our goal. Disclosures No relevant conflicts of interest to declare.

Introduction: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. Although PTCy-Haplo has been compared with different transplant platforms, there is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods:We retrospectively analysed outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n=215), MUD (n=235) and Haplo (n=789) donors registered in the EBMT database between 2010 and 2017. The median follow up period of the entire cohort was 2 years. Results: Median age of patients was 52 years (range, 18-76), 693 (56%) were male and 928 (78%) were CMV seropositive. AML was de novo in 1,046 (84%) patients, while 47 (6%),543 (66%) and 239 (29%) had standard, intermediate and high risk cytogenetics, respectively. Peripheral blood (PB) was used as the stem cell source in 814 (66%) patients. Regarding conditioning, 962 (78%) were chemotherapy based regimens and 500 (41%) patients received reduced intensity conditioning (RIC). Preferred conditioning regimens were thiotepa, busulfan, fludarabine for Haplo (n= 371; 47%) and busulfan, fludarabine for MSD (n= 83; 39%) and MUD (n= 102; 43%). Patients received a variety of PTCy containing immune suppressive regimens, the most frequently used being PTCy, calcineurin inhibitor and mycophenolate mofetil in Haplo (n= 684; 87%) and PTCy and calcineurin inhibitor alone in MSD (n= 52; 24%) and MUD (n= 74; 31%). In-vivo T-cell depletion (TCD) was used in 164 (13%) patients. Compared to MSD and MUD, Haplo patients were older and less frequently received RIC, TCD and PB but the distribution of cytogenetic risk group was similar between the donor types. Cumulative incidence of neutrophil recovery at 60 days was 95% (95% CI 94-96). The cumulative incidence of 100 day acute GVHD grade II-IV and III-IV, and 2-year chronic and chronic extensive GVHD were 25% (95% CI 23-28), 9% (95% CI 7-10), 31% (95% CI 28-34) and 12% (95% CI 10-14), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality (NRM) and the probability of leukemia-free survival (LFS) and overall survival (OS) were 25% (95% CI 22-28), 19% (95% CI 17-21), 56% (95% CI 53-59) and 63% (95% CI 60-66), respectively. On multivariable analysis, outcomes were not significantly different for MSD and MUD. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) but the risk was not significant for chronic GVHD (HR 1.2; 95% CI 0.8-1.8). Haplo-SCT carried a higher risk of NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no change in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). The most frequent cause of death was relapse for MSD (n= 36, 53%) and MUD (n= 41, 48%) and infection for Haplo (n = 107, 39%). Interestingly, the use of PB was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). Other variables that had an impact on LFS were: poor risk cytogenetics (HR 1.4; 95% CI 1.1-1.7), use of MAC-Chemo (HR 0.7; 95% CI 0.6-0.9), Karnofski performance status Conclusions:The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD and Haplo is safe and effective and rates of GVHD are low, especially chronic. HLA mismatch in Haplo has a negative impact on acute GVHD and NRM in this setting but also offers increased anti-leukemic efficacy. As seen in other transplant scenarios, PB is associated with more GVHD and less relapse. Figure Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

INTRODUCTION Allogeneic haematopoietic stem cell transplant (allo-HSCT) could be the only curative therapy for patients with hematological malignancies due to graft effect against tumor. However, approximately 40% of patients develop post-transplantation complications such as acute graft-versus-host disease (aGVHD). Cytokines and their receptors are involved in regulatory and inflammatory processes that occur during GVHD. Therefore, the analysis of polymorphisms (SNPs) that affect the expression or activity of these genes could be used as biomarkers to predict the development of these complication. The aim of this study was to select new polymorphisms in cytokine genes (interleukins, chemokines and their receptors) to build models to predict the development of aGVHD after allo-HSCT from an HLA-identical sibling donor. METHODS We retrospectively selected 88 patients with hematological malignancies who received an allo-HSCT from an HLA-identical sibling donor from 2000 to 2015. A total of 176 pre-transplant recipient (R) and donor (D) peripheral blood samples were collected. The genotyping was performed using an enrichment-capture gene panels (include 132 genes (73 interleukins, 59 chemokines) in a HiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with the GeneSystemssoftware (Sistemas Genómicos, Spain). Variants located in coding region, splicing sites, and UTR, 5'upstream and 3'downstream zones (+ 200pb) were analyzed. We selected polymorphisms corresponding to non-synonymous variants, represented in at least 5% of our cohort, with readings ≥30X in the canonical isoformwith an allele frequency ≥ 0.4. Fisher test was used to compare the differences among groups. Multiple logistic regression models were performed using combination of interleukins and chemokines polymorphisms selected previously that could be applied to clinical practice to predict aGVHD. The models with the highest AUC value, sensitivity and specificity value and the lowest number of genetic variants used were selected.Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of grades II-IV and III-IV at 100 days after transplantation were 48.93% and 18.08%, respectively. The clinical variables (age, gender, pathology, stem cell source and previous transplantation) were not correlated with II-IV or III-IV aGVHD. However, patients who received ablative conditioning regimen presented a lower incidence of III-IV aGVHD (p= 0.041). Using filters defined previously, we detected 481 polymorphisms (350 coincident, 68 specific R and 63 for D) in the interleukins group. On the other hand, we detected 339 polymorphisms (267 coincident, 29 specific R and 43 for D) in the group of chemokines. Finally, 17 polymorphisms were selected in the interleukin group and 10 in the chemokine group for its correlation with the aGVHD (p We developed multiple logistic regression models for II-IV and III-IV aGVHD in interleukins and chemokines genes (Table 3). The identification of these 15 polymorphisms could help us to prevent the developing II-IV and III-IV aGVHD. CONCLUSIONS We have identified new genetic polymorphisms correlate with the risk of developing aGVHD after allo-HSCT from an HLA-identical sibling donor. Based on these data, we have developed a genetic score that encompasses polymorphisms of greater relevance. In this way, patients at greatest risk for developing this type of post-transplantation complication who could benefit from personalized management through immunosuppression and other drugs. Disclosures No relevant conflicts of interest to declare.

Background: The number of non T depleted haploidentical stem cell transplantations (haplo SCT) with post transplantation cyclophosphamide (PTCy) in adult patients (pts) with acute lymphoblastic leukemia (ALL) is increasing (Shemtov N et al, Leukemia 2019). Although the original haplo SCT with PTCy were performed with bone marrow (BM) grafts, the use of peripheral blood stem cells (PBSC) as the stem cell source may provide some advantages in engraftment and anti-leukemic effect which may be of special importance in ALL. Aim: The goal of this study was to compare BM to PBSC as stem cell source for non-T-cell-depleted haplo SCT with PTCy in adult pts with ALL in first or second complete remission (CR). Methods: The study was based on the haplo SCT with PTCy in adult pts with ALL that met the study inclusion criteria and that were reported to the European Society for Blood and Marrow Transplantation (EBMT) registry from 2010 to 2018. Multivariate analyses (MVA) were performed using the Cox proportional hazard model. Results: A total of 314 pts were reported, 157 of whom received BM and 157 received PBSC as the stem cell source. The median age at transplantation was 37 years (range, 18-68 years) and 36 years (range, 18-73 years), 66% and 62% were males, respectively. Diagnosis was Ph negative B-ALL in 39% and 41% of the pts, Ph positive in 32% and 34 % and T ALL in 29% and 25%, respectively.61% and 65% were in CR1, while 39% and 35% were in CR2. Pts and donor characteristics did not differ between the groups. More pts in the BM group received myeloablative conditioning (MAC), 87% vs 71% in the PBSC group, p Conclusion: In pts with ALL in remission receiving haplo SCT with PTCy, the use of BM versus PBSC grafts resulted in better LFS, OS and GRFS. Disclosures Angelucci: Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC. Socie:Alexion: Consultancy. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background The intensity of a conditioning regimen has significant impact on outcomes of allogeneic hematopoietic cell transplantation in acute leukemia. In acute lymphoblastic leukemia (ALL) patients undergoing matched donor transplant, total body irradiation (TBI)- based myeloablative conditioning (MAC) regimen was associated with improved leukemia free survival (LFS) compared to chemotherapy (CT)-based MAC (Eder S. et al. 2017). Haploidentical hematopoietic cell transplantation(haplo-HCT) with post-transplant cyclophosphamide (PTCy) has emerged as a safe alternative in absence of a matched donor. The optimal MAC in haplo-HCT setting is yet to be defined. We studied the outcomes of TBI- vs. CT-based MAC in ALL patients undergoing haplo-HCT and reported to the Acute Leukemia Working Party of the EBMT. Methods The study included 427 ALL (B-ALL-75%) patients, that underwent haplo-HCT with PTCy during the years 2010-2018, following TBI- (n=188, 44%) or CT- (n=239, 56%) based MAC. Regimen intensity was defined by EBMT criteria and cases with busulfan dose Results In univariate analysis, day 100 incidences of acute GVHD II-IV and III-VI were 38% vs. 30% (p-0.07) and 19% vs. 13% (p-0.14) for TBI and CT cohort, respectively. Two-year overall and severe chronic GVHD incidences were 34% vs. 30% (p-0.51) and 17% vs. 12% (p-0.18) for TBI and CT cohort, respectively. Graft failure was reported in 6 (3%) and 19 (8%)(p-0.09) patients who received TBI and CT-based MAC, respectively. Death from veno-occlusive disease was reported in 4 (5%) TBI patients and 8 (7%) CT patients. There was no difference in reported deaths due to infection (28%) or interstitial pneumonitis (4%) among study cohorts. In multivariate analysis, TBI was associated with significant improvement in nonrelapse mortality (NRM) [HR=0.51, 95% CI:0.32-0.83, p In a subgroup univariate analysis of patients Conclusions TBI based MAC resulted in significant reduction of NRM, translating into a better LFS without impacting aGVHD III-IV, chronic GVHD, RI or OS when compared to CT based MAC. Non-significant difference in OS between TBI and CT cohorts might be related to lower number of events, short follow-up and/or salvage therapies after relapse. These novel findings based on a large cohort of ALL patients, support the use of TBI based MAC and bone marrow graft in haplo-HCT with PTCy. Disclosures Dholaria: Celgene: Honoraria. Labopin:Jazz Pharmaceuticals: Honoraria. Angelucci:Novatis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Participation in DMC; BlueBirdBio: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; Roche: Other: Local advisory board; Vertex Pharmaceuticals Incorp., and CRISPR Therapeutics: Other: Participation in DMC. Apperley:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background: The use of unmanipulated Haploidentical HSCT (Haplo-HSCT) with post-transplant Cyclophosphamide (PT-Cy) as GVHD prophylaxis has widely extended. Veno-occlusive disease (VOD) is a threatening complication after both autologous and allogeneic HSCT, with high mortality rates despite early medical treatment, including the use of defibrotide. The objective of this study was to describe characteristics and outcomes of patients with refractory very severe VOD after Haplo-HSCT with PT-Cy, treated with TIPS as salvage procedure. Methods: We retrospectively analysed 176 Haplo-HSCT with Cy-post consecutively performed between 2011 and May 2019 in a single centre. VOD was defined according to modified Seattle, Baltimore or revised EBMT criteria. Severity was retrospectively graded according to revised EBMT severity criteria into four categories: mild, moderate, severe and very severe. Complete response (CR) was defined as a normal total bilirubin level ( Results: Sixteen patients (9.1%) met the modified Seattle, Baltimore or revised EBMT diagnostic criteria for VOD. Ultrasound with Doppler ultrasonography was performed in all patients, and at least indirect signs of VOD were found in all cases. Based on revised EBMT severity criteria, there were 2 mild (12.5%), 2 moderate (12.5%), 2 severe (12.5%) and 10 very severe (62.5%) grade VOD. Twelve patients (75%) were treated with defibrotide, including all patients with very severe VOD, except one with CNS hemorrhage (Patient 1). Six patients with very severe VOD, were treated with TIPS due to rapid clinical or analytical deterioration or refractory hepatorenal syndrome, despite medical treatment including defibrotide (Table 1). All were male patients, with a median age of 31 years (range 22-36), all transplanted with myeloablative conditioning regimen. TIPS insertion was performed on a median time since VOD diagnosis of 5 days (range 1-28) without technical complications in any case. Median total bilirubin, ALT, creatinine and INR the day of procedure were 3 mg/dL (range 2.2-11.2), 1120 UI/L (range 10-2595), 2.45 mg/dL (range 2.06-3.58) and 1.96 (range 1.1-4) respectively. Median hepatic venous pressure gradient (HVPG) prior to and after TIPS was 22.5 (range 14-29) and 6.5 (range 2-10) mmHg respectively, with a median drop of 16.5 mmHg (range 9-19). Following TIPS, all patients showed clinical improvement with hepatomegaly, ascites and renal failure resolution, and all showed analytical improvement with bilirubin, creatinine and ALT values reduction, except for patient 2, whose TIPS indication was refractory hepatorenal syndrome with normal ALT levels (Figure 1). The 5 patients who had iniciated defibrotide before TIPS, completed 21 days of treatment. All patients met criteria for CR in a median of 8 days after TIPS insertion (range 2-82). The 100-day overall survival (OS) was 100%. Five patients were alive with normal liver and renal function at last follow up, and one patient died due to infection 7 months after Haplo-HSCT, with VOD in complete resolution. Conclusions: Incidence of VOD after Haplo-HSCT with PT-Cy is comparable to those reported after HLA-identical HSCT series. Most of the patients developed very severe VOD according to revised EBMT severity criteria. For patients with rapid progressive VOD, early TIPS insertion allowed completion of defibrotide therapy. The use of TIPS together with defibrotide resulted in complete response and no associated complications with a 0% of VOD associated mortality in spite of high severity. ALT values may be the best predictor of CR after TIPS procedure. In our experience, timely and individualized use of TIPS significantly improves outcome of very severe VOD after Haplo-HSCT. Therefore, TIPS should be promptly considered in rapid progressive cases. Disclosures No relevant conflicts of interest to declare.

Single-unit umbilical cord blood (CB) SCT is limited by low total nucleated cell (TNC) dose. Co-infusion of CD34+ cells from a third party HLA-mismatched donor, known as dual or haplo-cord transplant, reduces the period of post-transplant neutropenia and related complications. The aim of this study was to analyze the value of early post-transplant peripheral blood (PB) and T cell chimerism after 28 dual transplants regarding CB engraftment. Cumulative incidence of myeloid engraftment at 30 days was 93% with a median time to engraftment of 14 days (10-29). Patients who developed CB graft failure (n=5) showed very low percentages of CB cells on days +14, +21 and +28 with decreasing dynamics. On the other hand, percentages of CB cells in patients who achieved CB engraftment increased over time. Interestingly, such patients showed two distinct chimerism dynamics in PB, but all of them showed a predominance of CB T cells early after SCT with increasing dynamics over time. Early post-transplant chimerism dynamics in PB and T cells predicts CB graft failure enabling rapid therapeutic measures to be applied. On the other hand, early increasing percentages of CB T cells correlates with ultimate CB engraftment.

Introduction: Invasive Fungal Infection (IFI) is a serious complication after allogeneic stem cell transplantation (alloSCT). Its incidence and outcome are not well characterized in the setting of peripheral blood, non-manipulated haploidentical stem cell transplantation with postransplant cyclophosphamide (HaploSCT). The aim of the study is to analyze our experience among patients who underwent HaploSCT at our institution and developed an IFI, in order to identify the incidence, risk factors and its impact in survival. Materials and methods: One hundred and thirty-three patients underwent peripheral blood HaploSCT with postransplant cyclophosphamide at our institution between 2011 and 2017. IFI was classified according to the EORTC definitions. Proven and probable IFI were included. Results: Patients´ characteristics are shown in Table 1. Patients received primary antifungal prophylaxis with micafungin from the day before stem cell infusion, during admission and until neutrophil engraftment was stablished. Patients on steroid treatment due to GVHD received prophylaxis with micafungin or posaconazole. Twenty-three episodes of IFI were observed in 20 patients, 10 proven and 13 probable, with a cumulative incidence of IFI of 15% at 500 days. Most commonly isolated organism was Aspergillus spp (5 cases), followed by Candida spp (4 cases: 1 C. kruseii and 3 C. parapsilosis) and Fusarium spp (2 cases). Additionally we observed some isolated cases of Inonotus spp,Mucor spp and Trichosporon Ashii. Pulmonary involvement was the most frequent presentation (11 cases), followed by fungemia (5 cases, 4 Candida and 1 Trichosporon Ashii) and skin-pulmonary involvement (2 cases). Thirteen cases were diagnosed early, in the pre-engraftment period, 5 just after the engraftment and 5 cases developed later. Among patients with late occurrence of IFI, median time of IFI was 220 days, and all of them were associated with GVHD (3 grade III-IV acute GVHD and 2 moderate/severe chronic GVHD). IFI outcome was favorable in 14 out of the 23 documented IFI, with antifungal therapy. Treatment chosen was liposomal amphotericin B in 7 cases, voriconazole in 5 and combined treatment (with amphotericin B and azole) in 6. Death related to IFI was documented in 7 out of the 20 patients, with an IFI mortality cumulative incidence of 6.4%. Prior transplant (OR 4.5, p Conclusions: In our experience, cumulative incidence of IFI in the setting of HaploSCT was similar than the one observed in other studies with alloSCT. Mortality associated to IFI in the whole cohort was low (6.4 %). The most significant factor related to IFI development was having received a previous transplant, especially alloSCT. Therefore, this high risk population should be closely monitored and could benefit from prophylaxis with azoles. Disclosures No relevant conflicts of interest to declare.

Background: Post-transplant high dose cyclophosphamide (PT-CY) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). However, the use of PT-CY in HLA-identical HSCT is less explored. In this study, we analyzed the results of PT-CY as GVHD prophylaxis in HLA-identical sibling HSCT and compared them with those obtained after prophylaxis with methotrexate (MTX) plus cyclosporine (CsA). Methods: 107 HLA-identical sibling (10/10) HSCT from 2 Spanish centers have been analyzed: 50 performed consecutively between 2010 and 2015 using MTX-CsA as GVHD prophylaxis, and 57 performed consecutively between 2014 and 2018 using PT-CY. Results: Baseline characteristics and post-transplant complications are shown in Table 1. GVHD prophylaxis consisted in MTX days +1, +3, +6 and +11, and CsA from day -1 in the MTX-CsA group. The PT-CY group received cyclophosphamide 50 mg/kg/d on days +3 and +5 in 38 patients (65%), combined with CsA from day +5, and cyclophosphamide on days +3 and +4 in 19 patients (35%), followed by CsA and mycophenolate mofetil from day +5. Graft source was PBSC in 96% in the MTX-CsA group and 86% in the PT-CY group. Conditioning regimen was myeloablative in 64% and 40%, respectively. Neutrophil and platelet engraftment was significantly delayed in the PT-CY group (14.5 (11-27) vs 15.5 (13-37), p=0.02; 11.5 (8-180) vs 20.5 (10-43), p=0.02). After a median follow-up of 60 months for the MTX-CsA group and 15 months for the PT-CY group, 2-year overall survival (OS) was 56% (42-70) and 78% (67-90) (p=0.088), and event-free survival (EFS) was 48% (34-62) and 62.5% (42.5-82.5) (p=0.054), respectively. Cumulative incidence at 100 days of grade II-IV (52.2% vs. 22.6%, p=0.0015), and III-IV (24.4% vs. 8.8%, p=0.016) acute GVHD were significantly higher in the MTX-CsA group (Figure 1A). No differences were observed in the 2-year cumulative incidence of chronic moderate to severe GVHD (26% vs. 16.7% (p=0.306)). No differences were observed in the 2-years cumulative incidence of relapse (27% vs. 28% (p=0.47)). Non-relapse mortality (NRM) at 2-years showed a higher trend in the MTX-CsA cohort (24% vs. 8.8%, p=0.054). Finally, the composite endpoint of GVHD and relapse-free survival (GRFS) at 2-years was significantly better in the PT-CY group (48% vs. 24%, p=0.011) (Figure 1B). Conclusions: In our experience, GVHD prophylaxis using PT-CY combined with additional immunosuppression after HLA-identical sibling HSCT, using mostly peripheral blood as graft source, reduced the cumulative incidence of acute GVHD compared to standard prophylaxis with MTX-CsA, leading to an impact on GRFS. To our knowledge, this is the largest comparative retrospective cohort reported. Further prospective studies with longer follow-up are needed to confirm these observations. Disclosures No relevant conflicts of interest to declare.

Introduction Donor cell derived myeloid neoplasm (DCMN), defined as the development of de novohematological malignancies from cells of donor origin,is a late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We report on seven cases of DCMN in which whole-exome sequencing (WES) at different time-points after allo-HSCT, as well as in a sample from each donor, was performed. The ultimate objective was to accurately described the clonal architecture, spatial heterogeneity and identify somatic mutations that are induced in the process of leukemogenesis and clonal evolution of myeloid neoplasm. Donors were also analyzed to detect underlying condition predisposing to the development of DCMN. Patient and Methods Seven patients with a confirmed diagnosis of DCMN and their donors were recruited from different Spanish institutions. This cohort included a total of 32 BM samples at different time points after allo-HSCTand one PB sample from each donor (one case received dual allo-HSCT, CB and PB from both donors were obtained), which provided a total of 40 samples. Genomic DNA samples were prepared according to Agilent SureSelect-XT Human exon 50Mb enrichment kit (Agilent Technlogies, Santa Clara, CA) preparation guide and libraries were sequenced on Illumina HiSeq platform (Illumina, San Diego, CA). DNA sequencing data from recipient post-transplant BM samples, were matched against their donor PB sample and previous post-transplant BM samples to identify the acquisition of mutations along the post allo-HSCT period.Germline variants in donors were studied in order to detect mutations that predisposed to the development of a myeloid neoplasm.The research protocol was approved by the Ethic Committee of Gregorio Marañón General University Hospital. Patients´ and donors´ information was collected from their medical records. Results Clinical and biological characteristics of the 7 patients with DCMN and their donors are shown in Table 1. Mutational profiles obtained from the follow-up samples at different time-points post-HSCT demonstrated high intra-tumor genetic heterogeneity and clonal dynamic for all cases. The number of variants are increased over time and at the moment of DCMN diagnosis, the median number of variants was 28, ranging from 18 to 92 variants (Figure 1). WES identified in DCMN patients gene mutations commonly seen in adult AML or MDS, such as in SETBP1, DNMT3A, TET2, RUNX1, CSF3R, EP300and IDH2.In addition, others non-silent variants were acquired in all cases. Among the additional novel alterated genes, we found 23 strong candidateswith oncogenic potential. LUC7L2, NOP14, LAMA5, SKOR2, EML1, SNX13, RHPN2, IRS1, MTG2, TENM2, MEFV, GSE1, NOTCH4, DTX1, CNOT4, PNKP, GRB7,SENP7,TAF1L, ZKSCAN2, ZBTB20, ZNF461 and MEGF10. Analysis of CNVs revealed numerical alterations across the post allo-HSCT samples in patients 1, 2, 3, 4, 5 and 7. The most common chromosomal alterations in DCMN were monosomy 7 and other chromosome 7 abnormalities, which detected in the 86% (6/7) of the patients. Although none of the donors developed a myeloid neoplasm at the moment of diagnosis of DCMN in recipient, donor 1 revealed an abnormal karyotype (45,XY,-7) at the moment of the allo-HSCT. All other donors harbored at least one pathogenic or probably-pathogenic variants, most probably of germline origin, in genes involved in hematological or solid tumor predisposition. Conclusions The development of DCMN involves dynamic genomic processes that begin months before the clinical onset. In this study, our integrated multi-step analysis revealed the intra-tumor heterogeneity and evolutionary history of seven DCMN. The present study reveals a process of sequential clonal expansions promoted by the acquisition of somatic mutations in donor hematopoietic cells. Detection of heritable or acquired gene mutations in donors associated with predisposition to haematological malignancies could have clinical implications for the patients undergoing to allo-HSCT. Leukemic transformation ofdonor hematopoietic stem cells provides a useful in vivomodel to study the mechanisms involved in leukemogenesis. Novel approaches based on high-depth next generation sequencing to study consecutive samples from post-transplant period in these patients, appear promising to discover new genes involved in myeloid neoplasm and to decipher the mechanisms of leukemogenesis. Disclosures No relevant conflicts of interest to declare.

Introduction: Multidrug-resistant organisms (MDRO) are a challenge in patients undergoing stem cell transplant (SCT) which often result in an increase in mortality. To our knowledge, current literature defines only screening at the time of work-up for SCT-patients. The aims of the study were to assess the rate of MDRO colonization with weekly screening, rate of infection and the associated mortality in patients undergoing SCT. Patients and methods: Consecutive patients admitted at the SCT unit between January-18 to July-18 were reviewed in our institution. Screening consisted of rectal and perineal swab on admission and weekly until the date of discharge. In case of detection of MDRO , patients were isolated and infection control strategies were applied. Results: 41 patients were analysed, with 47 admissions, 6 patients had 2 admissions. The median duration of hospitalization was 27 days/patient (range 8-100). 168 rectal-and perineal swab were performed with a median of 3 swabs/patient (range 1-7). Patient characteristics are shown in Table 1. 36 patients (87%) spiked fever in a median of 8,5 days after admission (1-38days). 24,4% (n=10) had a positive screening: 2/10 patients at baseline and 8/10 patients (80%) were detected for the first time beyond baseline screen. Rate of MDRO colonization was 3% per week (95%CI 1.4-5.4). MDRO identified were : 4 patients with Extended-spectrum beta-lactamases producing E. Coli (ESBL-EC), Multidrug-resistant (MR) Pseudomonas aeruginosa (n=3), Vancomycin-resistant Enterococci (n=2) and 1 patient with carbapenem-resistant Citrobacter freundii. 6/10 patients developed MDRO infection (60%), all with previous MDRO positive detection: MR-Pseudomonas aeruginosa in urine culture (n=3) 2 treated with ceftolozane/tazobactam, 1 with meropenem+amikacin; ESBL-EC in urine culture (n=2) both treated with meropenem and 1 with Klebsiella pneumoniae carbapenemase in urine culture treated with ceftazidime/avibactam. The infection rate was 4,6% (95% CI 3.9-5.2). In 80% patients (n=8) antibiotic treatment was guided by positive screening, 3 patients were admitted to intensive care unit for sepsis. No mortality was associated to MDRO. In 76%of patients (n=28) screening was negative for MDRO. 24/28 (85%) spiked fever with a median of 10 days after admission (1-38days). None MDRO-infections in negative-screened patients were detected. Conclusions : Weekly screening for MDRO identified a high number of MDRO colonizations allowing to apply early strategies of infection control in high risk patients . Besides, MDRO infection occurred only in patients previously colonized, therefore, 80% of our cohort could benefit from guided treatment by the time of the febrile episode. Early identification of MDRO colonization might have helped to reduce MDRO related mortality. However, these findings should be confirmed with further studies, comparing baseline with weekly MDRO screening strategies. Disclosures No relevant conflicts of interest to declare.

Introduction: Cytokine Release Syndrome (CRS) is a systemic inflammatory response síndrome related to aberrant immune activation or immune hyperstimulation, leading to elevated cytokine levels (including IL-6, interferon-γ, IL-2) and inflammation. CRS has been described after infusion of T-repleted haploidentical progenitors in post-transplant cyclophosphamide (PTCy) based conditioning regimens. We analyzed the outcomes of 144 T cell-repleted transplants with PTCy (days +3, +4), MMF and CsA as GVHD prophylaxis in our institution. Patients and methods: A total of 105 haplo-HSCT and 39 HLA-identical HSCT (19 and 20 from sibling and unrelated donor, respectively) with PTCy were analyzed retrospectively in 141 consecutive patients from 2010 to 2017. Two patients with haplo-HSCT were excluded, one due to early death on day +1 and other for lack of information. CRS was defined and graduated according to Lee et al. criteria published in 2014.1 Chi-squared test was used to study the association of different qualitative clinical variables and CRS and Mann-Whitney U test for the association between CRS and total nucleated cells (TNC) infused. The determination of the best cut-off of TNC to stratify patients with CRS was performed with ROC curves. The stadistical program used was R v2.15.0. Results: The characteristics of the 142 transplants analyzed are shown in Table 1. CRS occurred in 77% of haplo-HSCT (79/103) and in 18% of identical HSCT (7/39). Most patients with CRS presented sings and symptoms in the first 24 hours after the infusión.The majority was grade 1. Only 5 patients who underwent haplo-HCT showed grade 2 CRS. They needed vasoactive drug, oxygen therapy (without mechanical ventilation) and low doses of corticosteroids. Of those 5 patients, 4 were lymphomas with a previous autologous transplant. The stem cell source of the 5 patients was peripheral blood (PB). We did not have cases of grades 3-4 CRS. No patient required Tocilizumab. The clinical and analytical characteristics of CRS are shown in Table 2. In the univariate analysis, the use of PB was significantly associated with the development of CRS (p = 0.001). No statistical association was found with other variables (underlying disease, disease status, cryopreserved product, previous autologous or allogeneic transplant, conditioning, age, sex, CD34 infused, etc.). In the haplo-HSCT cohort, patients who presented CRS showed higher content of TNC infused (median (range): 9.1 (1.17-18.77) vs. 6.9 (0.63-26) x108 / kg, p = 0.023). The best cut-off of TNC calculated was 6.02 x108 / kg (S 82%, E 47%, p = 0.02).CI of CRS in patients with TNC greater than 6.02x108 / kg was 84% compared to 53% in lower (HR 6.6, p = 0.0099, Figure1). Patients with CRS developed grade II-IV acute GVHD more frequently than those who did not present CRS (60% vs. 28.6%, p = 0.012). No association was observed between CRS and chronic GVHD, relapse, non relapse mortality, overal survival or event free survival. Conclusion: CRS appears more frequently in patients with haplo-HSCT compared to HLA-identical donors using PTCy and PB as stem cell source. In our experience, cases with grades 3-4 CRS are infrequent. The majority of CRS cases remit after PTCy and progress well with symptomatic treatment. In the haplo-HSCT cohort, the number of cells infused is associated with higher incidence of CRS and with the presentation of EICRa grade II-IV.Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome How I Treat Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014; 124(2):188-195. DOI: 10.1182/blood-2014-05-552729 Disclosures No relevant conflicts of interest to declare.

Background: Haploidentical (Haplo) stem cell transplantation (SCT) provide a curative option for nearly all Acute Myeloid Leukemia (AML) patients lacking an HLA matched donor. However, outcomes following Haplo-SCT vary and are dependent on a number of individual features. Integrative prognostic models for decision support towards a Haplo-SCT are lacking. We sought to develop a prediction model of Leukemia-Free Survival (LFS) for AML patients undergoing a Haplo-SCT. Methods: A total of 1,804 de-novo (80%) and secondary (20%) AML patients who received a non-T-cell depleted Haplo-SCT between the years 2005-2017 were included. All patients were reported to the registry of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). To account for non-linear associations, violation of the proportional hazard assumption, and to reduce bias associated with feature selection, a non-parsimonious non-parametric machine learning algorithm, Random Survival Forest (RSF), was used. RSF provides a continuous probabilistic estimation of LFS by fitting an ensemble of decision trees. Variables included in the model were reflective of patient, disease, and transplantation characteristics. Since RSF models are not readily interpretable (i.e., "black box" models) variable importance (VIMP) of covariates included in the model (Xv), were assessed by calculating the difference in prediction error before and after permuting Xv. The model's generalizability and accuracy were tested through repetitive bootstrapping (5000 iterations) and calculation of the C-index. Results: The median age of the patients was 53 years. The majority had an early disease status (complete remission [CR] 1[44%]) with intermediate cytogenetic risk (43%) and were undergoing allogeneic transplantation for the first time (93%). Reduced-intensity conditioning (RIC) was used in 57% of cases, and grafts were from peripheral blood in 54% of transplants. For graft-versus-host disease (GvHD) prophylaxis, 82% of the patients received post-transplant cyclophosphamide (PTCy) and 18% anti-thymocyte globulin (ATG). The median follow-up duration was 2.0 years. In the RSF prediction model, the top-ranking variables (Figure A) were disease status, GvHD prophylaxis, time from diagnosis to transplantation, and age. Bootstrapped C-index of the prediction model was 0.66. Prognostic discrimination was assessed by dividing the predicted LFS probabilities into quartiles that were then used to plot Kaplan-Meier curves, demonstrating LFS ranging from 24.8%-60.1% at 2-years (Figure B). Differing features of the four prognostic groups are listed in the Table. Conclusions: Our group has developed the first prediction model for LFS in AML patients treated with a Haplo-SCT. The model is based on a machine learning technique and provides an individualized estimation of LFS probability. It is conceivable that once this model is verified, it could serve as an important clinical tool when considering a patient to Haplo-SCT. Figure. Figure. Disclosures Angelucci: Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Celgene: Honoraria, Other: Chair DMC; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mohty:MaaT Pharma: Consultancy, Honoraria.

Introduction . Allogeneic stem-cell transplantation (SCT) is a curative approach in acute myeloid leukemia (AML) by providing dose-intensive chemo-radiotherapy and enhancing a graft-versus-leukemia (GVL) effect. The GVL effect is provided by alloimmune T- cells and is usually closely associated with graft-versus-host disease (GVHD). Patients with GVHD have a lower incidence of relapse, but at high grades a higher incidence of non-relapse mortality (NRM). However, GVL can also occur independently of GVHD. The use of haplo-identical SCT is rapidly increasing over the last decade due to the introduction of non-T depleted methods, in particular with post-transplant cyclophosphamide (PTCy), with expected outcomes that are similar to other donor sources. The GVL effect after T- depleted haplo-identical SCT is mostly related to natural-killer cell alloreactivity and is not necessarily associated with GVHD. However, there is no definite data whether GVL after SCT in the non-T depleted setting is similarly associated with GVHD as in the matched donor setting. Methods . We assessed the impact of acute and chronic GVHD on SCT outcomes in patients with AML following non-T depleted haplo-identical SCT with PTCy, by using a series of landmark analyses. Results . The study included 605 patients with AML in CR1 (73%) or CR2 (27%) after non-T depleted haplo-identical SCT with PTCy, given during the years 2009-2016. The median age was 53 years (range, 18-76). 71% had myeloablative conditioning and 29% had reduced-intensity conditioning . The overall rate of acute GVHD grade II-IV and III-IV was 28.4% and 8.0%, respectively. The rates of chronic GVHD all grades and extensive were 32.7% and 12.3%, respectively. The rate of relapse and NRM were 21.8% and 18.2% and the rates of leukemia-free survival (LFS) and overall survival, 2 years after SCT were 59.9% and 64.1%, respectively. 509 patients were alive and leukemia-free 100 days after transplant. 366 had no prior acute GVHD at this landmark, 107 had acute GVHD grade II and 36 had grade III-IV. The overall rate of subsequent relapse was 20.3%, 18.3% and 11.9%, respectively (P=0.60). The overall rates of subsequent NRM were 10.3%, 19.0% and 35.7%, respectively (P Conclusions. By a series of landmark analyses at 100 days, 6 months and 1 year after SCT, we did not find any association of acute GVHD grade II or III-IV or chronic GVHD (limited or extensive) with subsequent relapse. Acute GVHD grade III-IV was associated with a higher NRM and lower LFS rates after day100. All grades of acute GVHD were associated with a higher incidence of chronic GVHD. Previous extensive chronic GVHD was also associated with a higher NRM and a lower LFS. GVL is thus not associated with GVHD after non T-deleted haplo-identical SCT with PTCy. Future novel strategies for prevention of significant GVHD are warranted. Disclosures Angelucci: Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board. Mohty:MaaT Pharma: Consultancy, Honoraria.

Background: Graft failure (GF) is an unusual but threatening complication after allogeneic HSCT (allo-HSCT). Early diagnosis is crucial for therapeutic interventions to be effective. The monitoring of chimerism in peripheral blood (PB) and T lymphocytes (TL) has shown to contribute in the early detection of this complication. The objective of this study was to describe chimerism dynamics in patients who developed GF after allo-HSCT. Methods: Nineteen patients out of 416 procedures were diagnosed with GF after allo-HSCT since 2003 in our center. Chimerism studies were performed by STR-PCR (AmpFLSTR™ SGM Plus™, Thermo Fisher) in PB and TL weekly since day +14. Patients were classified into three groups: primary GF (absence of neutrophil engraftment by day +28), secondary GF (development of severe cytopenias and progressive mixed chimerism (MC) after initial achievement of neutrophil engraftment), and incipient GF (development of increasing MC with non severe cytopenias) [1]. Relapse/progression was ruled out in all cases. [1] Díez-Martín et al. Bone Marrow Transplant. (2004) 33, 1037-1041. Results: Seven patients were diagnosed with primary GF, 7 with secondary GF and 5 with incipient GF (Table 1). No evident causes of GF were detected in all primary GF cases. Chimerism analysis on day +14, +21 y +28 revealed persistent high percentages of recipient cells before GF were diagnosed, in PB and mainly and earlier in TL (Fig. 1A). Median time to salvage allo-HSCT was 45 days (range 35-77). Two patients were treated with donor lymphocytes infusion (DLI) and five with second allo-HSCT. Five patients achieved engraftment, and six achieved complete chimerism (CC). Six-months OS after salvage was 43%. The 7 patients diagnosed with secondary GF had achieved initial neutrophil engraftment in a median of 17 days (range 13-28). Median time to GF after allo-HSCT was 75 days (range 39-108). Six of them developed CMV reactivation before GF. Chimerism analysis before and at diagnosis of secondary GF, showed persistent high percentages of recipient cells, with a trend towards increasing dynamics in PB and mainly in TL (Fig. 1B). Median time to salvage therapy was 35 days (range 8-817) after GF confirmation. One patient was treated with DLI and six with second allo-HSCT. Five patients achieved engraftment and CC. Six-months OS was 57%. The 5 patients diagnosed with incipient GF showed persistent high percentages of recipient cells, with a trend towards increasing dynamics particularly in TL before and at diagnosis of GF (Fig. 1C). As salvage treatment, patients were treated with immunosuppression withdrawal followed by at least one DLI as salvage theraphy, in a median of 83 days (range 61-126) after allo-HSCT. All patients achieved CC in both PB and TL. Four patients developed grade II-IV GVHD. Six-months OS was 57%. Conclusions: Patients with primary GF presented MC in serial chimerism analysis after allo-HSCT, with persistent high percentages of recipient cells particularly in TC. Patients with secondary and incipient GF showed increasing MC mainly in TC, before GF was established. Early T-cell chimerism dynamics may be the best predictor of GF, allowing early therapeutic interventions. In our experience, timely and individualized second allo-HSCT after GF may improve outcome after primary or secondary GF. On the other hand, early DLI could benefit patients with incipient GF. Disclosures No relevant conflicts of interest to declare.