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Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare hematologic malignancy affecting 1.5-2.0 per million adults per year worldwide, which corresponds to approximately 1,000 cases in Europe. It is a highly aggressive disease characterized by skin and bone marrow involvement, with secondary sites including lymph nodes and viscera. BPDCN is associated with a poor prognosis, median overall survival of 8-14 months, and has no firm consensus for therapy. Tagraxofusp (TAG, SL-401) is currently the only approved first-line treatment for adult patients with BPDCN in Europe. TAG is a targeted therapy directed to CD123 that has shown efficacy in a controlled, prospective trial with prespecified endpoints. Specifically, TAG is a recombinant cytotoxin composed of human interleukin-3 fused to a truncated diphtheria toxin payload that targets CD123, the α-subunit of interleukin-3 receptor commonly overexpressed on the surface of BPDCN tumor cells. In the past, most adult and pediatric patients in Europe were treated with a plethora of experimental combination chemotherapies often imported from aggressive myeloid and lymphoid malignancy treatment regimens, followed by hematopoietic stem cell transplantation (SCT), as best available treatment. However, there is no robust evidence of the effectiveness and safety of these therapies for BPDCN, due to its rarity, the absence of prospective studies, and the variability in diagnostic criteria, definition of endpoints, and assessment of outcomes. As of July 2021, 65 patients with BPDCN have been treated with TAG in a clinical setting outside the US, as part of an expanded access program. Continued collection of clinical data from the use of TAG in a real-world setting in patients with BPDCN is important to increase the knowledge of clinical outcomes, especially in patient populations commonly underrepresented in clinical trials. This is the first real-world evidence prospective registry in patients with BPDCN receiving TAG. The study is designed to meet the requirements included in the marketing authorization by the European Commission, to further investigate the effectiveness and safety of TAG in the treatment of patients with first-line or relapsed/refractory BPDCN. Study Design and Methods This is a noninterventional, single-arm study (EudraCT: 2021-001684-24) in patients with BPDCN to assess clinical effectiveness and safety of TAG under real-world routine clinical practice conditions (12 mcg/kg intravenously [IV] once daily on days 1-5 of a 21-day cycle, per the summary of product characteristics general recommendation). Up to 125 patients are planned for inclusion in approximately 65 clinical sites in Europe estimated over 3 years. Eligible patients have a diagnosis of BPDCN and are scheduled to start TAG monotherapy, per physician's decision. The primary study objectives are to determine the complete response (CR) rate, defined as CR + clinical CR (CR with residual skin abnormality not indicative of active disease) after 3 months of treatment, and to assess the safety of TAG, in particular the incidence and severity of capillary leak syndrome (CLS). Secondary objectives include analysis of the rate of patients bridging to SCT, progression-free survival, overall survival, best overall response, duration of response, dose interruptions/administration of IV albumin supplementation in patients with CLS or CLS symptoms, incidence and severity of adverse events of special interest (AESIs), overall safety, and TAG treatment administered. AESIs include CLS and hepatic, renal, and cardiac events. Per routine clinical practice, quarterly data collection is anticipated during the study. In addition, data will be collected at screening, enrollment, early discontinuation, and study end (Figure). The end of the registry safety data collection will be 18 months after the last enrolled patient's first visit (LPFV). Interim analyses will be performed annually, and an effectiveness interim analysis is scheduled at 12 months post-LPFV. All effectiveness and safety analyses will be performed using descriptive statistics. Survival data will be summarized using the Kaplan-Meier method. Subgroup analyses for effectiveness and safety may be performed, on the basis of gender, age, or Eastern Cooperative Oncology Group performance status at baseline. Enrollment is planned to start by December 2021. Figure 1 Figure 1. Disclosures Platzbecker: Celgene/BMS: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Geron: Honoraria. Angelucci: Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Montesinos: Glycomimetics: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: 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, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy. Lemoni: AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Spyridonidis: Menarini: Current Employment. Casariego: Menarini: Current Employment. Mughal: Stemline: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press, Informa: Other: financial benefit and/or patents . Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is a standard of care for adults with high-risk acute lymphoblastic leukemia (ALL) in first or subsequent complete remission (CR). Myeloablative total body irradiation (TBI) combined with cyclophosphamide (Cy) is the most frequently used conditioning regimen. In order to reduce toxicity Cy may be replaced by fludarabine (Flu). The goal of this registry-based, retrospective study was to compare outcomes of allo-HCT following TBI/Cy vs. TBI/Flu conditioning. PATIENTS AND METHODS: Included in the analysis were 2255 patients aged 18-65 years, treated with allo-HCT from either a matched sibling (43%) or unrelated (57%) donor in CR1 (83%) or CR2 (17%), between the years 2010-2020. Patients with Ph(-) B-ALL, Ph(+) B-ALL, and T-ALL were represented in equal proportions. TBI 12Gy + Cy was used in 2105 cases while TBI 12Gy + Flu was administered to 150 patients. Patients treated with TBI/Flu were significantly older (median 35 years vs. 33 years, p=0.006), with poorer Karnofsky performance score ( RESULTS: Engraftment rate was 99% for both TBI/Cy and TBI/Flu patients. In a univariate analysis the use of TBI/Cy as compared to TBI/Flu was associated with a tendency to reduced incidence of relapse (24% vs. 29% at 2 years, p=0.1), increased incidence of grade 2-4 acute graft versus host disease (GVHD, 35.5% vs. 28%, p=0.08) and improved leukemia-free survival (LFS, 62% vs. 57%, p=0.18). The rates and causes of non-relapse mortality (NRM) did not differ significantly between the two conditioning groups. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with reduced risk of relapse (HR=0.69, p=0.049) and increased risk of grade 2-4 acute GVHD (HR=1.57, p=0.03) without significant effect on other transplantation outcomes. An additional analysis was performed with TBI/Cy treated patients (n=132) matched strictly to those treated with TBI/Flu (n=132) in terms of disease subtype, disease status and donor type with the nearest neighbor for patient age, patient and donor sex, in vivo T-cell depletion, Karnofsky score and source of stem cells; the use of TBI/Cy as compared to TBI/Flu was associated with significantly reduced rate of relapse (18% vs. 30% at 2 years, p=0.015) and a tendency to an improved LFS (65% vs. 59%, p=0.07) and overall survival (OS, 73% vs. 68%, p=0.16) without effect on NRM and GVHD. CONCLUSIONS: The use of myeloablative TBI/CY as conditioning prior to allo-HCT for adult patients with ALL in CR1 or CR2 is associated with stronger anti-leukemic effect leading to significantly lower relapse rate compared to TBI/Flu and therefore should be likely considered a preferable regimen. Disclosures Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Labopin: Jazz Pharmaceuticals: Honoraria. Socie: Alexion: Research Funding. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Huynh: Jazz Pharmaceuticals: Honoraria. Spyridonidis: Menarini: Current Employment. Perić: therakos: Honoraria; servier: Honoraria; MSD: Honoraria; Astellas: Honoraria; NOVARTIS: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria. Mohty: Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria.

Background: Treosulfan has been increasingly used in reduced toxicity regimens, especially in older or frail patients. Different doses of treosulfan plus fludarabine have shown an advantage over reduced intensity regimens, confirmed by a randomized phase 3 trial utilizing treosulfan 30 g/m² (or FT10) in the majority of patients. However, data comparing fludarabine with higher doses of treosulfan (FT14) to fludarabine combined with myeloablative doses of busulfan are limited. Aims: We compared outcomes between treatment alternatives of similar conditioning intensity: FT14 (fludarabine 150 or 160 mg/m 2 and treosulfan 42g/m 2, or FT14) over FB4 (fludarabine 150 or 160 mg/m 2 and busulfan 12.8 mg/kg). Methods: We retrospectively studied consecutive patients from the European Society for Blood and Marrow Transplantation (EBMT) registry, meeting the following inclusion criteria: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated or sibling donor between 2010-2020, c) HSCT at first or second complete remission (CR), d) conditioning regimen with either FT14 or FB4. Patients with ex vivo manipulated grafts were excluded. A sub-group analysis was performed according to age ( Results: In total, 2703 patients were included in the analysis comprising 2025 (75%) transplanted with FB4, and 678 (25%) with FT14. In the sub-group of patients younger than 55 years (n=1676), FT14 recipients (n=236) had a significantly increased age (p Similar differences in patient characteristics were observed in patients aged ≥55 years (n=1027). FT14 recipients (n=442) had a significantly increased age (p Conclusion: With the limitations of a retrospective analysis, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients with AML transplanted in first or second CR. The same was not true for older patients (≥55 years). It should also be noted that FT14 has been selected by treating physicians for higher risk HSCT, including patients who are older, have secondary disease, adverse cytogenetics, and unrelated donors. Therefore, further studies are needed to determine the optimal conditioning regimen for such patient populations. Figure 1 Figure 1. Disclosures Gavriilaki: Alexion, Omeros, Sanofi Corporation: Consultancy; Gilead Corporation: Honoraria; Pfizer Corporation: Research Funding. Labopin: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Hilgendorf: Novartis: Honoraria; AbbVie: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Support; Celgene: Other: Travel Support; SanofiGenzyme: Other: Travel Support. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Mielke: Gilead/KITE: Other: Travel support, Expert panel ; Novartis: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Celgene/BMS: Speakers Bureau. Zuckerman: AbbVie: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; BioSight Ltd: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Cellect Biotechnology: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Spyridonidis: Menarini: Current Employment. Mohty: Astellas: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria.

Background: Blinatumomab is approved for the treatment of adult patients (pts) with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukaemia (R/R Ph- BCP-ALL). We present interim 3-year results of a multi-country observational study in R/R Ph- BCP-ALL pts, including the subset with late first relapse (LFR, defined as first remission duration of ≥12 months [mos]). LFR pts were excluded from the pivotal studies of R/R Ph- BCP-ALL and data is limited on blinatumomab treatment outcomes in this population. Methods: This study included adult pts who initiated blinatumomab between 22 March 2017 and 12 February 2020 in routine clinical practice. Pts who received blinatumomab in a clinical trial or an expanded access program were excluded. Informed consent was sought according to local guidelines. Data was extracted from medical records: pts were categorized as LFR by the treating clinicians. Pts were followed-up until data cut-off date, death, loss-to-follow-up, or withdrawal: whichever came first. Denominators of percentages excluded pts with missing data unless indicated. Kaplan-Meier (KM) estimates were calculated to investigate survival outcomes at 24 mos: relapse-free survival (RFS) defined as the interval between complete remission with full/partial/incomplete recovery of peripheral blood counts (CR/CRh/CRi) and relapse (bone marrow blasts >5%) or death; and overall survival (OS) defined as the interval from blinatumomab initiation to death. Cumulative Incidence Function (CIF) estimates were calculated for: mortality (independent of relapse) following allogeneic haematologic stem cell transplant (alloHSCT), and relapse (independent of unrelated death) after alloHSCT. Results: A total of 118 R/R Ph- pts were included: median age was 45.5 years (interquartile range [IQR]: 29.0, 58.0) with 47.5% (n=56) being female. For the subset of R/R Ph- pts with LFR (n=38), median age was 34.5 years (IQR: 23.0, 50.0) with 50.0% being female. Among all pts: 22% (n=26) had previous HSCT (28.9% [n=11] in the LFR subset), 100% (n=118) were treated with ≥1 prior anti-cancer therapy, 42.4% (n=50) underwent first salvage, 8.5% (n=10) second salvage, and 0.8% (n=1) third salvage. Within 2 blinatumomab cycles, 73.7% (n=87) R/R Ph- pts achieved CR/CRh/CRi: among CR/CRh/CRi pts with evaluable minimal residual disease (MRD, n=44), 45.5% had MRD response (Table). The majority (78.5%, n=62) of pts proceeded to alloHSCT, of whom 64.5% (n=40) had achieved CR/CRh/CRi and had no additional myelosuppressive therapy (Table). The KM estimates for RFS and OS at 24 mos were 50.0% (95% confidence interval [CI]: 37.0, 62.0) and 58.0% (95% CI: 46.0, 68.0), respectively. In pts who achieved CR/CRh/CRi and had no additional therapy before proceeding to alloHSCT, the CIF estimates for relapse and mortality at 1 year following alloHSCT were 8.0% (95% CI: 2.0, 20.0) and 13.0% (95% CI: 5.0, 26.0) respectively. In the LFR subset, 78.9% (n=30) achieved CR/CRh/CRi within 2 cycles: among evaluable pts (n=15) 73.3% (n=11) had MRD response (Table). Most pts (83.3%, n=25) proceeded to alloHSCT, of whom 77.3% (n=17) had achieved CR/CRh/CRi and had no additional myelosuppressive therapy (Table). At 24 mos, the KM estimates for RFS and OS were 70.0% (95% CI: 47.0, 85.0) and 74.0% (95% CI: 51.0, 87.0), respectively. In pts who achieved CR and proceeded to alloHSCT without other therapy, the CIF estimates for relapse and mortality at 1 year were both 7.0% (95% CI: 0.0, 27.0). Among R/R Ph- pts, 89.8% (n=106) had adverse events (AEs) occurring between blinatumomab initiation and ≤30 days following the final infusion, 36.4% (n=43) reported serious AEs (SAEs) and 5.9% (n=7) fatal events: 1 fatal AE was blinatumomab-related. AEs were reported in 86.8% of LFR pts (n=33), and 28.9% (n=11) of pts experienced an SAE (no fatal events occurred). In both subgroups, the most commonly reported AEs (in >34% of pts) were infusion reactions (including cytokine release syndrome), serious infections, and neurological events (Table). Conclusion: In real-world clinical practice, blinatumomab was an effective therapy in pts with R/R Ph- ALL including those with LFR. Almost three quarters of pts achieved CR/CRh/CRi within two cycles. Most pts proceeded to alloHSCT, the majority in CR/CRh/CRi and without additional myelosuppressive therapy. The safety data are consistent with the established safety profile of blinatumomab. Disclosures Rijneveld: Servier: Research Funding; Amgen: Research Funding. Fracchiolla:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses. Šálek:Amgen: Consultancy, Honoraria, Research Funding. Chiaretti:Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Alam:Amgen: Current Employment, Current equity holder in publicly-traded company. Pezzani Grueter:Amgen: Current Employment, Current equity holder in publicly-traded company, Other: Travel, accommodations, expenses. Mohammad:Amgen: Current Employment, Current equity holder in publicly-traded company. Kormany:Amgen: Current Employment, Current equity holder in publicly-traded company. Kreuzbauer:Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi:Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company).

It is frustrating that after more than 3 decades, we still don’t know the optimal graft-versus-host disease (GVHD) prophylaxis regimen. In this issue of Blood, Kanakry and coworkers report on posttransplantation cyclophosphamide (PTCy) as a single-agent GVHD prophylaxis in HLA-matched bone marrow transplantation (BMT) and include an analysis of how much additional immunosuppressive therapy the patients eventually required.1

Introduction: ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats) activity remains a key tool in differential diagnosis of thrombotic microangiopathies (TMAs). However, ADAMTS13 testing is not readily available in many hospitals. Recently, PLASMIC and PLASIC scores have been developed to facilitate rapid recognition of TTP. We aimed to evaluate their usefulness compared to ADAMTS13 testing in a real-world cohort of TMA patients. Methods: We enrolled consecutive patients with samples referred to our Center for ADAMTS13 measurement due to TMA over the last 2 years. Samples were collected either at first diagnosis or relapse before initiation of treatment. ADAMTS13 activity was measured with a commercially available and validated ELISA kit (Technozym, Diapharma). Clinical data were retrospectively collected from referring centers. Management was based on treating physicians' decisions. TTP was defined as severe ADAMTS13 deficiency (activity≤10%); while secondary TMAs were diagnosed in patients with cancer, connective tissue disorders or hematopoietic cell transplantation recipients (transplant-associated TMA). Atypical hemolytic uremic syndrome (aHUS) remained a diagnosis of exclusion in patients with ADAMTS13>10%. PLASMIC was calculated based on seven variables: platelets, hemolysis, cancer, transplant, MCV, INR, creatinine; while MCV was not included in PLASIC, as previously described. ROC curve analysis was performed to determine the sensitivity and specificity of scores. Multivariate binary or logistic regression models were performed when appropriate. Results: We studied 50 TMA patients. Combined clinical and laboratory data conferred the following TMA classification: TTP in 36 patients (72%), transplant-associated TMA in 7 (14%), other secondary TMA in 5 and aHUS in 2. PLASMIC score was intermediate in 2 and high in another 4 patients without TTP. The PLASIC score was high in 5 patients without TTP, leading to less false positive results compared to PLASMIC (p Plasma exchange was commenced in the majority of patients (42/50, 84%). Among TTP patients, the majority (77%) received rituximab as salvage or prophylactic treatment. Rituximab administration was associated with platelet (p=0.003) and ADAMTS13 (p=0.015) levels at diagnosis. The complement inhibitor eculizumab was administered in 3 patients with TA-TMA, who achieved TMA resolution. With a median follow-up of 2.9 years (range 0.3-26.3), overall survival was significantly lower in patients with secondary TMAs (p Conclusion: PLASMIC and PLASIC scores are excellent tools in TMA patients without secondary causes. While PLASMIC and PLASIC scores conferred similar outcomes, the PLASIC score requires six instead of seven variables, is classified as low/high omitting the intermediate category and leads to less false positive results. Further validation of the PLASIC score might confirm its clinical value. In addition, the role of ADAMTS13 levels in guiding rituximab administration needs to be further investigated. When an underlying etiology is detected, ADAMTS13 testing is necessary to exclude TTP and facilitate further therapeutic decisions. Figure 1 Disclosures Panayiotidis: Bayer: Other: Support of clinical trial.

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). In light of encouraging results by complement inhibition treatment, a few studies and case series have reported complement-related genetic variants in patients with TA-TMA. However, several issues remain undisclosed, regarding both the incidence of such variants and the clinical importance of pre-transplant genetic profiling. Within this context, we hypothesized that pre-transplant genetic susceptibility is evident in adult TA-TMA patients but not in their donors or control transplanted patients and also investigated the association of genetic variants with response to treatment and survival. Methods: To this end, we enrolled consecutive adult allogeneic HCT recipients diagnosed with TA-TMA according to the International Working Group criteria between 2014-2017. Patients were managed based on institutional policy with conventional treatment including withdrawal of calcineurin or mTOR inhibitors, steroid administration and/or plasma infusion/plasma exchange. To test our hypothesis, we also studied donors of the enrolled patients with available samples and age- and sex-matched control HCT recipients. Genomic DNA was extracted from pre-transplant peripheral blood samples of TA-TMA patients, donors and controls. Probes were designed using the Design studio (Illumina). The amplicons cover the exonic regions of complement regulatory genes (complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, CD46, thombomodulin/THBD) and TMA-associated ADAMTS13, spanning 15 bases into the intronic regions. After quality assessment, each sample was treated independently in order to produce the appropriate mapping of the reads against the human reference genome hg19. Variant calling was performed using the Genome Annotation Toolkit and variant annotation using annovar together with supplemental databases. Variants with minor allele frequency lower than 1% were considered rare. Results: We studied 30 patients that presented TA-TMA at median + 73 (9-540) days with full hematopoietic constitution, 18 donors of our patients and 30 controls, without significant differences in transplant characteristics (Table). Donors of patients presented significantly lower number of detected (p=0.039) and rare (p=0.049) variants per sample, as well as variants in exonic, splicing or UTR regions (p=0.025) compared to TA-TMA patients. In control patients, we also observed a significantly lower number of rare variants in ADAMTS13 (p=0.002), CD46 (p=0.001), CFH (p=0.010), CFI (p=0.031) and CFB (p=0.016) compared to TA-TMA patients (Graph). Variants previously reported to be pathogenic in TMAs were found in ADAMTS13 and CFB. While heterozygous pathogenic mutations were present in both TA-TMA and control samples, homozygous pathogenic mutations were evident only in 4 TA-TMA patients (p=0.038). Regarding clinical outcomes, 21 of 30 TA-TMA patients (70%) were refractory to conventional treatment. Refractory patients presented a significantly increased incidence of variants in exonic, splicing or UTR regions (p=0.045) compared to responders. 12 patients received eculizumab based on institutional policy. Despite initial laboratory response to eculizumab treatment, only 4 of 12 survived. 19 out of 30 patients succumbed to treatment-related mortality, which was also associated with significantly increased number of variants in exonic, splicing or UTR regions (p=0.012). Conclusions: Increased incidence of pathogenic, rare and exonic variants in TA-TMA patients supports a relevant role for genetic susceptibility that is not evident in control HCT recipients or patients' donors. This, combined with the finding that exonic variants were associated with refractoriness to treatment and increased mortality, indicates that pre-transplant genetic profiling may be useful to intensify monitoring and early intervention in high-risk patients. In this complex setting, the functional and clinical role of genetic variants needs to be further investigated in prospective studies. Disclosures Gavriilaki: European Hematology Association: Research Funding. Stamatopoulos:Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Background and study design. Reduced intensity conditioning transplantation (RICT) is a commonly applied treatment option for AML patients >50 years of age. Prospective, controlled studies comparing RICT with standard chemotherapy are warranted. In this study, we aimed to prevent selection biases. Thus, patients were included prior to HLA typing of potential sibling donors, and statistical analyses were based on an intention-to-transplant, donor versus no-donor approach. Hence, the analyses also include events occurring during the donor search period and also the transplantation procedures along with post-transplant events. Patients and procedures. Between 2003 and 2016, 163 patients with AML in CR1 were included in Canada (n=69), Sweden (n=63), and Germany/Finland/Norway/New Zealand (n=31). Eighteen patients were excluded due to enrolment after the start of donor typing (n=14), lack of data (n=1), low-risk AML (n=2) or withdrawn consent (n=1). Thus, results from 145 patients with high (n=48) or intermediate (n=97) risk disease were available for analysis. Included patients were a median of 63 (50-70) years old, deemed fit for RICT and had at least one willing and healthy but not yet HLA typed sibling. The ensuing HLA typings thus yielded one RICT group including patients with ≥1 confirmed matched sibling donor (MSD), and one control group with no MSD. Date of inclusion was defined as date of HLA typing of the first potential MSD. The protocol-specified conditioning regimen for RICT was fludarabine (150-180 mg/m2) and busulfan (8 mg/kg orally or 6.4 mg/kg i.v., used in 95% of patients). Immunosuppression was ciclosporin alone (9%), with methotrexate (53%) or with MMF (35%). Peripheral blood stem cells were used in 95% of transplantations. Control patients received consolidation chemotherapy as per local routines. Statistics. Baseline factors were compared between study groups using Fisher´s exact test and rank sum tests. The primary endpoint was overall survival (OS) with secondary endpoints of relapse-free survival (RFS), relapse incidence (RI) and non-relapse mortality (NRM). Kaplan-Meier curves were used to estimate OS and RFS and cumulative incidence functions were used to estimate NRM and RI considering competing risks. The logrank test was employed for group comparisons of event rates with time censored at 5 yrs post inclusion. Results. The median follow-up time of surviving patients was 7.9 (0.24-14) yrs. Age, AML risk group and time from CR to inclusion did not differ between the study groups. Time lag from diagnosis to study inclusion was 65 (32-256) days (Controls) and 64 (29-319) days (RICT), P=0.74, Mann-Whitney test. Time from CR1 to inclusion was 22 (0-218) days (Controls) and 19 (0-131) (RICT). Excluding conditioning, patients in the RICT group received fewer chemotherapy cycles than controls. The time from start of last chemotherapy to transplant was median 63 (36-212) days. The incidence of acute (grade 2-4) and chronic extensive GvHD in transplanted patients was 25% and 39%, respectively. The non-relapse mortality at 3 years post inclusion (Table) was 12% (RICT group) and 4% (Controls). Causes of death was primarily AML, accounting for 73% and 88% of all deaths in the RICT and control groups, respectively. Twenty pts with an identified donor did not reach RICT due to relapse (n=12), co-morbidities (n=5), death (n=2), other (n=1). Total mortality at time of analysis was slightly lower in the RICT group (66% vs 75%). Overall survival (primary endpoint) at 3 years was 45% (CI 33-56) and 48% (36-60), in RICT and control groups, respectively. At 10 years after inclusion, OS in study groups were similar; RICT 27% (CI 15-41), Control 25% (CI 15-36). There were no significant differences between study groups with respect to primary or secondary endpoints (OS: P=0.27, RFS:P=0.98, RI: P=0.50, NRM: P=0.10, logrank tests. Figure). Conclusions. Applying an intention-to-treat analysis we did not demonstrate clinical benefit of sibling donor search and stem cell transplantation after a reduced intensity busulfan/fludarabine based regimen in AML patients ≥50 years in CR1. Early relapse was the main reason for preventing transplants in patients with an identified donor. Support from study groups: Canadian BMT Group, Australasian Leukaemia and Lymphoma Group, Norwegian/Swedish BMT Group, Swedish AML group Disclosures Kiss: Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wallhult:Jazz Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau; Daichii-Sankyo: Speakers Bureau. Finke:Riemser: Consultancy, Honoraria, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Sabloff:Celgene: Membership on an entity's Board of Directors or advisory committees.

Malignant cell contamination in autologous transplants is a potential origin of tumor relapse. Ex vivo expansion of CD34+ blood progenitor cells (BPC) has been proposed as a tool to eliminate tumor cells from autografts. To characterize the influence of culture conditions on survival, growth, and clonogenicity of malignant cells, we isolated primary mammary carcinoma cells from pleural effusions and ascites of patients with metastatic breast cancer and cultured them in the presence of stem cell factor (SCF), interleukin-1β (IL-1β), IL-3, IL-6, and erythropoietin (EPO), ie, conditions previously shown to allow efficient ex vivo expansion of CD34+ BPC. In the presence of serum, tumor cells proliferated during a 7-day culture period and no significant growth-modulatory effect was attributable to the presence of hematopoietic growth factors. When transforming growth factor-β1 (TGF-β1) was added to these cultures, proliferation of breast cancer cells was reduced. Expansion of clonogenic tumor cells was seen in the presence of SCF + IL-1β + IL-3 + IL-6 + EPO, but was suppressed by TGF-β1. Cocultures of tumor cells in direct cellular contact with hematopoietic cells showed that tumor cell growth could be stimulated by ex vivo expanded hematopoietic cells at high cell densities (5 × 105/mL). In contrast, culture under serum-free conditions resulted in death of greater than 90% of breast cancer cells within 7 days and a further decrease in tumor cell numbers thereafter. In the serum-free cultures, hematopoietic cytokines and cellular contact with CD34+ BPC could not protect the tumor cells from death. Therefore, ex vivo expansion of CD34+ BPC in serum-free medium provides an environment for efficient purging of contaminating mammary carcinoma cells. These results have clinical significance for future protocols in autologous progenitor cell transplantation in cancer patients.

Tumor cells have been found in autologous hematopoietic cell transplants used after high-dose chemotherapy. To specifically eliminate contaminating mammary tumor cells during ex vivo expansion of CD34+ hematopoietic progenitor cells, we used recombinant immunotoxins (ITs) directed against cell-surface antigens expressed on mammary carcinoma cells. ITs were expressed from fusion cDNAs combining a single-chain antibody fragment (scFv) directed against the Erb-B2 or epidermal growth factor (EGF) receptors with a truncatedPseudomonas exotoxin A fragment devoid of its cell-binding domain. CD34+ hematopoietic progenitor cells did not express Erb-B2 and EGF receptors as detected by Western blotting. Ex vivo expansion of total hematopoietic cells or of colony-forming cells from CD34+ progenitors in the presence of stem-cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (Epo) was not affected when ITs were added to the cultures. In contrast, MDA-MB 453 and MCF-7 mammary carcinoma cells were depleted in a dose- and time-dependent manner by more than 3 log in coculture with CD34+ cells over a period of 7 days in the presence of 100 to 1,000 ng/mL of anti–Erb-B2 IT. This included elimination of the subpopulations with regrowth potential. Similarly, addition of either anti–Erb-B2 or anti-EGF receptor ITs to primary breast cancer cells isolated from patients with metastatic disease resulted in elimination of cytokeratin-positive cells in seven of seven samples. ITs are highly efficient and convenient to use for the depletion of mammary tumor cells during ex vivo expansion of hematopoietic progenitor-cell autografts.

Background: Allogeneic stem cell transplant (SCT) recipients suffer from a defective T cell mediated immunity causing potentially fatal reactivation of latent viruses. After T cell depleted SCT we have observed over 80% CMV reactivation and significant additional costs ($58-74k/patient). Despite aggressive monitoring and pre-emptive therapy, reactivation and/or positive CMV serology brings a significantly higher risk for non-relapse mortality (NRM). Adoptive transfer of ex vivo generated virus specific donor T cells is effective as a treatment of infection post-SCT but it has not been tested as a prophylaxis of early reactivation. Here in a Phase I study we transferred multi-virus specific T cells (MVSTs) immediately post SCT, targeting CMV, Ebstein-Barr virus (EBV), BK and adenovirus (Ad) as a novel strategy to prevent viral reactivation in the recipients of T cell depleted sibling HLA-matched SCT. Methods: Subjects were eligible if enrolled in HLA-matched T cell depleted transplant protocol (13-H-0144) and deemed at risk for CMV reactivation. MVST cells were manufactured from SCT sibling donors. Elutriated lymphocytes were stimulated with autologous dendritic cells (DCs) pulsed with seven overlapping peptide libraries (pepmixes) spanning the length of immunodominant proteins from CMV (pp65 and IE1), EBV (BZLF1 and EBNA1), BK (LT and VP1) and Ad5. Cultures were maintained in G-Rex flasks for 14 days in presence of IL-7, IL-15 and IL-2 (after 72hrs), tested for sterility, phenotype, potency and cryopreserved. MVST cells were thawed and administered intravenously as early as possible (day 0 to +60) post SCT. A Phase I 3+3 dose escalation design was used at the following dose levels: Cohort 1 - 1x10e5 total nucleated cells (TNC)/kg, Cohort 2 - 5x10e5 TNC/kg, Cohort 3 - 1x10e6 TNC/kg. The primary safety endpoint at day 42 post infusion was the occurrence of dose limiting toxicity (DLT), (Grade IV GVHD or any other severe adverse even (SAE) deemed to be at least "probably" or "definitely" related to the MVST infusion. Patients were followed to day +100 post SCT for secondary outcomes, including efficacy (Figure) and immune reactivity (for donor/recipient pairs). Results: MVST cells recognized the majority of pepmixes, were polyfunctional and robustly proliferated in response the cognate antigens, but minimally against allogeneic targets- suggesting a limited ability to induce GVHD. CDR3 sequencing of T cell repertoire showed a significant reduction in diversity and a striking dominance of a limited number of clonotypes in the final MVSTs. Nine subjects were enrolled and treated with MVST cells. MVSTs were successfully generated for all subjects, meeting the release criteria. Median time from SCT to MVST administration was 16 days (range D +6 to +52 post-SCT). Two subjects received MVST after day +30 due to cardiac instability and scheduling. There were no immediate infusion-related adverse events or DLT by day 42. One subject in cohort II developed a self-limiting grade I cytokine release syndrome in the setting of low-level EBV reactivation. One patient (cohort 1) developed de novo grade III aGVHD post-MVST infusion. CMV reactivation post-MVST occurred in 4 out of 8 evaluable subjects (50%) who completed D+100 post-SCT vs. 45 out of 52 patients (50% vs 87%; p value=0.031) in a historical cohort of recipients of T cell depleted SCT. In all cases CMV reactivation occurred during treatment with high dose steroids. In two cases MVST were generated from CMV seronegative donors and showed minimal activity against pp65 and IE1. In eight evaluable subjects who reached D+100 post-SCT there was no EBV-related disease, but we saw self-limiting low level EBV replication in 6 out of 8 cases. There were no cases of BK or Ad-related disease or viremia. ELISPOT analysis at D+100 revealed robust reconstitution of anti-viral immunity in analyzed recipients (vs. donors, Figure, B) Conclusions: This is the first report demonstrating that it is safe and feasible to use adoptively transferred allo-MVST immediately post-SCT to rapidly reconstitute anti-viral immunity and ameliorate the detrimental impact of the early viral reactivation in SCT recipient. No DLTs were seen. MVSTs had a markedly reduced allo-reactivity and carried a minimal risk of GVHD. Our results also suggest efficacy of this strategy in reducing viral reactivation. A Phase II portion of this study is currently enrolling patients. Figure. Figure. Disclosures Sabatino: Kite: Employment, Equity Ownership.

We have previously reported on the efficacy of the JAK1/2 inhibitor ruxolitinib in corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) in 95 patients (pts) (Leukemia 2015;29(10):2062-8). To assess long-term follow-up results, we collected data from the same pts treated in 19 centers in Europe and the US. Pts were classified as SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). Median numbers of pre-ruxolitinib GVHD treatment lines were 3 (1-7) and 3 (1-10) for SR-aGVHD and SR-cGvHD, respectively. The median follow-up was 19 and 24 months for aGVHD and cGVHD, respectively. The 1-year overall survival (OS) from was 62.4% (CI: 49.4%-75.4%) and 92.7% (CI: 84.7%-100%) for SR-aGVHD and SR-cGvHD, respectively. The estimated median OS (50% death) was 18 months for aGVHD and not reached for cGVHD patients. The median duration of ruxolitinib treatment was 5 and 10 months for patients with SR-aGVHD and SR-cGVHD, respectively reflecting the different biology of the diseases. At follow-up, 22/54 (41%) of SR-aGVHD patients and 10/41 (24%) of SR-cGVHD patients have an ongoing response and are free of any immunosuppression. GVHD relapse or progression after achieved PR/CR was observed in 14/45 (31%) and 13/36 (36%) patients with SR-aGVHD and SR-cGVHD, respectively. Response to re-treatment with Ruxolitinib or any immunosupressive therapy was seen in 11/14 (78%) and 11/13 (86%) patients with SR-aGVHD and SR-cGVHD, respectively. Cytopenia (any grade) and CMV-reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. These findings extend our previous report by showing that patients with SR-aGVHD and SR-cGVHD may benefit long-term from ruxolitinib treatment with an OS that is relatively high for steroid-refractory GVHD. GVHD-relapse or GVHD-progression rates were moderate and more than 75% of the relapse/progression patients responded to re-treatment with ruxolitinib or other immunosuppression. Disclosures Meyer: Stanford University: Patents & Royalties. Marks:Pfizer: Honoraria. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Kobbe:Celgene: Honoraria, Other: travel support, Research Funding; Jansen: Honoraria, Other: travel support. Negrin:Stanford University: Patents & Royalties. Brune:Meda Pharma: Consultancy. Mielke:JAZZ Pharma: Speakers Bureau; Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Gilead: Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau. Kuball:Gadeta B.V,: Membership on an entity's Board of Directors or advisory committees. Kröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Peschel:MophoSys: Honoraria. von Bubnoff:BMS: Honoraria; Amgen: Honoraria; Novartis: Honoraria, Research Funding.

Toxicity-reduced conditioning is being used for allogeneic stem cell transplantation in older and/or comorbid patients. We report on the treatment of 133 patients (median age: 55.6 years [23-73 years]) with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS; n = 81), myeloproliferative syndromes (MPS; n = 20), and lymphoid malignancies (n = 32) using conditioning with FBM: fludarabine (5 × 30 mg/m2), 1,3-bis(2-chloroethyl)-1-nitrosourea (or carmustine, BCNU; 2 × 200 mg/m2), and melphalan (140 mg/m2). Patients 55 years or older received fludarabine with reduced BCNU (2 ×150 mg/m2) and melphalan (110 mg/m2). After engraftment, chimerism analyses revealed complete donor hematopoiesis in 95.7% of patients. With a median follow-up of 58.5 months, 3- and 5-year overall survival (OS) was 53.0% and 46.1%, event-free survival (EFS) was 46.4% and 41.9%. No significant differences in OS and EFS were evident considering disease status (early vs advanced), patient age (

Background: Allogeneic hematopoietic cell transplantation is a potentially curative therapy for patients with hematological malignancies. However a fraction of patients will develop corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) which both cause a high mortality and impaired quality of life. Pre-clinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib by modification of T cells and dendritic cells. Methods: In this retrospective analysis, 19 stem cell transplant centers in Europe and the United States reported clinical outcome data from 95 patients who had received ruxolitinib as salvage-therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grade III or IV) or SR-cGvHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGvHD (1-10). The median follow-up times were 26.5 (3-106) for SR-aGVHD and 22.4 (3-135) weeks for SR-cGVHD-patients. Results: The ORR was 81.5% (44/54) in SR-aGVHD including 25 CRs (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). The median time to response was 1.5 (1-11) and 3 (1-25) weeks after initiation of ruxolitinib treatment in SR-aGVHD and SR-cGVHD, respectively. Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3%-90.7%,95% CI) and 97.4% (92.3%-100%,95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and CMV reactivation were observed during ruxolitinib-treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Relapse of the underlying malignancy occurred in 9.3% (5/54) and 2.4% (1/41) of the patients with SR-aGVHD or SR-cGVHD, respectively. Conclusion: Ruxolitinib constitutes a promising new treatment option for SR-aGVHD and SR-cGVHD. Its activity in SR-aGVHD and SR-cGVHD should be validated in a prospective trials in both, SR-aGvHD and cGvHD. Disclosures Bertz: GILEAD Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bug:TEVA Oncology, Astellas: Other: Travel Grant; NordMedica, Boehringer Ingelheim, Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis: Research Funding.

Background Thiotepa is an alkylating compound with an effective antineoplastic activity that was used in the past mainly for solid tumors and lymphoma, partially due to its ability to penetrate the blood-brain-barrier. Moreover, beside its myelosupressive activities, thiotepa has immunosuppressive properties making it an attractive agent to be used in the conditioning pre-transplantation. In the current retrospective registry study, we analyzed thiotepa-based conditioning regimen for allo-HSCT in adult patients with ALL using the EBMT ALWP database. Methods Inclusion criteria were: adults with de novo or secondary ALL who underwent first allo-HSCT between 2000 and July 2014 with a thiotepa-based regimen. Donors were either HLA-matched siblings or matched unrelated donors. Haploidentical and cord blood transplantations were excluded as well as patients who received a previous allo-HSCT. Results A total of 323 patients with adult ALL were identified. Median age was 43 years (range, 18 - 76); 59% were males and 41% females. Disease status at allo-HSCT was CR1 in 48.9%, CR2 in 21.7%, CR3 in 6.2% and 23.2% of the patients had an active disease at time of transplant. Transplantation was performed from a HLA-matched sibling (49.8%) or a matched unrelated donor (51.2%). Sixty-five per cent of patients received a myeloablative and 35% a reduced-intensity conditioning regimen, respectively. Stem cell source was peripheral blood stem cells in 84% of the transplants, while 16% received bone marrow grafts. Neutrophil engraftment (defined as >0.5x109/L) was 98% with a median day of 15 (range, 2 - 41). Platelets engraftment (defined as >20x109/L) was 92% with a median day of 14 (range, 7 - 98). Incidence of acute GvHD (Grade> II) was 26.6%, while chronic GvHD occurred in 35.9% at one year (24.6% with extensive disease). With a median follow-up of 16.8 months, the non-relapse mortality was 12.4% and 25.3% at 100 days and one year, respectively. Relapse incidence at 1 year was 33.3%.The one-year leukemia-free survival and overall survival incidences were 57% and 66%. Table 1 shows the outcome according to donor and disease status at time of allo-HSCT. When looking for conditioning regimen more precisely, comparing thiotepa / busulfan ± melphalan (n=213) to thiotepa / other (n=110), higher relapse incidence at one year (34.9% vs 30.3%, p=0.016) and lower leukemia-free survival (38.8% vs 45.9%, p=0.0203), respectively were observed, without difference in non-relapse mortality (23.8% vs 26.3 %, n.s.) and overall-survival (59.6% vs 51.1%, p=0.109). Conclusion This large survey suggests that TTP-based conditioning therapy in adult ALL is feasible and effective, with main outcomes being comparable to literature published results achieved with other regimens. | | LFS, 1 year | p-value | OS, 1 year | p-value | Relapse, 100 days | Relapse, 1 year | p-value | NRM, 100 days | NRM, 1 year | p-value | | ------------------------------------- | ------------------ | ------- | ----------------- | ------- | ------------------------ | ---------------------- | ------- | -------------------- | ------------------ | ------- | | HLA- matched sibling | 49% | 0.0262 | 62% | 0.0133 | 13.1% | 31.9% | 0.4641 | 8.7% | 18.3% | 0.0042 | | matched unrelated donor | 33% | 46% | 15.2% | 34.7% | 16.2% | 32.1% | Table 1. Donor | | LFS, 1 year | p-value | OS, 1 year | p-value | Relapse, 100 days | Relapse, 1 year | p-value | NRM, 100 days | NRM, 1 year | p-value | | --------- | ------------------ | ------- | ----------------- | ------- | ------------------------ | ---------------------- | ------- | -------------------- | ------------------ | ------- | | CR1 | 49%