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The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation.Statement of SignificanceWe demonstrate diverse cellular origins of lineage switched relapse within MLL-AF4 pro-B acute leukaemia. Irrespective of the developmental origin of relapse, dysregulation of NuRD and/or other epigenetic machinery underpins fundamental lineage reprogramming with profound implications for the increasing use of epitope directed therapies in this high-risk leukaemia.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact ofABOlocus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, similar to 1.2), the A1 and B haplotypes are associated with an similar to 1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, similar to 0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. Figure 1 Figure 1. Disclosures Soria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.

Next-Generation Sequencing (NGS) has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia (AML). However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of 7 reference laboratories aimed to deliver molecular results to the clinics. We report the technical cross-validation results for NGS and clinical validation in 2960 AML samples. Three cross-validation rounds (CVR) were performed to establish consensus parameters for NGS analysis and variant reporting. In the first CVR we evaluated the starting situation of the NGS studies. In the second CVR the laboratory network established minimum quality parameters and consensus recommendations to guarantee a valid NGS assay. The third CVR strengthened the established parameters and refined the clinical variant classification. The clinical validation was performed in 2960 samples from 2703 patients: 1530 male and 1173 female with a median age of 67.5 years old. 2522 samples were collected at diagnosis, 275 at relapse and 163 at refractory AML from October 2017 to October 2019. NGS analysis was performed according to already implemented protocols and only variants accomplishing the established quality control parameters were considered. In the first CVR the error rate (ER) was 39% with a high variability in the studied genes. Then, 30 genes were agreed as key genes for AML pathogenesis: 8 were considered mandatory due to their implication in clinical guidelines, targeted therapy and risk stratification and the study of the remaining 22 was recommended based on panel availability (Table 1). In the second CVR the ER was reduced to 14.4% and the NGS quality metrics were 4032X of mean read depth and 98.3% of median uniformity. Therefore, the laboratory network established a minimum read depth of 500X and uniformity >85% as quality control parameters. Due to the high variability in the detection of low VAF variants (1 CVR: ER 8043 variants were reported in the 2960 samples, with 96.5% of patients showing at least 1 mutated gene. The mean number of variants per sample was 2.71 (range 0-9), the number of mutations in ≥65 years old patients (2.9 vs. 2.5, P At least 1 mutation in one of the 8 clinically relevant genes was detected in the 78.7% of patients: 39.8% of patients had targetable mutations (FLT3-ITD/TKD and IDH1/2 mutations) and 35.6% of patients, variants found in ASXL1, RUNX1 and TP53 were the only clinically relevant variant detected. The study of clonal evolution through paired-sample analysis showed that mutations in FLT3, KRAS, NRAS and PTPN11 were particularly unstable at relapse or refractoriness. We show the development of the first national strategy for validation of NGS studies with centralized analysis in an AML cooperative group. We have developed a laboratory network with standardized protocols to ensure technical quality and equity in access to NGS studies. The unification of analysis and interpretation criteria represents a significant increase in the quality of diagnostic tests and translational research. N/A-NI-AML-PETHEMA-007343, PI18/01340, PI19/00730, FI19/00059 Figure 1 Figure 1. Disclosures Ayala: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene: Honoraria. Tormo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perez-Simon: JANSSEN, TAKEDA, PFIZER, JAZZ, BMS, AMGEN, GILEAD: Other: honorarium or budget for research projects and/or participation in advisory boards and / or learning activities and / or conferences. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Montesinos: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; 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; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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; Pfizer: 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; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy.

Introduction and objective. Despite a high complete remission (CR) rate obtained with frontline therapy most adults with T-ALL eventually relapse. Although promising therapies are emerging, salvage options for T-ALL are currently limited. Little is known about outcome of patients (pts) with relapsed T-ALL (R T-ALL) treated with contemporary MRD-oriented trials. Our goal was to analyze the outcome of pts with R T-ALL included in two successive MRD-oriented trials (ALL-AR-03 and ALL-HR-11) from the Spanish PETHEMA Group. Methods. Retrospective study of R T-ALL adults diagnosed between 2003 and 2019 and included in the protocols ALL-AR-03 (NCT00853008) and ALL-HR-11 (NCT01540812). The clinical characteristics at baseline and at relapse, salvage therapies and outcomes (CR and OS) were analyzed and a study of prognostic factors for OS was performed. Results Forty-nine patients were identified (ALL-AR-03 [n=27], ALL-HR-11 [n=22]). Median age (range) at diagnosis was 29 (16-58) yrs, 38 males (78%), CNS involvement 6 (12%), mediastinal mass 30 (61%), WBC count 40.8 x109/L (0.6-351.0), early T-cell precursor 11 (23%), pre-T 8 (16%), cortical 16 (33%), mature 9 (18%), T unspecified 5 (10%). Post-induction-1 MRD level ≥0.1%: 14/42 (33%), ≥0.01%: 17/39 (44%). Nine pts (18%) required 2nd induction therapy (resistant disease after induction-1 [n=5], MRD≥0.1% after induction-1 [n=4]). Allogeneic HSCT in CR1: 8 pts. Interval CR1-relapse: 11.2 [0.1-36.7] months. Relapse was located in BM (n=20, 41%), BM+extramedullary (n=16, 33%) and extramedullary (n=13, 26%). CNS at relapse was involved in 18 pts (37%, isolated in 8 cases). Median number of rescue lineages was 2 (range 1-5). The most frequent first salvage schedules were FLAG-Ida (n=24, 49%), HyperCVAD (n=8, 16%) and nelarabine (n=4, 8%) (other schedules in 13 pts). Second CR was attained in 21/48 pts (44%). The patients with poor morphologic and/or poor MRD response after Induction-1 in first line therapy (n=9) did not respond to first salvage therapy (0/9 vs. 21/39, p=0.003). AlloHSCT was performed in 19 pts (15 in CR2) (HLA-identical sibling: 9, URD: 9, haploidentical: 1, myeloablative conditioning: 16). Thirty-nine pts died (progression: 27, toxicity of rescue regimens: 7, TRM: 5) and 9/10 alive patients were submitted to HSCT (the remaining is on rescue therapy). Median OS (95%CI) was 6.1 (4.9-7.2) months, 5yr OS probability 21% (9%-33%) (Figure 1). By multivariable analysis, only the CR after first salvage regimen emerged as favorable prognostic factor for OS (HR 3.110, 95%CI: 1.579-6.124) (Figure 2). Conclusion. This study shows poor outcome of adults with R T-ALL, with CR to first salvage therapy of 44% and a median OS of 6 months. Poor early response to first line therapy correlated with poor response to salvage-1. The only independent predictor for better survival was CR to first salvage regimen. This study highlights the unmet need for novel effective therapies for T-ALL. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation; ISCIII (PI19/01828), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future". Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Barba:Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire: Consultancy; Amgen, Celgene, Novartis, Pfizer: Speakers Bureau. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Giménez Conca:AbbVie: Honoraria, Speakers Bureau.

Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction and/or consolidation therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can specifically apply to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial (NCT01540812) from the Spanish PETHEMA Group was to evaluate response of HR Ph-neg adult ALL patients to a different post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (centrally assessed by 8-color flow cytometry [FCM]) at the end of induction (week 5) and consolidation therapy (week 17).. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60y, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or KMT2A rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or in those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD Results: On April 2019, 307 HR ALL pts were evaluable. Median (range) age was 40 (15-60) y, 192 were males, 211 precursor B-ALL and 96 T-ALL, with a median WBC count of 12.9 (0.2-564) x109/L. Results of Induction-1 (n=304, 3 on induction): therapy-related death: 12(4%), resistance: 39(13%), CR: 253(83%). MRD Conclusions: This trial, in which post-induction therapy was only based on MRD results assessed by FCM, suggests that avoiding alloHSCT does not hamper the outcome of HR Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation. Better post-remission alternative therapies are specially needed for patients with poor MRD clearance. Supported by grants PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain. Disclosures Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy.

Congenital homozygous dysfibrinogenemia was diagnosed in a man with a history of 2 thrombotic strokes before age 30. His hemostatic profile was characterized by a dramatically prolonged plasma thrombin clotting time, and no clotting was observed with reptilase. Complete clotting of the abnormal fibrinogen occurred after a prolonged incubation of plasma with thrombin. The release of fibrinopeptides A and B by thrombin and of fibrinopeptide A by reptilase were both normal. Thrombin-induced fibrin polymerization was impaired, and no polymerization occurred with reptilase. The polymerization defect was characterized by a defective site “a,” resulting in an absence of interaction between sites A and a, indicated by the lack of fragment D1 (or fibrinogen) binding to normal fibrin monomers depleted in fibrinopeptide A only (Des-AA fm). By SDS-PAGE, the defect was detected on the γ-chain and in its fragment D1. The molecular defect determined by analysis of genomic DNA showed a single base change (A→T) in exon VIII of the γ-chain. The resulting change in the amino acid structure is γ 330 aspartic acid (GAT) → valine (GTT). It is concluded that the residue γ-Asp330 is essential for the normal functioning of the polymerization site a on the fibrinogen γ-chain.

Background: Patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) often do poorly with conventional salvage regimens of chemotherapy. Next-generation sequencing (NGS) panels can rapidly identify recurrent molecular abnormalities, thus helping to orient patients (pts) in appropriate targeted therapies or clinical trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with a better outcome. Methods: From 2013 to 2018, all pts with r/r DLBCL having molecular portrait of tumor before enrollment in early clinical trials (eaCTs) for r/r DLBCL were analyzed for clinical and histomolecular characteristics, tumor response, progression-free survival (PFS) duration of response and overall survival. The objective were to evaluate the feasibility and potential benefit of using tumor genotyping for guiding enrollment in eaCTs. Molecular screening methods included immunohistochemistry, PCR-based assays and next-generation sequencing. All pts gave their written consent for the study. Results: Sixty-two pts with r/r DLBCL had tumor molecular portraits. At the time of tumor molecular portrait, the median age was 69 years (range 26-77), median of previous line of therapies was 2 (range 1-9) and 14 pts (23%) had prior received auto stem-cell transplant. Fifteen out of the 62 pts (24%) were molecularly oriented (MO) in eaCTs. Identification of potentially actionable targets was found in 30/62 (48%) of pts, of whom 15/30 (50%) received a molecularly-informed therapy. Beyond molecular portrait, fifty pts were enrolled in eaCTs (15 pts were MO and 35 were non-MO oriented) and 12 pts were not enrolled in eaCTs. The MO-oriented group included the following therapeutic targets: CD79A/B or MYD88 (n=10 pts), EZH2 or ARIDI1A (n=3 pts), MYC (n=1 pt) and BRAF (n=1 pt). The overall responses rate was 60% (6 PR and 3 CR) in MO group versus 23% (5 PR and 2 CR) in non-MO group (p= 0.01). The median of PFS in MO and non-MO groups were 2.2 months and 1.9 months, respectively (p=0.23; HR=0.69 [CI95:0.38-1.26]). The median duration of response in MO and non-MO groups were 10.9 and 9.3 months, respectively (p=0.78; HR=0.76 [CI95: 0.26-2.18]. The mean PF2/PF1 ratio in MO and non-MO groups were 2.34 [CI95: 0.27-4.41] and 1.67 [CI:0.53-2.81], respectively (p=0.093; HR=0.61 [CI95: 0.33-1.14]. The median overall survival in MO and non-MO groups were 8.9 and 7.7 months, respectively (p=0.34; HR=0.69 [CI95: 0.33-1.47]). Conclusions: Molecularly oriented treatments of recurrent diffuse large B-cell lymphoma demonstrates higher responses rates. A subset of patients with recurrent or refractory diffuse large B-cell lymphoma may benefit from incorporation of tumor genotyping to guide their enrollment in clinical trials. Accelerating the use of prospective genomics tumor molecular portraits may increase the chances for a precision medicine for recurrent diffuse large B-cell lymphoma. Disclosures Soria: Medimmune: Employment. Ribrag:BMS: Consultancy, Honoraria, Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria; NanoString Technologies: Consultancy, Honoraria; argenX: Research Funding; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy; pharmamar: Other: travel; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Amgen: Research Funding.

Background: Treatments of patients with relapsed or refractory multiple myeloma (r/r MM) remains a challenge and there is no molecular-informed personalized therapies available in this context. Cytogenetics and next-generation sequencing (NGS) panels can rapidly identify recurrent molecular abnormalities, thus helping to orient patients (pts) in appropriate targeted therapies or clinical trials. We aimed to evaluate whether selecting pts through tumor genotyping is associated with a better outcome. Methods: From 2013 to 2018, all pts with r/r MM screened for molecular and/or cytogenetics before enrollment in early clinical trials (eaCTs) were included. Molecular screening methods included bone marrow cytogenetics, sanger assays for BRAF screening or next-generation sequencing on sorted CD138 positive bone-marrow cells. The actionable targets and therapies related were BRAF V600E mutation with BRAF inhibitor and t(11;14) with BCL2 inhibitor. The objective were to evaluate the feasibility and potential benefit of using tumor genotyping to orient patients with molecularly-informed multiple myeloma in personalized therapies or eaCTs. The tumor responses rates, median duration of treatments and overall survival (OS) were assessed in molecularly oriented (MO) and non-molecularly oriented (non-MO) pts. Efficacy was evaluated using International Myeloma Working Group Uniform Response Criteria. Results: Forty-six pts with r/r MM were enrolled, mean age was 66 y (range 52-81), median of previous lines of therapies was 3 (range 1-8). Prior systemic therapies included immunomodulatory agents (n=46, 100%), alkylating agents (n=43, 94%) or proteasome inhibitors (n=44, 95%), and 28 (62%) pts had previously received auto stem-cell transplant. Identification of potentially actionable targets was found in 13 (28%) pts, including 8 (17%) pts with t(11;14) and 5 (11%) pts with BRAF V600E mutations. Eight (17%) out of the 46 pts were treated in molecularly oriented (MO) personalized therapies or eaCTs, and 38 (83%) pts were treated in non-MO therapies or eaCTs. The MO pts received BRAF inhibitor alone or in combination with MEK inhibitor (n=5), or BCL2 inhibitor given in combination with bortezomib and dexamethasone (n=3). The overall response rate was 75% (4 VGPR, 1 PR and 1 CR) in MO pts versus 11% (4 PR) in non-MO pts (p Conclusions: Molecular-oriented treatments of relapse or recurrent multiple myeloma can be associated with higher responses rates and prolonged durations on therapy. Accelerating the use of prospective genomics tumor molecular portraits may increase the chances of precision medicine for patients with relapse or recurrent multiple myeloma. Disclosures Le Bras: Amgen: Consultancy. Belhadj:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Soria:Medimmune: Employment. Ribrag:Amgen: Research Funding; Gilead: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Incyte Corporation: Consultancy; BMS: Consultancy, Honoraria, Other: travel; epizyme: Consultancy, Honoraria; argenX: Research Funding; MSD: Honoraria; pharmamar: Other: travel; Servier: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel.

Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important covariates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL−1 (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3′ splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant.