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Background: Trisomy 4 is a recurrent but rare cytogenetic abnormality reported in patients with acute myeloid leukemia (AML). The prognostic significance of this abnormality in AML patients is not clear. Prognosis of AML patients with trisomy 4 seems to be poor as compared to that of patients with intermediate-risk cytogenetics. Allogeneic hematopoietic stem cell transplantation (allo-HCT) may improve survival if applied early in first complete remission (CR). However, neither prospective clinical nor larger retrospective cohort studies are available to support these results from small series. Aims: To characterize AML patients with trisomy 4 and compare outcomes according to different treatment strategies. Methods: We retrospectively studied 123 AML patients with trisomy 4 (median age at diagnosis, 58 years; range, 16-76 years) treated between 2000 and 2019 within 2 large study groups. Standard statistical methods were applied. Results: Median white blood cell count at diagnosis was 4.8/nl (range, 0.4-255/nl) and platelets 46/nl (range, 2-330/nl). Type of AML was de novo in 97 (79%), secondary after myelodysplastic syndrome/myeloproliferative neoplasm in 18 (15%), and therapy-related in 8 (6%) patients. Sixty-two (50%) patients were female. Cytogenetic analysis revealed trisomy 4 as the sole abnormality in 28 (23%), additional abnormalities in 95 (77%) patients, most frequently ≥3 (n=66) abnormalities, trisomy 8 (n=41), karyotypes characterized by trisomies only (n=21) and t(8;21) or inv(16) (CBF; n=10). A total of 98 patients (80%) had NPM1 and FLT3-ITD mutation testing. Of those, 21 (21%) and 15 (15%) harbored NPM1 and FLT3-ITD mutations. Only 2 (3%) of 72 patients were CEBPA double mutated. Data on response to intensive anthracycline-based induction therapy were available in 117 patients. Early death rate was 5% (n=6). CR was achieved in 68% (n=79) with 22 (19%) requiring an intensive salvage treatment cycle. Notably, patients with trisomy 4 as sole abnormality had a CR rate of 89% (n=25/28). There was no difference in the CR rate in FLT3-ITD positive (n=10/15) as compared to FLT3 wild type (n=56/83) patients (67% each, P=0.99). Univariable analysis revealed trisomy 4 as sole abnormality (OR, 5.76; P=0.007) and NPM1 (OR, 12.08; P=0.02) as favorable factors. An allo-HCT was performed in 40 (34%) patients, of whom 19 patients were transplanted in first CR after induction therapy. Nine patients achieved CR after salvage chemotherapy and went on to allo-HCT; another 12 patients received allo-HCT with active disease. Type of donor was matched-related in 8, matched-unrelated in 30, and unknown in 2 of the 40 patients, respectively. Median follow-up of the intensively treated cohort was 73 months (95%-CI, 36-91 months). Five-year overall survival (OS) and relapse-free survival (RFS) were 31% (95%-CI, 23-42%) and 27% (95%-CI, 18-42%). OS rates were significantly higher in patients with CBF leukemia or patients with trisomy 4 as compared to all other abnormalities (Figure 1; P Conclusions: Clinically, patients with trisomy 4 are very heterogeneous in particular with respect to cytogenetic and molecular abnormalities. In our cohort, patients with trisomy 4 as a sole abnormality had a high CR rate and favorable clinical outcome. In the total cohort, allo-HCT did not improve RFS. Figure 1 Figure 1. Disclosures Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Haenel: Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Crysandt: Incyte: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Fransecky: Medac: Honoraria; Amgen: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria. Martinez-Lopez: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Platzbecker: AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Takeda: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Müller-Tidow: Pfizer: Research Funding; Janssen: Consultancy, Research Funding; Bioline: Research Funding. Levis: Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Montesinos: Stemline/Menarini: 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; Pfizer: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; Daiichi Sankyo: Consultancy, 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; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; 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. Röllig: Roche: Honoraria, Research Funding; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria; AbbVie: Honoraria, Research Funding. Schlenk: Novartis: Honoraria; Pfizer: Honoraria, Research Funding, Speakers Bureau; Hexal: Honoraria; Neovio Biotech: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria; Agios: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Research Funding; Boehringer Ingelheim: Research Funding.

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workup. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly-diagnosed AML patients. Presence of dysplasia according to MFC and WHO criteria had no prognostic value in the elderly. NGS of dysplastic cells and blasts isolated at diagnosis identified three evolutionary patterns: stable (n=12/21), branching (n=4/21) and clonal evolution (n=5/21). In patients achieving complete response, integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in approximately 80% of newly diagnosed AML patients, using techniques other than single-cell multiomics. ACKNOWLEDGEMENTS: The authors acknowledge the patients, caregivers, and the biobank of the University of Navarra. This work was supported by grants from the Área de Oncología del Instituto de Salud Carlos III, Centro de Investigacion Biom ´ edica en ´ Red (CIBER-ONC) (CB16/12/00369, CB16/12/00233, CB16/12/ 00489, and CB16/12/00284), Instituto de Salud Carlos III/Subdireccion General de Investigaci ´ on Sanitaria (FIS numbers PI16/ ´ 01661, PI16/00517, and PI19/01518), and the Plan de Investigacion´ de la Universidad de Navarra (PIUNA 2014-18). This work was supported internationally by the Cancer Research UK, FCAECC, and AIRC under the Accelerator Award Program (EDITOR).

PurposePatients with Fanconi anaemia (FA), a rare DNA repair genetic disease, exhibit chromosome fragility, bone marrow failure, malformations and cancer susceptibility. FA molecular diagnosis is challenging since FA is caused by point mutations and large deletions in 22 genes following three heritability patterns. To optimise FA patients’ characterisation, we developed a simplified but effective methodology based on whole exome sequencing (WES) and functional studies.Methods68 patients with FA were analysed by commercial WES services. Copy number variations were evaluated by sequencing data analysis with RStudio. To test FANCA missense variants, wt FANCA cDNA was cloned and variants were introduced by site-directed mutagenesis. Vectors were then tested for their ability to complement DNA repair defects of a FANCA-KO human cell line generated by TALEN technologies.ResultsWe identified 93.3% of mutated alleles including large deletions. We determined the pathogenicity of three FANCA missense variants and demonstrated that two FANCA variants reported in mutations databases as ‘affecting functions’ are SNPs. Deep analysis of sequencing data revealed patients’ true mutations, highlighting the importance of functional analysis. In one patient, no pathogenic variant could be identified in any of the 22 known FA genes, and in seven patients, only one deleterious variant could be identified (three patients each with FANCA and FANCD2 and one patient with FANCE mutations)ConclusionWES and proper bioinformatics analysis are sufficient to effectively characterise patients with FA regardless of the rarity of their complementation group, type of mutations, mosaic condition and DNA source.

TPS7071 Background: BCL2 inhibition as a means of targeting intrinsic apoptotic pathways that confer a survival advantage to leukemic blasts has become a key therapeutic strategy for patients with myeloid malignancies. LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity as compared to the FDA approved oral BCL-2 inhibitor venetoclax. We propose to investigate LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory (r/r) MDS, CMML or AML. Methods: The primary objectives of the trial are 1.) To determine the safety, tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose / optimal biological dose (OBD) of LP-108 as a single agent (Arm 1) and in combination with azacitidine (Arm 2) in patients with relapsed/refractory MDS/CMML/AML; 2.) To characterize the pharmacokinetic profile of LP-108 as monotherapy and in combination with a fixed dose of azacitidine. The secondary objectives of the trial are 1.) To evaluate the objective response rate of LP-108 (monotherapy or combination therapy) in r/r MDS/CMML/AML as well as progression free survival, duration of response and overall survival. In Arm 1 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 for a 28 day cycle (firs table). DLTs will be determined in the first 28 days. In Arm 2 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 in combination with a fixed dose of azacitidine (second table). DLTs will be determined in the first 28 days. DLT for both arms is defined as some ≥ Grade 3 non-hematological toxicities or prolonged myelosuppression. Patients may continue treatment until disease progression, unacceptable toxicity, or per investigator discretion. Patients age ≥ 18 years with r/r MDS with excess or blasts or with high or very-high risk disease per the R-IPSS, or r/r MDS for Arm 2, r/r AML, or frontline older and/or unfit AML for Arm 2, or r/r CMML may enroll. Patients with prior hypomethylating agents or venetoclax exposure may enroll. The blast count at the time of starting therapy must be ≤ 30 x 109 cells/L. Hydroxyurea is allowed prior to and during treatment. Ejection fraction ≥ 50% is required. Calculated creatinine clearance shall be ≥ 30 mL/min. Strong CYP3A4 inducers and inhibitors are prohibited. Patients on weak/moderate azole antifungals were allowed to enroll. Enrollment to Arm 1 is complete and there have been no DLTs to date. Enrollment to Arm 2 is pending. Arm 1 Dose Escalation Scheme (LP-108 monotherapy). Clinical trial information: NCT04139434. [Table: see text][Table: see text]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.

SARS-CoV-2 infection can impact survival of patients with acute myeloid leukemia (AML). International experts recommend considering delaying or stopping AML treatment, test patients who need intensive induction and s prioritizing outpatient treatment. However there is little published evidence in AML. Objective To analyze the clinical futures and outcome of SARS-CoV-2 infection in AML patients. Methods and patients Observational multicenter study between March and May 2020; 117 patients reported from 47 Spanish centers, but 13 had no PCR or antibody test documented, finally including 104 patients from 45 hospitals. Results The median age was 68 years, men (56.7% vs 43.3%), and the median time from AML diagnosis to SARS-CoV-2 was 4 months. The mean of comorbidities was 1.2, high blood pressure (40.4%), heart disease (17.3%), diabetes (13.5%), smoking (8.8%), chronic obstructive pulmonary disease or emphysema (7.7%), renal failure (6.7%) and liver dysfunction (1.9%). Cytogenetic risk was low in 16.9%, intermediate in 57.1% and high in 26.0%; 55.7% had active disease, 39.2% complete remission and 5.1% partial response. 29.4% were off-therapy and 70.6% under antileukemic treatment at the time of SARS-CoV-2: induction chemotherapy (25.3%), hypomethylating (19.3%), clinical trial (17.0%), consolidation chemotherapy (14.8%), venetoclax (3.4%), FLT3 inhibitors (3.4%) and/or maintenance (1.1%). Overall 3.7% were newly diagnosed (no prior therapy), 77.8% had received one line of treatment, 14.8% two and 3.7% four. 15.4% had prior allogeneic transplantation. Only 4.0% of the patients were asymptomatic, while the main signs and symptoms were fever (77.8%), pneumonia (75.0%), cough (65.3%), dyspnea (52.0%), diarrhea (20.4%), nausea and/or vomiting (12.2%), rhinorrhea (10.2%) and headache (7.4%). Analytical parameters were: neutrophils 3112 cells/µL (1900-7300), lymphocytes 1090 cells/µL (1000-3000), interleukin 6 118 pg/mL (0-100), ferritin 4505 ng/mL (15-150) and D-dimer 2823 ng/mL (20-500), with liver enzymes altered in 23.9% of cases. 84.2% received specific treatment for coronavirus infection: chloroquine or hydroxychloroquine (82.2%), lopinavir/ritonavir (54.0%), corticosteroids (39.6%), azithromycin (33.0%), tocilizumab (15.8%), plasma convalescent (3.0%), clinical trial medication (3.0%), remdesivir (2.0%) and/or anakinra (1.0%). The course was mild in 14.7% (no hospitalization), moderate in 32.0% and severe in 53.3%. The implementation of intensive measures was assessed in 48.2%(14.9% admitted to the ICU and the remaining 33.3% rejected). The mean time to negativization was 20.5 days, duration of symptoms 17.6 days and the hospital stay 11.1 days. In 48.1% of the cases treatment for AML was maintained, in 26.6% delayed and in 25.3% modified due to coronavirus disease.47.5% died, establishing an association between mortality and age over 60 years (58.3% vs 36.4%, p=0.043), ≥2 lines of treatment (72.7% vs 44.3%, p=0.020), active disease (62.5% vs 29.4%, p=0.002) and pneumonia (61.2% versus 22.7%, p=0.002). Overall 47.5% overcame the infection, and in 5.0% SARS-CoV-2 genetic material was still detected at the time of analysis. A non-significant lower mortality rate was observed among: previous transplantation (45.7% vs 64.3%, p=0.19), neutrophil >1900 cells/µL (41.1% vs 60.0%, p=0.09), lymphocyte >1000 cells/µL (42.9% vs 63.6%, p = 0.09) and hydroxychloroquine/chloroquine plus azithromycin (35.3% vs 60.0%, p=0.10). Conclusions SARS-CoV-2 infection produces high mortality among AML patients. Mortality was correlated with age, active disease and pneumonia. Disclosures Martinez-Lopez: Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Consultancy, Research Funding.

Background: The current standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is R CHOP; however, approximately 40% of patients are not cured. The CD79b-targeting antibody-drug conjugate, polatuzumab vedotin, is approved in relapsed/refractory DLBCL in combination with bendamustine and rituximab, and has also demonstrated promising first line activity and safety when combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). Thus, in the Phase III POLARIX study (NCT03274492) we compared pola-R-CHP with R-CHOP in patients with previously untreated DLBCL. Methods: In this double-blind, placebo-controlled, international study, patients with previously untreated DLBCL and an International Prognostic Index (IPI) of 2-5 were randomized 1:1 to receive six cycles of pola-R-CHP (with a vincristine placebo) or R-CHOP (with a polatuzumab vedotin placebo); all patients also received two additional cycles of rituximab. Patients received polatuzumab vedotin 1.8mg/kg or vincristine 1.4mg/m² administered on Day 1, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m², doxorubicin 50mg/m², and placebo on Day 1, and oral prednisone 100mg once daily on Days 1-5. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed event-free survival (EFS), independent review committee-assessed complete response (CR) rate at the end of treatment by positron emission tomography-computed tomography (PET-CT), disease-free survival (DFS), overall survival (OS), and safety. Results: Overall, 879 patients were randomized, 440 to pola-R-CHP and 439 to R-CHOP. Median age was 65 (range 19-80) years, and the majority of patients had IPI 3-5 (62.0%). At the data cut-off of June 28, 2021, and after a median follow-up of 28.2 months, PFS was superior with pola-R-CHP vs R CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57-0.95; P Conclusion: The pola-R-CHP combination demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death compared with R-CHOP, with a similar safety profile in the first-line treatment of patients with DLBCL. Disclosures Tilly: Karyopharm: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance and travel, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy; Teva: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Acerta: Consultancy; Amgen: Consultancy; Apobiologix: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Lundbeck: Consultancy; Merck: Consultancy; Morphosys: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Friedberg: Bayer: Membership on an entity's Board of Directors or advisory committees; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Bristol-Myers Squibb: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Velos: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Herbaux: Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria; Janssen: Honoraria. Burke: Verastem: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy, Speakers Bureau; Kymera: Consultancy; Bristol-Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Gilead: Consultancy; Genentech, Inc.: Consultancy. Matasar: Memorial Sloan Kettering Cancer Center: Current Employment; Merck Sharp & Dohme: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Rocket Medical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, 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; Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria. Rai: Chugai Pharmaceutical Co., Ltd: Speakers Bureau; ONO Pharmaceutical Co., Ltd: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Eisai Co., Ltd: Speakers Bureau. Izutsu: AbbVie: Honoraria; Allergan Japan: Honoraria; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Oberic: Celgene: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Janssen: Honoraria, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Jurczak: Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months. Greil: Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Pinto: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; MSD: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Abrisqueta Costa: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hirata: Genentech, Inc.: Current Employment; Genentech/Roche: Current holder of stock options in a privately-held company. Jiang: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yan: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lee: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Flowers: AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Salles: Bayer: Honoraria; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Debiopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Consultancy; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rapt: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Velosbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy. OffLabel Disclosure: Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b on malignant B-cells. Polatuzumab vedotin in combination with bendamustine and rituximab (pola-BR) improved complete response rate and overall survival compared with BR alone in patients with relapsed/refractory diffuse large B-cell lymphoma. Pola-BR is approved for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies.

Introduction Tafasitamab is a humanized, Fc-modified, anti-CD19 monoclonal antibody (mAb) shown to enhance antibody-dependent cellular cytotoxicity and phagocytosis. It is approved by the FDA under accelerated approval (July 2020) in combination with lenalidomide (LEN) for treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adult patients ineligible for autologous stem cell transplantation. To evaluate if newly diagnosed DLBCL patients would also benefit from this regimen, this Phase Ib study (First-MIND; NCT04134936) was designed to first assess the safety and tolerability of tafasitamab ± LEN in addition to rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in newly diagnosed DLBCL patients. Methods Eligible patients were ≥18 years old, with treatment-naïve DLBCL, international prognostic index (IPI) 2-5 and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients with known double- or triple-hit and transformed lymphoma were excluded. Patients were randomized 1:1 to either six 21-day [D] cycles of R-CHOP (R-CHO, D1; P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1-10) (Arm B). Granulocyte colony-stimulating factor and venous thromboembolism prophylaxis was mandatory. The primary safety endpoint was incidence of treatment-emergent adverse events (TEAEs); secondary endpoints included overall response rate (ORR), positron emission tomography (PET)-complete response (CR) rate, and partial response (PR) rate at end of treatment (EOT). Tumor measurements by PET/CT or PET/MRI at EOT were performed according to Lugano 2014 criteria within 6±2 weeks after Day 21 of the last treatment cycle the patient started. Results From December 2019 to August 2020, 83 patients were screened in nine countries across 34 sites in Europe and the US; 66 were randomized (Arm A, n=33; Arm B, n=33). Data cut-off for this analysis: 13 March 2021. Median age was 64.5 years (range 20-86). Many patients had high-risk disease: IPI 2: 24/66 (36.4%), IPI 3: 29/66 (43.9%), IPI 4: 11/66 (16.7%), IPI 5: 2/66 (3.0%); ECOG PS ≥2: 6/66 (9.1%). Most patients had Stage III/IV disease 62/66 (93.9%); 29/66 (43.9%) had bulky disease. All patients experienced at least one TEAE. The most frequent Grade ≥3 TEAEs by system organ class were blood and lymphatic disorders (81.8% patients overall), experienced by 24 patients (72.7%) in Arm A and 30 patients (90.9%) in Arm B. Grade ≥3 neutropenia and thrombocytopenia occurred in 19/33 (57.6%) and 4/33 (12.1%) (Arm A), and 28/33 (84.8%) and 12/33 (36.4%) (Arm B) patients, respectively; Grade ≥3 febrile neutropenia was experienced by 6/33 (18.2%) patients in each arm. Grade ≥3 infusion-related reactions to both rituximab and tafasitamab occurred in no patients in Arm A and one patient (3.0%) in Arm B, and 7/33 (21.2%) (Arm A) and 9/33 (27.3%) (Arm B) patients had a Grade ≥3 infection and/or infestation (Figure 1). Serious TEAEs occurred in 14/33 (42.4%) patients in Arm A and 17/33 (51.5%) patients in Arm B. Two out of 33 (6.1%) and one out of 33 (3.0%) patients discontinued study treatment due to TEAEs in Arms A and B, respectively. There were four deaths unrelated to tafasitamab and/or LEN (COVID-19 pneumonia, sepsis, and urosepsis). The average relative dose intensity of R-CHOP in each cycle was maintained in both arms. ORR at EOT was observed in 25/33 patients (75.8%; 95% confidence interval [CI]: 57.7-88.9) in Arm A and 27/33 patients (81.8%; 95% CI: 64.5-93.0) in Arm B. Conclusion These data suggest that both regimens are tolerable and do not impair dosing and scheduling of R-CHOP. Toxicities were similar to those expected with R-CHOP with or without LEN. With tumor follow-up still ongoing, the ORR at EOT suggests that patients with treatment-naïve DLBCL may achieve clinically meaningful efficacy tafasitamab and LEN in addition to standard treatment. A Phase III, multicenter, randomized, double-blind, placebo-controlled trial will assess efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP in newly diagnosed patients with high intermediate and high risk DLBCL, and is currently recruiting (frontMIND study; NCT04824092). Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Belada: Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Gilead Sciences: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen-Cilag: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MorphoSys AG: Consultancy, Research Funding; Debiopharm Group: Consultancy; Pharmacyclics: Research Funding; Archigen Biotech: Research Funding; Reddys: Research Funding. André: Johnson & Johnson: Research Funding; Roche: Other: Travel/accomodation/expenses, Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses. Pérez Persona: Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Staber: Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria. Trneny: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Brackertz: MorphoSys AG: Current Employment. Shah: MorphoSys AG: Current Employment. Sporchia: MorphoSys AG: Current Employment. Burke: MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; Bristol Myers Squibb: Consultancy; Kymera: Consultancy; X4 Pharmaceuticals: Consultancy; AbbVie: Consultancy; SeaGen: Consultancy, Speakers Bureau; Kura: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Beigene: Consultancy, Speakers Bureau. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Tafasitamab is a humanized Fc-modified cytolytic CD19 targeting monoclonal antibody. In combination with lenalidomide (LEN), it received accelerated approval in July 2020 for adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), including arising from lowâ€'grade lymphoma, who are ineligible for autologous stem cell transplant (ASCT). Following FDA approval, we are now evaluating the safety and efficacy of tafasitamab in combination with LEN as an add-on to first-line therapy with R-CHOP in newly diagnosed patients with DLBCL.

Background: Clonal evolution in AML originates long before diagnosis and is a highly dynamic process. Having a greater understanding of leukemogenesis may contribute to develop treatment strategies that target the tumor evolutionary process. However, dissecting leukemic transformation at the onset of AML is challenging without single-cell sequencing, and most clinical laboratories do not have infrastructure to perform these studies routinely. Patients with newly diagnosed AML may present dysplasia. If these residual, mature, dysplastic cells were generated before the differentiation blockage of blasts preceding leukemic transformation, it could be hypothesized that studying the genetic landscape of dysplastic cells and blasts could uncover the evolutionary process from dysplasia to AML. This hypothesis has never been investigated. Aim: Reconstruct clonal evolution from dysplasia to AML based on the genetic signature of dysplastic cells and leukemic blasts, analyzed using integrated MFC immunophenotyping and sorting with NGS. Methods: Presence of dysplasia according to aberrant phenotypic differentiation of the neutrophil, monocytic and erythroid lineages was investigated using MFC and EuroFlow MDS/AML panels in 283 newly diagnosed AML patients (median age 74; range 29-90). Patient-specific phenotypes were leveraged to isolate a total of 99 cell types from 22 AML cases for targeted (48 MDS/AML related genes) and whole-exome sequencing (WES), with a mean depth of 3246x and 141x, respectively. In patients with measurable residual disease (MRD) by MFC at the time of complete remission, tumor resistant cells were FACSorted for WES using patient-specific aberrant phenotypes. T cells were used as germline control in both approaches. Mutations were considered if ≥0.05 allele frequency in leukemic blasts or dysplastic cells and ≤0.2 in T cells. Results: We first assessed the applicability of our hypothesis by investigating how many patients show dysplasia at the onset of AML. Dysplastic cells were observed in 252 of 283 (89%) cases. Phenotypic abnormalities were more frequently noted in the neutrophil lineage (47%), followed by the monocytic (40%) and erythroid cells (13%). Up to 169/283 (60%) patients showed multi-lineage dysplasia. Only nine cases showed no signs of dysplasia, whereas the remaining 22 had undetectable hematopoiesis. Targeted sequencing of dysplastic cells and blasts in 16 patients uncovered three evolutionary patterns of leukemogenesis. Stable transition in those displaying identical mutational landscapes in blasts and residual mature dysplastic cells (9/16); clonal selection in cases where blasts originated from leukemic stem cells other than the ones driving dysplasia, due to mutations absent in blasts and present in dysplastic cells (4/16); and clonal evolution in cases showing new mutations in blasts onto mutations shared between these and dysplastic cells (3/16). Interestingly, most patients displaying stable transition from dysplasia to AML had mutated ASXL1, RUNX1 and/or TP53 (8/9). Mutations present in dysplastic cells while absent in blasts from patients showing a clonal selection evolutionary pattern, were more frequently detected in genes related to signaling pathways (eg JAK2, KRAS and NRAS). By contrast, clonal evolution was characterized by new mutations affecting FLT3ITD and STAG2. The higher throughput of WES of dysplastic cells and blasts from six patients unveiled a more complex dynamic process of leukemogenesis, with all three evolutionary patterns being detectable in nearly all cases. Most interestingly, we found patients with mutations in dysplastic cells and blasts at diagnosis, but not in MRD cells (eg NBPF1 and ZNF717); and patients showing mutations in dysplastic and MRD cells, but not in blasts at diagnosis (eg MUC2 and KIR2DL3). These findings uncover that genetic alterations that are critical in leukemic transformation and chemoresistance, may not overlap (Figure). Conclusions: We showed for the first time that it is possible to reconstruct leukemogenesis in nearly 90% of newly-diagnosed AML patients, using techniques that are commonly available in clinical laboratories. The possibility to identify the genetic drivers of leukemic transformation and chemoresistance, could be clinically meaningful to develop tailored treatment strategies aiming at the eradication of genetically diverse leukemic clones. Figure 1 Figure 1. Disclosures Prósper: Oryzon: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria, Research Funding. 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. 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. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Montesinos: Celgene: Consultancy, 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; Daiichi Sankyo: Consultancy, 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; 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; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Tolero Pharmaceutical: Consultancy; Forma Therapeutics: Consultancy; Glycomimetics: 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. Paiva: Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs have demonstrated efficacy in monotherapy and in combination with targeted therapies. However, there is little direct comparative data on AZA and DEC in first-line treatment, and we do not know which group of patients might benefit from each drug. Results of the full analysis set (FAS) were presented previously (Labrador J, et al. ASH 2020). Here, we report long-term clinical efficacy from prespecified patient subgroup analyses. METHODS We conducted a retrospective study to compare real-life clinical outcomes between AZA and DEC in patients with AML ineligible for intensive chemotherapy included in the PETHEMA registry, and analyzed clinical variables associated with response and overall survival (OS) between AZA and DEC. RESULTS A total of 626 patients were included for the FAS between 2006 and 2019. 487 (78%) received AZA and 139 (22%) received DEC. Baseline characteristics were comparable in both groups, except for the percentage of bone marrow blasts (44% vs. 34% in the DEC group compared to AZA, p=0.010). In the FAS, there was no difference in the CR, CR/CRi or ORR (CR/RCi + PR) rate: 18%, 20.5% and 32% with AZA vs. 23%, 25% and 39.5% with DEC (p=0.20, p=0.27 and p=0.12). In the subgroup analysis, DEC was associated with higher CR/CRi rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.088 - 0.801), bone marrow blast count < 50% (95% CI: 0.293 - 0.965), secondary AML (95% CI: 0.223 - 0.918) and adverse cytogenetics (95% CI: 0.171 - 0.857) (Figure 1A). DEC was associated with higher ORR rate than AZA in patients with ECOG ≥ 2 (95% CI: 0.116 - 0.782), leukocytes < 10 x10 9/L (95% CI: 0.321 - 0.920) and bone marrow blasts < 50% (95% CI: 0.321 - 0.920) (Figure 1B) 120 days-mortality was 25.4% after AZA and 27.1% after DEC, p=0.70. Patients who did not achieve at least a PR had significantly higher 120-day mortality with both HMAs (OR 8.85 and 8.22 for AZA and DEC, respectively). In the subgroup analysis, patients with leukocytes ≥ 10 x10 9/L (95% CI: 1.069 - 4.157) and those with estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73m 2 (95% CI: 1.249 - 4.664) had higher 120-day mortality with DEC than with AZA (Figure 1C) With a median follow-up of 12 months, median OS was 10.4 months (95% CI: 9.2 - 11.7) for AZA vs. 8.8 months (95% CI: 6.7 - 11.0) for DEC (p = 0.455). The subgroup analysis revealed that patients ≥ 80 years (95%: CI 1.005 - 2.341), with leukocytes ≥ 10 x10 9/L (95% CI 1.039 - 2.062), platelet count CONCLUSIONS Our study provides real-life data on the outcomes of AML patients treated with AZA compared to DEC in a large retrospective cohort with long-term follow-up. In addition, we identify for the first time some baseline characteristics that could benefit from AZA or DEC in terms of responses, 120-day mortality and OS. These findings could help us to choose the most appropriate HMA in monotherapy or for the development of new combinations. Figure 1 Figure 1. Disclosures de la Fuente: Novartis: Research Funding; Abbie: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. 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. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Tolero Pharmaceutical: Consultancy; 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; Janssen: 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; Daiichi Sankyo: Consultancy, 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; Glycomimetics: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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.

INTRODUCTION The hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are a common choice for initial treatment in elderly patients with acute myeloid leukemia (AML). However, about 60% of patients are resistant and most will relapse after a complete response (including CR/CRi). Although relapse or refractoriness to HMAs is very common, very little is known about the therapeutic management of these relapsed or refractory AML (RR-AML) patients after HMAs. METHODS We conducted a retrospective study to describe and compare salvage treatment patterns and real-life clinical outcomes of those AML patients treated upfront with AZA or DEC included in the PETHEMA-AML Registry. RESULTS Between 2006 and 2019, we included 626 AML patients treated in first-line with HMAs, 487 (78%) received AZA and 139 (22%) received DEC. Overall response rate (CR/CRi+PR) was 33.7%, 32% in the AZA vs 39.5% in the DEC group (p=0.120). Patients treated with DEC had a higher median relapse free survival than those treated with AZA (25.6 vs. 17.5 months, p=0.027). No differences were observed in the overall survival between AZA and DEC. We observed 59.7% resistance after HMAs, 60% after AZA and 58.8% after DEC; and 6.5% had other type of response (< PR), 7.9% with AZA and 1.6% with DEC. In addition, 76/121 patients who achieved CR/CRi (62.8%) relapsed, 66/90 in the AZA group (73.3%) vs 10/31 in the DEC group (32.3%) (p=0.000). After relapse or resistance, 74.5% of patients received supportive care only (BSC), which included patients receiving transfusions and other supportive measures, including oral agents to control the white blood cell counts; 71.5% of patients in the AZA group and 84.3% of patients in DEC group (p= 0.004). No differences were observed in baseline characteristics at diagnosis of patients treated with BSC only, except for a higher proportion of patients with adverse cytogenetic risk in the AZA group (46.6% vs. 33.7%, p=0.039). Only 135 patients received a salvage therapy, 116 in the AZA group and 19 in the DEC group. Thirty-five out of 135 RR-AML treated patients (26%) continued receiving HMAs: 31 (26%) in the AZA group and 4 (22%) in the DEC group. In the AZA group, 19 (16%) patients continued with AZA and 12 (10%) switched to DEC, while in the DEC group 2 patients (11%) continued with DEC and 2 (11%) switched to AZA. Fifty-one patients (37.8%) received FLUGA (fludarabine and Ara-C), FLAG-IDA-Lite (fludarabine, Ara-C and idarubicin), Low-dose Ara-C or other non-intensive regimens, 43 patients (37%) in the AZA group and 8 (42%) in the DEC group. Other salvage therapies were administered in 34% of patients (33% in the AZA group and 37% in the DEC group). Salvage therapy was not available in 1% of patients. Response assessment was available in 113/135 of RR-AML treated patients, 98 in the AZA group and 15 in the DEC group. In the AZA group, 13.2% of the patients achieved a CR (n=13), 5.1% achieved CRi (n=5), 6.1% achieved a PR (n=6), 65.3% resistance (n=64) and 8.1% died (n=8). However, no patients in the decitabine group responded to salvage therapy, 86.7% resistance (n=13) and 13.3% died (n=2). If we exclude those patients who died before response was evaluated, the ORR (CR/CRi+PR) after salvage therapy was statistically significant between AZA (n=24/90, 26.7%) and DEC group (n=0/13, 0%), p=0.035. CONCLUSIONS This study shows and compares, for the first time to our knowledge, the patterns of salvage therapy in patients with RR-AML treated upfront with HMAs. Despite the similar response rate with both HMAs, the relapse free survival was lower after AZA. The absence of responses in patients with RR-AML initially treated with DEC could justify the similar OS between AZA and DEC observed. However, we should be very cautious due to the low number of RR-AML patients treated. Disclosures de la Fuente: BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Novartis: Research Funding. 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. Pérez-Simón: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: 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; Sanofi: Membership on an entity's Board of Directors or advisory committees, 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; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; 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.

Introduction Approximately 15-20% of treatment-naïve patients with diffuse large B-cell lymphoma (DLBCL) have CD20-low tumors, while CD19 is homogeneously expressed in >90% of cases of DLBCL. CD20-low DLBCL is associated with poor response to rituximab-based regimens (Johnson NA, et al. 2009). CD19 functions as a positive regulator of B-cell receptor signaling and is important for B-cell activation and proliferation and is therefore an attractive therapeutic target in addition to CD20. Tafasitamab (MOR208) is a humanized, Fc-enhanced, anti-CD19 monoclonal antibody with improved antibody-dependent cellular cytotoxicity and phagocytosis. Monotherapy with tafasitamab has shown clinical activity in relapsed/refractory (R/R) non-Hodgkin's lymphoma (Jurczak W, et al. 2018). In the Phase II, single-arm L-MIND study (NCT02399085) in patients with R/R DLBCL, combined treatment of tafasitamab with lenalidomide resulted in a high proportion of patients having a complete response (Salles GA, et al. 2020). First-MIND (NCT04134936) is a Phase Ib, randomized study of tafasitamab + R-CHOP (Arm A) or tafasitamab + lenalidomide + R-CHOP (Arm B) in patients with newly diagnosed DLBCL. Here, we report data from the safety run-in phase. Study design and methods Patients must be aged ≥18 years, treatment naïve, with histologically confirmed DLBCL not otherwise specified and have intermediate- to high-risk disease (International Prognostic Index [IPI] 2-5) and an ECOG performance status of 0-2. Known double- or triple-hit lymphoma and transformed lymphoma are excluded. Treatment consists of six 21-day cycles of tafasitamab (12 mg/kg intravenously [IV], on Day [D] 1, 8 and 15) in addition to R-CHOP (Arm A) or tafasitamab (12 mg/kg IV, on D1, 8 and 15) + lenalidomide (25 mg orally, on D1-10) in addition to R-CHOP (Arm B). Granulocyte-colony stimulating factor prophylaxis was mandatory in all patients. The study includes a safety run-in phase and a main phase. In the safety run-in phase, 24 patients were enrolled. The primary objective is to assess safety; secondary objectives include ORR, PET-CR rate at end of treatment, PFS, event-free survival, long-term safety, pharmacokinetics and immunogenicity of tafasitamab. Exploratory objectives include the assessment of circulating cell-free tumor DNA. Approximately 60 patients will be recruited in 9 countries across Europe and the US. Results Recruitment is ongoing. Thirty-six patients were randomized; 18 in each arm. The data presented for the safety run-in phase consist of 24 patients: 13 patients in Arm A and 11 patients in Arm B. All completed the first treatment cycle; 88% of patients entered into Cycle 2 and 50% of patients entered into Cycle 3 of treatment. At baseline, their median age was 67 years (range: 47-76; Arm A) and 65 years (range: 40-74; Arm B). Overall, 33% of patients were male and 67% female; IPI scores were: IPI 2, 33%; IPI 3, 42%; IPI 4, 25%. Most patients had advanced stages III/IV (92%) and approximately 50% had bulky disease. Cell of origin was determined to be germinal center B-cell (GCB) DLBCL in 13%, non-GCB DLBCL in 42% and not yet classified in 46% of cases. A total of 248 treatment-emergent adverse events (AEs) by system organ class were documented: 111 in Arm A and 137 in Arm B. Grade ≥3 neutropenia was observed in 54% (Arm A) and 46% (Arm B) of patients. Thrombocytopenia Grade ≥3 was observed in 8% (Arm A) and 18% (Arm B) of patients. Diarrhea, fatigue and vomiting were comparable between the two arms. Febrile neutropenia was uncommon in both arms, with one event each (Figure 1). To date, 23 serious AEs were observed: 11 in Arm A (Grade 2, 1; Grade 3, 6; Grade 4, 4) and 12 in Arm B (Grade 2, 3; Grade 3, 7; Grade 4, 2). One suspected unexpected serious adverse reaction was reported in Arm B - pneumocystis jirovecii pneumonia. No treatment-associated deaths occurred. Conclusions R-CHOP can be safely combined with tafasitamab or tafasitamab + lenalidomide in patients with treatment-naïve DLBCL. Toxicities appear to be similar to what is expected with R-CHOP alone or in combination with lenalidomide. Enrollment is ongoing and updated safety and early efficacy data will be presented at the meeting. Disclosures Belada: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nowakowski:NanoString: Research Funding; Seattle Genetics: Consultancy; Curis: Consultancy; MorphoSys: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees. André:Takeda: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Johnson & Johnson: Research Funding; Celgene: Other, Research Funding; CHU UCL Namur, site Godinne, Yvoir, Belgium: Current Employment; Bristol-Myers-Squibb: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Stevens:Amgen, MorphoSys: Consultancy. Trněný:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb Company: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel Expenses; Roche: Consultancy, Honoraria, Other: Travel Expenses; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Other: Travel Expenses. Pérez Persona:Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Klöpfer:MorphoSys AG: Current Employment. Brackertz:MorphoSys AG: Current Employment. Lohrmann:MorphoSys AG: Current Employment. Lahiry:MorphoSys AG: Current Employment. Shah:MorphoSys AG: Current Employment. Fingerle-Rowson:MorphoSys AG: Current Employment. Brugger:MorphoSys AG: Current Employment. Burke:Epizyme: Consultancy; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Kura: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Bayer: Consultancy; Astra Zeneca: Consultancy; Adaptive: Consultancy; Morphosys: Consultancy.

BACKGROUND: Older patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. While DNMT3A, TET2, IDH1/2 and TP53 mutations have been previously associated to better response to hypomethylating agents, there are no molecular biomarkers for low-dose cytarabine (LDAC)-based regimens. AIMS: To predict outcome in AML older patients at diagnosis based on mutation status in the context of FLUGAZA trial. FLUGAZA trial was focus on >65 years AML de novo patients comparing azacytidine vs. fludarabine and LDAC (FLUGA Scheme). METHODS: We analyzed bone marrow (BM) samples at diagnosis from 209 out of 285 AML patients treated according Flugaza trial (NCT02319135), azacytidine-arm (n=97) and FLUGA-arm (n=112). In this trial, patients were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacytidine (AZA) followed by 6 consolidation cycles with AZA. Median age at diagnosis was 75 years (65-90). Both treatment groups were balanced for age, leucocytes count, baseline BM blasts, karyotype risk (ELN), and FLT3-internal tandem duplication and NPM1 gene mutations. Mutational profile analysis was carried out by NGS targeted gene sequencing (Ion Torrent S5XL System-Thermo Fisher Scientific) using a 43 genes custom panel implicated in leukemia prognosis. RESULTS: We detected 893 variants, 247 Indels and 646 SNVs. 206 (23.1%) of them were included as pathogenic or like-pathogenic by clinvar database. Ninety-five percent of patients (n=203) had at least one detectable mutation, and the median number of mutations was 4 (range = 0-8 mutations). The most common gene mutations were TET2 (N=55), FLT3 (n=52), SRSF2 (n=49), TP53 (n=45), DNMT3A (n=45), ASXL1 (n=45), RUNX1 (n=43), IDH2 (n=36), IDH1 (n=34), NPM1, (n=33) and NRAS (n=23). This mutational landscape is different to previous published in younger patients (Grimwade, Blood 2016), with higher number of patients with mutations in TP53 (21.5 vs 8%), SRSF2 (23.9 vs 2%), IDH1 (16.3 vs 7%) and IDH2 (17.2 vs 9%) and lower number of patients with mutation in NMP1 (15.8 vs 33%). The median OS of global series was 6 months (range 0-40). Multivariate Cox regression in the global series showed that NRAS and TP53 mutations predict reduced OS (Table 1). Distribution of mutations between both arms was not homogeneous (Figure 1) and NRAS (p=0.012) was more frequent among patients randomized to the FLUGA-arm. However, TP53 mutation frequency distribution was homogeneous: 23.7% in AZA-arm and 19.6% in FLUGA-arm (p=NS). In the AZA-arm, patient´s age was the only variable associated with not achieving composite complete remission (CR plus CR with incomplete recovery) and TET2 and EZH2 mutations were predictors to achieve composite CR. In the FLUGA-arm, TP53 and NRAS mutations were associated with not reaching composite CR (table 2). In the AZA-arm, cytogenetic was the only variable associated with risk of early death. In the FLUGA-arm, leucocyte count, TP53 and NRAS mutations were associated with risk of early death (table 3). In the AZA-arm, BCORL1 mutations (4.1%) were the only variable associated with high risk of relapse. In the FLUGA-arm, BCOR (7.1%) and TP53 (19.6%) mutations were associated with high risk of relapse (table 4). CONCLUSION The mutational profile of AML in elderly patients is different from the previously published in young patients. We have confirmed that a molecular pattern can identify patients with poor prognosis in elderly AML patients. NRAS and TP53 mutations confer a poor prognosis in LDAC (FLUGA-arm) patients, but this effect disappeared in the AZA-arm. BCOR and BCORL1 mutations were associated to a reduced DFS. These results confirm that azacytidine could be more efficacious than LDAC treatment for older patients with AML and mutations in TP53, NRAS, TET2 and EZH2. The percentage of patients who presented mutations in these genes amounted to 77% in this AML series. The study is registered at www.ClinicalTrials.gov as NCT02319135. This study was supported by the Subdirección General de Investigación Sanitaria (ISCIII, Spain) grants PI13/02387 and PI16/01530. Disclosures Salamero: Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Daichii Sankyo: Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fernandez: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; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: 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; Janssen: 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.

3501 Background: In certain subsets of patients (pts) with diffuse large B-cell lymphoma (DLBCL), the failure rate of standard R-CHOP treatment is high. Pts with high-risk disease (International Prognostic score [IPI] 3-5) have a particularly poor prognosis, with 3-y survival rates of ~62% with R-CHOP alone. The cereblon E3 ligase modulator avadomide (CC-122) showed activity in pts with relapsed or refractory DLBCL. We report results of avadomide plus R-CHOP in previously untreated pts with high-risk DLBCL. Methods: CC-122-DLBCL-002 (NCT03283202) is a phase 1/2 study of avadomide plus R-CHOP-21 in pts newly diagnosed with DLBCL not otherwise specified with IPI scores 3-5 who were aged ≥18 y. Pts received standard R-CHOP and escalating doses (1-3 mg) of oral avadomide for up to six 21-d cycles (Table). All pts received pegfilgrastim support. Primary objectives were to assess safety, tolerability, and complete response (CR) rate. Secondary objectives include evaluation of additional efficacy parameters (objective response rate [ORR], progression-free survival [PFS], and overall survival) and biomarkers. Results: As of July 30, 2019, 35 pts were enrolled in the phase 1 part of the study. Median age was 66 y (range, 20-75), 23 pts (66%) were aged > 60 y, 18 (51%) had an IPI score of 3, and 17 (49%) had an IPI score of 4-5. Thirty-two pts (91%) completed 6 cycles of treatment. Median relative total dose intensity of avadomide was 99% and the average relative dose intensity of R-CHOP was 95%. Six pts had dose-limiting toxicities: 1 pt had neutropenia and bacterial hepatic infection; 1 had pneumonia; 1 had febrile neutropenia (FN); 1 had FN and hypotension; 1 had FN due to skin infections; and 1 had sepsis. The recommended phase 2 dose was 3 mg 2/3 wk. Grade 3/4 adverse events in ≥10% of pts were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and FN (11%). Among 34 efficacy-evaluable pts, the ORR was 88% (n = 30/34), including a CR rate of 79% (n = 27/34) at the end of treatment. With a median follow-up of 10 mo, the 1-y PFS rate was 80% (95% CI, 58-92). Correlative analyses will be presented at the meeting. Conclusions: Avadomide plus R-CHOP was well-tolerated with no significant additive toxicities. The promising efficacy in this high-risk pt population warrants further evaluation of immunomodulatory drugs combined with immunochemotherapy for pts with previously untreated DLBCL. Clinical trial information: NCT03283202 . [Table: see text]

Background and objective. Specific immunochemotherapy is the standard treatment of patients with Burkitt leukemia or lymphoma (BL/L). The BURKIMAB08 trial showed 3-yr overall survival (OS) probability of 72% (Ribera JM et al, Cancer. 2013; 119:1660-8). However, the toxicity was high, and 11% of patients died in complete response (CR). In the BURKIMAB14 trial, dose-intensity of chemotherapy blocks was reduced in patients ≤55 years who achieved CR, with the aim to decrease the death rate without impact on efficacy. We present the results of this trial in 80 patients with BL/L and compare them with those of the BURKIMAB08 trial. Patients and method. All patients received a pre-phase with cyclophosphamide, prednisone and rituximab. Patients in localized stages (I-II non-bulky) received 4 blocks of immunochemotherapy (A1, B1, C1, A2), with 33% reduction of doses of iphosphamide, methotrexate and ARA-C in patients ≤55 years in CR (assessed by PET-CT) after B1 cycle. Patients in stages III-IV and mature B-ALL received 6 immunochemotherapy blocks (A1, B1, C1, A2, B2, C2), with the same dose reduction in cycles C1, A2, B2, C2 in patients ≤55 years in CR after B1 cycle. Patients >55 years received reduced intensity chemotherapy (as in BURKIMAB08) in both induction and post-induction cycles. The CR rate, cumulated incidence of relapse (CIR) and OS were analyzed and compared with those from the BURKIMAB08 trial. Results. From 2014-2019, 80 patients with BL/L were enrolled. Median age (range): 48 (17-80) years, 57 (71%) ≤55 years, 61 males (76%), 15 (19%) patients in stages I-II non-bulky and 65 (81%) in stages III-IV, 25 of whom (38%) had mature B-ALL. 18 patients (23%) were HIV positive, 13 (17%) showed CNS involvement at diagnosis and 23 (31%) bulky mass (>10 cm). 45 patients (60%) had intermediate-high or high IPI. All patients in stages I-II non-bulky showed CR. 4/65 patients in stages III-IV or mature B-ALL are receiving induction therapy, 1/65 withdrew the trial, 7/60 (12%) died in induction, 2/60 (3%) were resistant and 51/60 (85%) achieved CR. Of them, 6 relapsed, 3 withdrew the trial and 3 died in CR (one in the group of localized stage). OS probability at 3 years was 74% (95%CI: 64%-84%) (localized stages 100% [NE], advanced stages 68% [56%-80%], p=0.047, without difference in patients in stages III-IV vs. mature B-ALL, Figure 1). Patients >55 years showed a significantly lower probability of OS (61% [41%-81%] vs. 80% [68%-92%], p=0.022, Figure 2). A lower but non-statistically significant OS probability was observed in HIV-infected vs. non-HIV-positive patients (61% [36%-86%] vs. 78% [67%-89%], p=0.310). The CIR for patients in advanced stage/mature B-ALL was 13% (3%-28%)A trend for lower death rate in CR was observed in BURKIMAB14 vs. BURKIMAB 08 trial (3/62 vs. 16/151, p=0.180), without differences in CIR (9% [3%-21%] vs. 12% [6%-20%]) or in OS (74% [64%-84%] vs. 72% [65%-79%], respectively). Conclusions. The results of the BURKIMAB14 trial are promising, especially for patients in localized stages and for those Supported in part with the grants PI14/01971 FIS, Instituto Carlos III, SGR 288 (GRC) y Fundación "La Caixa". Figure 1. OS according to stage (I-II, vs. III-IV vs. mature B ALL) Figure 2. OS according to age (≤55 y vs >55 y) Figure 1 Disclosures Abrisqueta: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Fernandez:Teva: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, 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, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Sancho:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001). RESULTS There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001). To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, 12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients. Disclosures Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos: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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; 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.

Introduction: The phase 3 international, randomized, double-blind ROBUST clinical trial (NCT02285062) compared progression-free survival between patients with previously untreated ABC-type DLBCL treated with placebo plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (placebo-R-CHOP) versus lenalidomide + R-CHOP (R2-CHOP) for 6 21-day cycles. HRQoL, as measured by the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EuroQoL 5-dimension 3-level (EQ-5D-3L) patient-reported questionnaires, was evaluated as a secondary endpoint for the 2 treatment arms. Methods: For each treatment group, FACT-Lym and EQ-5D-3L scores were measured at baseline (BL), mid-, end-of-treatment (EOT), and post-treatment, in 12-week intervals from Week 34 onward. Patients were evaluated if they had completed BL and ≥ 1 post-BL calculable FACT-Lym subscale measurements. Non-inferiority (NI) of R2-CHOP versus placebo-R-CHOP was measured for 4 key FACT-Lym subscales: Physical Well-Being (PWB), Additional Concerns (AC), Functional Well-Being (FWB), and Trial Outcome Index (TOI). NI was assessed at EOT (typically 3-4 weeks after completing Cycle 6) and at post-treatment follow-up at Week 34 by analysis of covariance (ANCOVA). The NI margins were prespecified as 1 less than the higher published minimal important difference (MID) for each subscale. Since a range of MIDs have been published, a more conservative value was also used as a sensitivity analysis. Time to improvement (TTI), using published responder definitions, was also assessed for the FACT-Lym subscales. EQ-5D-3L scores were summarized descriptively. Results: Demographic and baseline disease characteristics were balanced across the 2 treatment arms (N = 285 per arm). The percentage of patients who completed the FACT-Lym out of the expected population remained > 85% at all time points with > 50 patients still on the study in each treatment arm up to Week 142. Completion rates and reasons for missing assessments were balanced across the 2 treatment arms. FACT-Lym subscale scores were generally higher after EOT, similar for both treatment groups, and mean changes from BL were close to or above MID (where defined), except for the Social/Family Well-Being subscale. Mean differences in FACT-Lym TOI between treatment arms are shown in Table 1. As positive treatment differences favor R2-CHOP and -10 was the predefined NI margin, NI was demonstrated for the FACT-Lym TOI subscale at both EOT and Week 34 assessments. Superiority of R2-CHOP was demonstrated at EOT as the confidence interval (CI) lies completely above 0 (P < 0.04); however, this difference was not clinically meaningful. Furthermore, NI was also demonstrated when using the sensitivity analysis margin of -4.5. ANCOVA models were also fitted for the other key subscales of PWB, AC and FWB (Table 2). NI was demonstrated for all NI margins at both time points for the PWB and AC subscales. The FACT-Lym FWB subscale demonstrated NI for both margins at EOT and Week 34 for the primary NI margin of -2 based on the MID minus 1, but did not demonstrate NI when an NI margin of -1, based on an alternative published MID, was used. The TTI curves and associated summary statistics were similar for the 2 treatment arms, with a median TTI for the FACT-Lym TOI of 21 weeks (95% CI 15-22) for patients treated with R2-CHOP and 18 weeks (95% CI 15-22) for patients treated with placebo-R-CHOP. Mean EQ-5D-3L visual analogue scale (VAS) and Utility Index (UK weights) change from baseline scores were higher in both treatment arms and the mean changes were above, or close to, the published MID (7 for VAS, 0.1 for Utility Index) at EOT assessments. Prespecified sensitivity and subgroup analyses supported the conclusions from the primary HRQoL analyses. Conclusions: The predefined NI levels were met for the 4 key FACT-Lym subscales. Similar results were observed across the other HRQoL assessments, sensitivity, and subgroup analyses. Adding lenalidomide to the R-CHOP regimen did not adversely affect the HRQoL of patients with DLBCL as measured by FACT-Lym and EQ-5D-3L. These data serve as a benchmark for future clinical trials combining next-generation immunomodulatory drugs with standard R-CHOP to improve clinical efficacy while maintaining HRQoL in patients with DLBCL. HRQoL analyses should become an integral part of future clinical trials of novel combination regimens in DLBCL. Disclosures Chiappella: Roche: Speakers Bureau; Teva: Speakers Bureau; Servier: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau. Cocks:Adelphi Values: Employment; Amgen: Consultancy; BMS: Consultancy; Celgene Corporation: Consultancy; Endomag Ltd.: Consultancy. Greenwood:Adelphi Values: Employment. Williams:Adelphi Values: Employment. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Janssen: Consultancy, Research Funding. Yamamoto:SymBio: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Astra-Zeneca: Consultancy, Research Funding; Sumitomo Dainippon: Honoraria; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Gilead Sciences: Research Funding; Solasia Pharma: Research Funding; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; ARIAD: Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Kyowa Kirin: Honoraria; MSD: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; HUYA/IQVIA Services Japan: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jurczak:Bayer: Research Funding; Takeda: Research Funding; Gilead: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Incyte: Research Funding; Celgene Corporation: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding. Özcan:Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; BMS: Other: Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding; Bayer: Research Funding; Janssen: Other: Travel support, Research Funding; Celgene Corporation: Research Funding, Travel support; AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Jazz: Other: Travel support; Amgen: Honoraria, Other: Travel support. Belada:Roche: Consultancy; Gilead Sciences: Consultancy; Takeda: Consultancy. Margunato-Debay:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Zhai:Celgene Corporation: Employment, Equity Ownership. Braverman:Celgene Corporation: Employment. Vitolo:Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

Introduction: Multiple Myeloma (MM) is an incurable disease. In young patients, autologous bone marrow transplantation (ABMT) remains a cornerstone treatment after induction therapy. Induction therapy has varied during time, from alkylating polychemotherapy (VBAD,VCMP) or VAD chemotherapy (AVAD) to Velcade-Dexametasone based regimens (VD). We present results of follow-up of a large cohort of patients treated with ABMT. We described overall survival (OS; from transplant to death by any cause) and progression free survival (PFS; from transplant to death by any case or progressive disease defined by reappearance by inmunofixation, or duplication of monoclonal peak after ABMT) , and the impact of induction therapy regiments. Patients: 183 patients transplanted from 2002 to 2017. The median age of the patients was 59 years (33-72). Before 2008 all the patients were treated in alkylating based chemotherapy (42 patients). After 2008 patients were treated with VD based regimens (141patients). Only 12 patients received maintenance therapy based in PETHEMA trials 2005 and 2012. No one patient received a planed second transplant; only 32 patients received a second transplant after relapse as consolidation therapy. Results: Median follow-up of patients still alive is 3.65 years (0.15-14.77). Median OS of all patients was 9.12 years (95% confidence interval (CI): 6.28-NR); Median PFS was 3.02 years(95% CI: 2.46-3.76). At 13 years only 2% of patients remains progression free (CI: 0.00-17%). There were significant differences between patients treated before and after VD regimens. The median OS of patients treated with APVAD was significantly shorter compared to VD (6.22 years, CI[3.39-12] vs. NR, CI[6.28-NR], p=0.025) (HR=0.49, p=0.01). Conclusions: VD schemes of induction before ABMT have improved remarkably OS inpatients with Myeloma; nonetheless, plateau is not observed in EFS. Further analysis must address if EFS could represent a strong indicator of OS, mainly due to novel effective salvage therapies after relapse/refractoriness could be a confounding factor. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Introduction and Objective: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-NT) is associated with Epstein-Barr virus (EBV) and is much more common in Asia and Latin America than in western countries. Data on disease presentation and outcome from European series are very limited. The objective of the study is to analyze the clinical characteristics at diagnosis, treatment received and outcome of a series of patients from Spain. Patients and Methods: Eigthy-seven patients with ENKTL-NT diagnosed from 2000 to 2017 were identified in 24 academic centers in Spain. Clinical data were collected retrospectively. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Variables included in the univariate analysis were: race, gender, age, previous sinusitis, nasal localization, Ann Arbor stage, ECOG performance status (PS), B symptoms, LDH, beta2-microglobulin, albumin and C-reactive protein. Multivariate analyses were performed by Cox proportional hazard regression model. Results: Clinical characteristics at diagnosis are shown in Table 1. Seventy-seven patients received active treatment, 31 (40%) with chemotherapy (CT) alone, 39 (51%) with CT and radiotherapy (RT), 7 (9%) with RT alone (median dose 50 Gy). First line therapies were: CHOP/CHOP-like in 30 (42%) patients, high-dose L-Asparaginase-containing regimens in 27 (38%), and other regimens in 14 (20%); 12 patients proceeded to stem-cell transplant in first line (10 auto / 2 allo). Response rate was evaluable in 70 patients (by PET/TC in 55%): CR 35 (50%), PR 9 (13%), SD/progression 26 (37%). Median number of CT lines was 2 (1-6). With a median follow-up of 38 months, 3 yr OS was 38% (95% CI 27-49), and 3 yr PFS 25% (95% CI 14-35). Causes of death were: progression 35 (67%), toxicity 12 (23%), second neoplasms 5 (10%). The variables at diagnosis significantly associated with poor OS were: age ≥ 60 yr, extranasal disease, Ann Arbor III-IV, ECOG PS 2-4, increased LDH, and decreased albumin. In the multivariate analysis including all the previous variables, ECOG 2-4 PS (HR 3.3, 95% CI 1.4-7.0) and low albumin (HR 3.6, 95% CI 1.4-9.3) maintained the negative influence in OS. Patients treated with regimens that included high dose L-Asparaginase had 3 yr OS of 61% (95%CI 40-82), compared with patients treated with CHOP/CHOP-like 3 yr OS of 19% (95%CI 5-32) (p=0.009). These differences were statistically significant both in patients with nasal involvement (3 yr OS 82% with L-Asparaginase vs 21% with CHOP, p=0.01) or with localized disease (3 yr OS 71% with L-Asparaginase vs 24% with CHOP, p=0.03). Differences were not statistically significant in patients with extranasal involvement (3 yr OS 48% with L-Asparaginase vs 14% with RCHOP, p=0.2), or advance disease (3 yr OS 48% with L-Asparaginase vs 14% with CHOP, p=0.2), probably because the low number of patients. Conclusion: This is the largest series reported of Caucasian patients with ENKTL-NT. Patients are young at diagnosis and one fourth had a previous history of chronic sinusitis. This population has a poor outcome, being progression the main cause of death. Poor clinical condition at diagnosis (high ECOG PS and low albumin level) is the main factor related with poor survival. Therapies with high dose L-Asparaginase improve the survival in this western population compared with the classical CHOP regimen. Disclosures González-Barca: Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Martín:Celgene: Consultancy, Honoraria, Other: Travel expenses; Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Panizo:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Sanchez Blanco:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria. Marin Niebla:Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Amgen: Other: Medical education of Staff, Speakers Bureau. Queizan:Janssen: Consultancy. Lopez:Roche: Research Funding.

Cytogenetic analysis is still an important and mandatory component of Acute Myeloid Leukemia (AML) diagnosis and prognosis. Pretreatment cytogenetic and molecular genetic findings are one of the major independent prognostic markers in AML, and they determine chemotherapy response and outcome. However, cytogenetic does not provide alternative treatments when a patient have a high cytogenetic risk, and requires relatively long time until obtaining the results despite the treatment of these patients should begin as soon as possible. The aim of this study is providing data about the utility of a new AML Precision Medicine (PM) Test as a complementary tool to conventional cytogenetic to overcome the main obstacles this later has. For this purpose, AML bone marrow from 111 patients were received at the laboratory 24h from extraction and incubated for 48h in 96-well plates containing single drugs or combinations, representing up to 31 different treatments that are currently given in the clinical practice. The analyses were performed in the automated flow cytometry PharmaFlow platform and the test results can be sent to the hematologists 72h after the extraction of the sample. Pharmacological responses were calculated using pharmacokinetic population models. Induction response was assessed according to the Cheson criteria (2003). Patients attaining a complete remission (CR) or CR with incomplete blood count recovery (CRi) were classified as responders and the remaining as resistant, excluding early deaths. The probability of being resistant or non-responder was modeled using binary logistic generalized additive models (GAM) with Cytarabine (CYT) and Idarubicin (IDA) area under the curve (AUC) data and over the cytogenetic risk (favorable/intermediate/adverse). The empirical ROC curves were calculated for the probabilities of being non-responder from each GAM. Final scores and treatments ranking are based on a therapeutic algorithm that integrates ex vivo activity of single drugs, quantified by the AUC and synergism, referred as α parameter, using a surface interaction model. Clinical and cytogenetic risk data of the patients were monitored and collected. A simple logistic model of the probability of being non-responder over the cytogenetic risk (favorable/intermediate/adverse) explained less variability (29.4%) than the GAM over the AUC values (40.8%) in the subset of 111 patients in whom the cytogenetic risk was informed. Figure 1 shows the results of the clinical correlation of cytogenetics vs PM Test in the cohort of 111 patients analyzed. In both approaches prediction of sensitive patients (Negative Prediction Value, NPV) is better than resistant patients (Positive Predictive Value, PPV), being the PM Test slightly better in predicting the sensitive patients (NPV=93% vs 88%), while the cytogenetics shows a 20% improvement in the prediction of resistant patients (PPV= 76% vs 56% with PM Test). The correlation achieved by the PharmaFlow PM test was 80% that is almost similar than the correlation obtained with the cytogenetic data using the same cut off point (86%). Figure 1 (right) also shows an example of the classification of AML treatments with the PharmaFlow PM Test in a patient sample according to a color scale from higher (green) to lower (red) ex vivo activity. In summary, despite the PharmaFlow PM Test and cytogenetics provide similar information, results from cytogenetic risk are available typically in 10-14 days, and thus after patient treatment, while results from this novel PM Test are available in 48-72h, prior to treatment. Hence, this novel approach provides information to hematologist with higher predictive value than risk factor (deviance explained 40.8% vs 29.4%) and ahead of treatment, and thus represent a valuable in-time prior to treatment decision making. In addition, the PM Test can provide alternative treatments to AML patient in a basis of their ex vivo activity. Disclosures Ballesteros: Vivia Biotech: Employment. Martinez Lopez:Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. Hernandez:Vivia Biotech: Employment. Primo:Vivia Biotech: Employment. Gorrochategui:Vivia Biotech: Employment. Rojas:Vivia Biotech: Employment. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Background Multiple studies have shown the clinical activity of alvocidib followed by cytarabine and mitoxantrone in newly diagnosed and relapsed/refractory (R/R) AML. Alvocidib's anti-leukemic pharmacologic activity appears to be predominantly due to the inhibition of transcriptional regulator, CDK9, resulting in suppression of CDK9-regulated genes, such as the BCL-2 family member, MCL-1. Pre-treatment bone marrow samples from newly diagnosed AML patients revealed an increased sensitivity to alvocidib in those with MCL-1 dependence of ≥40% as measured by a BH3 profiling biomarker assay (J Clin Oncol 33, 2015 suppl; 7062). Thus, we hypothesized that alvocidib, followed by cytarabine and mitoxantrone, may be preferentially active in those with MCL-1 dependence (≥ 40%). Here, the findings from stage 1 of the Zella 201 trial in which this biomarker assay is used to select for patients with MCL-1 dependence, are reported. Aims To evaluate the efficacy and safety of alvocidib, in combination with cytarabine and mitoxantrone, in MCL-1 dependent R/R AML patients. Methods The key eligibility criteria were: ages 18-65 years; refractory to 1-2 cycles of induction therapy, or in first relapse AML with complete remission (CR) duration ≤ 2 years; ≥ 40% myeloblast MCL-1 dependency determined by BH3 profiling; ECOG PS 0-2; and no major organ dysfunction. Patients who received prior allogeneic stem cell transplant (alloSCT) were eligible, if it was greater than two months after SCT and there was no active GVHD. Treatment consisted of alvocidib 30 mg/m2 as a 30-minute IV bolus followed by 60 mg/m2 over 4 hours on Days 1-3, cytarabine 667 mg/m2/day by continuous IV infusion days 6-8, and mitoxantrone 40 mg/m2 IV on day 9 starting 12 hours after completing cytarabine. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permittedin responders. The primary endpoint was the rate of CR+CR with incomplete recovery (CRi). Stage I was determined to be positive if ≥13 CRs were seenin the first 23 evaluable patients. Key secondary endpoints were overall survival, event-freesurvival, the combinedresponse rate and safety assessed by adverse events and laboratory results. Results A total of 163 patients were screened, of which 47 (29%) were determined to be MCL-1 dependent. Of these, 25 patients were enrolledin Stage 1 (Table 1), with 21 evaluable for response. Median MCL-1 dependence score was 55% (range: 41-98%). Of the 21 evaluable patients, 11 (52%) were refractory to frontline therapy (resistant disease or CR < 90d). The overall CR/CRi rate in evaluable patients was 62% (13/21) meeting the primary endpoint of stage 1. Seven out of 11 (64%) patients with primary refractory disease achieved a CR and five of these patients proceeded to an alloSCT. Overall, 10 patients received a post-study alloSCT. The most common NCI CTCAE ≥Grade 3treatment-emergent nonhematologic AEs noted in >1 patient in the safety population (n=25) were tumor lysis syndrome (20% Grade 3, 8% Grade 4); diarrhea (24% Grade 3); increased AST (12% Grade 3, 8% Grade 4), sepsis (16% Grade 5, 4% Grade 4); and peripheral edema, (8% Grade 3). To date, overall 30- and 60-day mortality rates were 16% and 20%, respectively, due to sepsis (n=4), and mitral valve rupture (n=1). Conclusion Our findings indicate that alvocidib given beforecytarabine and mitoxantrone in MCL-1-dependent AML has clinical activity, particularly in those refractory to frontline therapy. Given these findings, stage 2 of the Zella 201 trial has been initiated,randomizing patients to alvocidib, cytarabine, and mitoxantrone versus cytarabine and mitoxantrone alone in MCL-1 dependent R/R AML. Furthermore, a Phase Ib study of alvocidib followed by 7+3 induction in newly diagnosed AML (Zella 101) is being conducted. Disclosures Zeidner: Rafael Pharmaceuticals: Other: Travel Fees; Takeda: Other: Travel fees, Research Funding; Merck: Research Funding; Asystbio Laboratories: Consultancy; Tolero: Honoraria, Other: Travel Fees, Research Funding; Celgene: Honoraria. Lin:Jazz Pharmaceuticals: Honoraria. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Anthony:Tolero Pharmaceuticals, Inc: Employment. Bearss:Tolero Pharmaceuticals, Inc: Employment.

Hypomethylating agents are able to prolong the overall survival of some patients diagnosed with acute myeloid leukemia. The aim of this study was to evaluate the clinical use of azacitidine as front-line therapy in unfit acute myeloid leukemia (AML) patients and to develop a clinical prediction model to identify which patients may benefit more from the drug. One hundred and ten untreated unfit AML patients received front-line azacitidine therapy in Spain, and response and survival were evaluated in them following European LeukemiaNet (ELN) guidelines. A clinical prediction rule was obtained from this population that was validated and refined in 261 patients treated in France, Austria and Italy. ELN response was achieved in 21.0% of the 371 patients (CI95% 17.0-25.5) and did not depend on bone marrow blast cell percentage. Median overall survival was 9.6 months (CI95% 8.5-10.8) and 40.6% of the patients were alive at 1 year (CI95% 35.5-45.7). European ALMA score (E-ALMA), based on performance status, white blood cell counts at azacitidine onset and cytogenetics, discriminated three risk groups with different survival and response rates. Azacitidine seems a reasonable therapeutic option for most unfit AML patients, i.e. those displaying a favorable or intermediate E-ALMA score. (C) 2014 Elsevier Ltd. All rights reserved.

We analyzed the value of new NCCN-IPI index in patients affected of Large B cell lymphoma (LBCL) treated with DA-EPOCH-R in order to assess the validity of this index in patients treated homogenously with dose adjusted R-EPOCH. Patients and protocol: We analyzed the use of NCCN-IPI (Zhou et al, 2014) index in a retrospective cohort of 98 DLBCL patients treated with -EPOCH. These patients were included in DA-EPOCH using IPI(Shipp M.A., 1993) as criteria of inclusion, including only patients (95 patients, 96%)with suspected bad prognosis based in IPI (2-5) and 3 patients with primary mediastinal large B cell lymphoma (PMLBCL). R-EPOCH was administered as reported previously(Wilson et al, 2013). Only 10 patients (10%) were Ann Arbor stage I or II. Results: The median age of the cohort was 57,13(15-82), 47 woman, 75 patients alived. The median follow-up of the patients alive is 6,7 years (1,3-11). Ann Arbor stage was IVB in 44 patients, and IVA in 21. Responses during treatment: Complete response (CR): 81 (82%), refractory during treatment: 7 (7%), death during treatment: 7 (7%). The number of patients who relapsed after treatment was 19 (20%). The median overall (OS) survival of all patients was not reached, (at 5 years, 0.669, CI: 0.562-0.798). The progression free survival (PFS) at 5 years is 0.62, CI: 0.483-0.795. We classify by the new NCCN-IPI the patients in Low-Intermediate risk (L-I)(3 patients, 3%), High-Intermediate risk (H-I)(38, 44%) and High risk (HR) (45, 52%). The OS at 5 years in H-I is 0.839 (CI: 0.73-0.96) and HR was 0.56 (CI: 0.421-0.754), p=0.025. The PFS at 5 years in H-I is 0.65 (CI: 0.518-0.826) and HR is 0.57 (CI: 0.43-0.755), p=0.4. Conclusions: NCCN-IPI discriminates well prognosis between HR/H-I patients with DLBCNHL treated with DA-EPOCH-R. The results of this retrospective analysis of high and intermediate high-risk patients compares better than the published in patients treated with R-CHOP. PFS were similar in H-I and HR; differences in OS could be explain by differences in outcome after salvage treatment with autologous stem cell Disclosures No relevant conflicts of interest to declare.