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The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

In this randomized phase 2 study (GEM-KyCyDex), the combination of weekly carfilzomib 70 mg/m2, cyclophosphamide and dexamethasone was compared to carfilzomib and dexamethasone (Kd) in relapsed/refractory multiple myeloma (RRMM) after 1-3 prior lines (PLs). 197 patients were included and randomized 1:1 to receive KCd (97 patients) or Kd (100 patients) in 28-day cycles until progressive disease or unacceptable toxicity occurred. Patient median age was 70 years, and the median number of PLs was 1 (1-3). More than 90% of patients had previously been exposed to proteasome inhibitors, ≈70% to immunomodulators, and ≈50% were refractory to their last line (mainly lenalidomide) in both groups. After a median follow-up of 37 months, median progression-free survival (PFS) was 19.1 and 16.6 months in KCd and Kd, respectively (P=0.577). Of note, in the post hoc analysis of the lenalidomiderefractory population, the addition of cyclophosphamide to Kd resulted in a significant benefit in terms of PFS: 18.4 vs. 11.3 months (Hazard ratio 1.7 [1.1-2.7]; P=0.043). The overall response rate and the percentage of patients who achieved complete response was around 70% and 20% in both groups. The addition of cyclophosphamide to Kd did not result in any safety signal, except for severe infections (7% vs. 2%). In conclusion, the combination of cyclophosphamide with Kd 70 mg/m2 weekly does not improve outcomes as compared with Kd alone in RRMM after 1-3 PLs, but a significant benefit in PFS was observed with the triplet in the lenalidomide-refractory population. The administration of weekly carfilzomib 70 mg/m2 was safe and convenient, and, overall, the toxicity was manageable in both arms.

Purpose:TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas.Patients and Methods:Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD.Results:Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT).Conclusions:TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

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We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Background: Evaluation of MRD is standard in patients with AML. However, the role of decentralized MRD assessment for risk stratification in AML remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using MFC. Aim: To evaluate the role of decentralized MRD assessment using MFC for risk stratification and putative treatment individualization of patients with AML. Methods: This study was performed on 1,076 AML patients in complete remission (CR) after 7+3 induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories over a period of 20 years in the PETHEMA group. We conducted a survey of technical aspects of MFC based MRD testing in the laboratories of the 60 participating Hospitals, to determine the impact of methodological heterogeneity in the prognostic value of MFC. Results: We first investigated the most effective MRD cutoff to stratify patients' risk at first remission. Patients were segmented into progressively higher cutoffs, starting at 0.01% followed by 0.05%, 0.1%, 0.5% and 1%. Our results showed that 0.1% reached higher statistical significance to discriminate patients with different relapse-free survival (RFS, HR: 0.77; P = .001) and overall survival (OS, HR: 0.73; P = .001). In multivariate analyses together with patients' age, WBC, genetic risk and post-consolidation therapy, MRD status was selected as an independent prognostic factor for OS. To further define the utility of "real-world" MRD assessment using MFC in risk stratification of AML, recursive partitioning was performed using the prognostic and treatment related factors selected in the multivariate Cox model for OS. Of the four variables evaluated, hematopoietic stem cell transplantation (HSCT, regardless of autologous or allogeneic source) vs no transplant emerged as the best single discriminator for OS, followed by genetic risk, age and MRD status. There were two branching points defined by MRD status; the first in patients ≤60 years with intermediate genetic risk who were not transplanted and the second in patients with adverse genetics who were not transplanted, in whom Forty-nine of the 60 hospitals (82%) responded to the survey on questions regarding the measurement of MRD using MFC in the PETHEMA LMA 1999, 2007 and 2010 protocols, providing information corresponding to 966 of the 1,076 (90%) patients regarding the number of markers, preparation of samples, instruments, approach (ie, LAIP, DfN or LAIP+DfN), number of cells to define a cluster, etc. The survey revealed significant heterogeneity intra- and inter-protocols that reflected improvement in MFC assessment of MRD over time, in the absence of harmonization nor standardization at the national level. Accordingly, we investigated if the heterogeneity in methodological, interpretation and reporting aspects of MFC based MRD testing were hampering its ability to predict outcome independently of other patient and treatment related factors. Strikingly, our results showed that except for the denominator used to calculate MRD burden (ie, total nucleated cells vs leukocytes), lack of standardization in all other parameters had an impact on the ability of MFC to predict outcomes in AML (Figure). Namely, panels with ≤4 markers or ≤2 combinations failed to identify patients with significantly different RFS according to MRD status, and MFC-based MRD monitoring was prognostic only when >500,000 cells were measured. Only MRD assessment using patient-specific panels was predictive of outcome. Conclusions: We report here one of the largest studies investigating the role of MRD monitoring using MFC. Our results confirmed that detection of MRD identifies patients in CR/CRi with inferior survival, but uncovered that decentralized MRD testing lacks significance when compared to other baseline risk factors and in the context of risk-adapted post-consolidation strategies. Thus, while this study demonstrated that "real-world" decentralized assessment of MRD using MFC does provide prognostic information in AML patients at first remission, our results question its readiness for risk stratification towards clinical decisions outside trials, at least until adequate standardization of this technique is achieved. Figure Disclosures Paiva: SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Alonso Dominguez:Celgene: Research Funding; Incyte: Research Funding; Pfizer: Research Funding. Martinez-Lopez:Janssen: Speakers Bureau; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Roche: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Vivia Biotech: Honoraria; Novartis: Research Funding; BMS: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Sossa:Astellas: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novo: Honoraria. San-Miguel:Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

Objective: To calculate, for the first time, the direct and social costs of transfusion-related adverse events in order to include them in the National Healthcare System's budget, calculation and studies. In Spain more than 1,500 patients yearly are diagnosed with such adverse events. Method: Blood transfusion-related adverse events recorded yearly in Spanish haemovigilance reports were studied retrospectively (2010-2015). The adverse events were coded according to the classification of Diagnosis-Related Groups. The direct healthcare costs were obtained from public information sources. The productivity loss (social cost) associated with adverse events was calculated using the human capital and hedonic salary methodologies. Results: In 2015, 1,588 patients had adverse events that resulted in direct health care costs (4,568,914€) and social costs due to hospitalization (200,724€). Three adverse reactions resulted in patient death (at a social cost of 1,364,805€). In total, the cost of blood transfusion-related adverse events was 6,134,443€ in Spain. For the period 2010-2015: the trends show a reduction in the total amount of transfusions (2 vs. 1.91 M€; -4.4%). The number of adverse events increased (822 vs. 1,588; +93%), as well as their related direct healthcare cost (3.22 vs. 4.57M€; +42%) and the social cost of hospitalization (110 vs 200M€; +83%). Mortality costs decreased (2.65 vs. 1.36M€; -48%). Discussion: This is the first time that the costs of post-transfusion adverse events have been calculated in Spain. These new figures and trends should be taken into consideration in any cost-effectiveness study or trial of new surgical techniques or sanitary policies that influence blood transfusion activities. Resumen: Objetivo: Calcular por primera vez los costes económicos y sociales relacionados con las reacciones adversas postransfusionales para actualizar estudios e incluirlos en los presupuestos del Sistema Nacional de Salud. En España, anualmente, más de 1500 pacientes sufren dichas reacciones adversas. Método: Se estudiaron retrospectivamente (periodo 2010-2015) las reacciones adversas a la transfusión recopiladas anualmente en los informes nacionales de hemovigilancia. Dichas reacciones se codificaron mediante clasificación de Grupos Relacionados con el Diagnóstico. Los costes directos sanitarios se obtuvieron de fuentes públicas de información. La pérdida en productividad (coste social) asociada a las reacciones adversas se contabilizó utilizando los métodos del capital humano y salarios hedónicos, respectivamente. Resultados: En el año 2015, en España, 1588 pacientes tuvieron reacciones adversas que derivaron en costes sanitarios (4.568.914 €) y costes sociales debido a hospitalización (200.724 €). Tres reacciones adversas resultaron en muerte del paciente (1.364.805 €). Como suma, el coste total de las reacciones adversas a la transfusión fue de 6.134.443 €. Periodo 2010-2015: la tendencia refleja una reducción en el número total de transfusiones (2 vs. 1,91 M€; -4,4%), un incremento en el número de reacciones adversas (822 vs. 1.588; +93%), en costes sanitarios (3,22 vs. 4,57M€; +42%) y en costes sociales (110 vs. 200M€; +83%), y un descenso en costes de mortalidad (2,65 vs. 1,36M€; -48%). Discusión: Por primera vez se han calculado en España los costes de las reacciones adversas a la transfusión. Los nuevos datos y tendencias deberían ser considerados en estudios de coste-eficiencia sobre técnicas quirúrgicas o políticas sanitarias con repercusión en actividades de transfusión sanguínea. Keywords: Adverse effects, Blood transfusion, Health care costs, Costs and cost analysis, Trends, Palabras clave: Reacciones adversas, Transfusión sanguínea, Costes de la atención en salud, Costes y análisis de costes, Tendencias

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

Background: Phase I clinical trial for oncology drugs have the highest clinical failure rate. Drug candidates may be discarded if they don´t show activity. Yet these drugs may have valuable activity in patient subgroups. Biomarkers attempt to identify these sensitive subpopulations, but are normally evaluated and validated in Phase II when good drugs may have been discarded. OPB-111077 is a novel, oral, low-molecular-weight compound that inhibits STAT3 and mitochondrial electron transport. A prior Phase I trial on 145 patients from all tumor types gave only 1 partial response (PR). A strong anti-proliferative activity was identified in Acute Myeloid Leukemia (AML) samples ex vivo. This new biomarker was used for patient selection in this trial. We present a novel design of a Phase Ib trial directly selecting patients with a potential biomarker, that can benefit the patient without increasing toxicity risks, in Relapsed/Refractory (RR) AML patients. Method: This is an open-label, phase Ib dose-escalation clinical trial to evaluate the safety profile, maximum tolerated dose (MTD) and preliminary efficacy of oral OPB-111077 in AML relapsed or refractory to chemotherapy patients. Patients > 18 years old with high risk AML, ECOG ≤2 and adequate organ functions were selected for biomarker screening. Biomarker consisted on a dose response curve for antiproliferative activity of agent in a bone marrow sample of patients incubated 72-96-120h (Figure), quantified as the Area Under the Curve (AUC). Patient samples whose ex vivo biomarker showed low sensitivity (70% worst) we excluded, since they were potentially predicted as resistant to the agent. The remaining 30% with higher sensitivity were included. OPB-111077 was administered orally on a once daily dose schedule in 28-day cycles until intolerable toxicity or disease progression. Two dose schemas were evaluated: 200 (DL1) and 250 mg/day (DL2). Dose limiting toxicities were any Grade ≥ 3 non-hematologic toxicity and any unexpected non-tolerable grade II that requires delay beyond 1 week until recovery and evaluated during the first 28 days of treatment. Adverse events were graded according to NCI-CTCAE vs 4.03 and response criteria was based on those given by Cheson et al. IC50 and area under the curve (AUC) determined by the Vivia ex vivo biomarker were correlated with clinical response. Results: We screened 47 RR AML patients, twelve patients were included and selected by personalized medicine test (5 in DL1 and 7 in DL2), median age 76 years, 92% men, 42% ECOG 0 were included in the study. AML patients were refractory in 41.7% and patients were in median of relapses 2 (range 1-6). No DLT was reported. Adverse events related to study treatment were reported in three patients, all G 1-2: in DL1 one patient had vomiting; in DL2 one patient had extrasystoles and other had anorexia, diarrhoea, epigastric discomfort, nausea and vomiting. Two patients died during study treatment due to disease progression and respiratory infection. Half of the patients discontinued study treatment due to disease progression and 25% due to adverse events (respiratory failure G5, respiratory infection G5 and extrasystoles G2). Over the 6 patients evaluable for efficacy, 3 of them achieved PR and 3 treatment failure as best response. Progression free survival and overall survival were 57 days (95% CI: 37 - 77) and 95 days (95% CI: 27 - 163) respectively. The biomarker AUC and IC50 values stratified patients consistent with their clinical response, although without enough sampling potency for statistical significance. Figure shows the relative position of patients included in the study in the context of the overall population of samples considered to build up the mixed effect population pharmacodynamic model used to analyze samples results and define inclusion criteria. In green those that correspond to patients who showed a positive response; in orange those who failed. Conclusions: OPB-111077 is generally well tolerated and has a manageable toxicity profile. The MTD was not reached. The 50% PR rate achieved by OPB-111077, albeit in a few patients, is substantially higher that the 0.7% (1/145) PR rate achieved in a prior phase I trial on all tumor types1. This innovative Phase Ib design selecting patients using a biomarker may enable to rescue drug failures in the future. References: 1. Tolcher A, Flaherty K, Shapiro GI et al. Oncologist. 2018, 23(6):658-e72 Figure Disclosures Martinez-Lopez: Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BMS: Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Vivia Biotech: Honoraria; Altum: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novartis: Research Funding; Takeda: Speakers Bureau; Incyte: Research Funding, Speakers Bureau. Gorrochategui:VIVIA BIOTECH: Current Employment. Rojas:VIVIA BIOTECH, S.L.: Current Employment. Primo:Vivia Biotech: Current Employment. Perez De Oteyza:MACROGENICS: Research Funding. Ballesteros:Vivia Biotech: Current Employment.

Introduction: Carfilzomib dosed at 56 mg/m2 twice a week in combination with dexamethasone (Kd) is a standard of care for RRMM after 1-3 prior lines (PL) based on the ENDEAVOR study. Later, the ARROW study showed Kd dosed at 70 mg/m2 weekly to be superior to Kd dosed at 27 mg/m2 twice a week on RRMM patients (pts) after 2-3 PL. On the other side, Cyclophosphamide is an alkylating agent that has been widely combined with proteasome inhibitors and immunomodulatory drugs in MM, improving their efficacy with a good safety profile. In this phase 2 randomized study, we have compared Kd plus cyclophosphamide (KCyd) with Kd in RRMM after 1-3PL, both with K dosed weekly at 70 mg/m2. Patients and methods: RRMM after 1-3 PL of therapy were included in the trial. Consistently with the ENDEAVOR population, previous therapy with proteasome inhibitors was allowed but refractory patients were excluded. Pts were randomized 1:1 to receive K at a dose of 70 mg/m2 iv on days 1, 8 and 15 plus dexamethasone at a dose of 20 mg PO the day on and the day after K plus/minus KCyd at a dose of 300 mg/m2 IV on days 1, 8 and 15 of each 28 days-cycle, as continuous treatment until progressive disease or unacceptable toxicity. The primary endpoint was PFS and key secondary endpoints included response rates, safety profile, and OS. Results: Between January 2018 and February 2020, 198 RRMM pts were included. 97 pts were randomized to KCyd and 101 to Kd. The baseline characteristics of the patients were well balanced between both groups. The median age was 70 years, and 70% and 28% of pts were older than 65 and 75. The median number of PL was one; 61% of pts had received 1 prior line. 94% and 92% of patients had been exposed to bortezomib in the KCyd and Kd and all of them were sensitive. 72% and 67% of patients had been exposed to IMiD's and 51% and 55% of them were IMiD's-refractory in the KCyd and Kd. Only 4 and 6 patients in KCyd and Kd, had received anti-CD38 antibodies being all refractory. After a median f/u of 15.6 months, median PFS was 20.7 m and 15.2 m in KCyd and Kd (p=0.2). In pts after 1PL, median PFS has not been reached in any arm (p=0.4) and in patients after 2-3PL, KCyd resulted in a median PFS of 20.7 vs 11m for Kd (p=0.4). Of note, in the IMiD-refractory population, the addition of Cy to Kd resulted in a significant benefit in terms of PFS: 26.2 months vs 7.7 months in the Kd arm (p=0.01). OS is immature with 23 and 25 events so far in KCyd and Kd, respectively. The ORR was 78% for KCyd and 73% for Kd: 20% of patients in both arms achieved at least complete response, 33% and 28% very good partial response, respectively, and 25% partial response in both arms. The MRD-ve rate was 4% and 5%. As far as toxicity is concerned, neutropenia was the only hematological adverse event more frequently reported in KCyd compared with Kd, of any grade (24% vs 11%) and grade 3-4 (13% vs 7%). This did not translate into more infections and the rate was comparable in both arms (5% G3-4 in both arms). Thrombocytopenia of any grade and grade 3-4 occurred in 14%/1% and 18%/10% in KCyd/Kd. Cardiovascular events of any grade occurred in 22% and 30% of patients in KCyd and Kd. Nine pts in KCyd developed G3-4 cardiovascular events, these included atrial fibrillation (1pt), cardiac failure (2 pts), myocardial infarct (2 pts), and hypertension (4 pts). In the Kd arm, 11 patients developed G3-4 cardiovascular events and consisted of hypertension in most of them (9 pts). Conclusion: Cyclophosphamide added to Kd 70 mg/m2 weekly in RRMM pts after 1-3 PL prolonged the PFS as compared to Kd particularly in the lenalidomide-refractory population. The administration of K at a dose of 70 mg/m2 weekly was safe and more convenient and overall, the toxicity profile was manageable in both arms. Disclosures Mateos: Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: 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; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ocio:Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Asofarma: Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; GSK: Consultancy; MDS: Honoraria; Secura-Bio: Consultancy; Oncopeptides: Consultancy. Sureda Balari:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; BMS: Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria. Oriol:Celgene/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Rosinol Dachs:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Blade Creixenti:Takeda: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND AND OBJECTIVE: Few treatment options exist for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first- and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy. RESULTS: Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. CONCLUSION: Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors.

BACKGROUND: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. METHODS: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. FINDINGS: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.

Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n = 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n = 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P = .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P = .65), and 3-year overall survival (72% vs 74%, P = .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235.

Background: Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus lowdose dexamethasone (Rd) are standards of care for elderly untreated multiple myeloma patients. Methods: We did a phase 2b, parallel-group, multicentre, open-label randomised trial at 44 hospitals in Spain. We randomly assigned 242 patients (1:1) to receive 9 cycles of VMP followed by 9 cycles of Rd or alternating cycles of VMP and Rd for 18 cycles. The primary endpoints were 18-month progression-free survival and safety profile, which were similar between arms at an initial analysis after a median follow-up of 30·3 months. We did an updated pooled analysis of progression-free and overall survival, overall and by age, cytogenetic risk and minimal residual disease status. Findings: After a median follow-up of 51 months, the median progression-free survival and overall survival were 31·2 and 63·5 months, respectively. The median progression-free survival was 33, 32, and 24 months for patients aged 65-75, 75-80, and >80 years, respectively, (p=0·017); median overall survival was not reached vs 57 vs 33 months (p

Next-generation sequencing has substantially improved our understanding of the genomic landscape of multiple myeloma; however, the application of this technology has been confined mostly to research studies. Here, we report on a customized panel to characterize the mutational profile of 79 newly diagnosed patients with multiple myeloma, older than 65 years and who were not transplant candidates, applying the highest read depth to date that has been used for equivalent studies in multiple myeloma. Overall, we identified 53 genes mutated in 85% of patients, including KRAS, NRAS, BRAF, DIS3 and TP53, and found a complex subclonal structure. In addition, the total number of mutations, as well as mutations in TP53 and the Cereblon pathway, were negatively associated with survival. The latter result is particularly noteworthy as patients enrolled in this phase II clinical trial were treated with lenalidomide, which targets this pathway. Our next-generation sequencing strategy not only identified a group of patients with poor outcome, but also provided an extensive genetic profile that should prove useful in the search for new biomarkers and therapeutic targets in multiple myeloma, at an affordable price and with a small amount of sample, which are indispensable features for translating personalized medicine protocols to clinical practice.

Although survival of elderly myeloma patients has significantly improved there is still a subset of patients who, despite being fit and achieving optimal responses, will die within 2 years of diagnosis due to myeloma progression. The objective of this study was to define a scoring prognostic index to identify this group of patients. We have evaluated the outcome of 490 newly diagnosed elderly myeloma patients included in two Spanish trials (GEM2005-GEM2010). Sixty-eight patients (13.8%) died within 2 years of diagnosis (early deaths) due to myeloma progression. Our study shows that the use of simple scoring model based on 4 widely available markers (elevated LDH, ISS 3, high risk CA or >75 years) can contribute to identify up-front these patients. Moreover, unsustained response (, This study was supported by the Cooperative Research Thematic Networkgrants RD12/0036/0058 and RD12/0036/0046 of the Redde Cancer (Cancer Network of Excellence); Instituto deSalud Carlos III, Spain, Instituto de Salud Carlos III/SubdirecciónGeneral de Investigación Sanitaria part-financedby the European Regional Development Fund (FIS: PI12/01761; PI12/02311; PI13/01469; PI14/01867, G03/136;Sara Borrell: CD13/00340); Asociación Española Contra el Cáncer (GCB120981SAN) and FEDER.

Background: Heterozygous somatic mutations in the genes encoding RNA splicing factors SF3B1, U2AF1, SRSF2 or ZRSR2 induce aberrant splicing in cancer cells and are among the most common mutations in patients with MDS, AML or CMML. H3B-8800 is an orally available small molecule that binds to the SF3b complex and induces alternative splicing changes in cells. Because splicing factor mutant cells depend on residual wild-type function of splicing factors for survival, we hypothesized that H3B-8800 would induce preferential cell killing of mutant cells by further perturbing splicing to synthetic lethality. In pre-clinical models, H3B-8800 preferentially kills spliceosome mutant cells and induces antitumor activity in xenograft leukemia models with core spliceosome mutations (Seiler M et al Nature Medicine 2018). Therefore, we conducted a phase I clinical trial (NCT02841540) of H3B-8800 in patients with MDS, AML or CMML. Here we describe the safety profile and clinical outcomes of the dose escalation cohorts in this phase I trial. Methods: This phase I trial explored the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of H3B-8800 in patients with myeloid cancers. Dose escalation cohorts, employing a standard 3+3 design, examined 2 different once daily dosing regimens (schedule I: 5 days on/9 days off; schedule II: 21 days on/7 days off) in a 28-day cycle, with stratification based on lower-risk (LR) versus higher-risk (HR) myeloid neoplasms. Results: As of June 16th, 2019, 84 patients were enrolled at 24 centers in the US and Europe. Dose ranged from 1-40 mg among 65 patients on schedule I, while 19 patients were enrolled with dose ranging from 7-20 mg on schedule II. The patient population included AML (n=38), CMML (n=4), HR-MDS (n=20), LR-MDS (n=21) and 1 MDS with unknown risk level. Most patients (88%) had spliceosome mutations of interest. The most common mutations were in SRSF2 (p.P95H in 17, p.P95L in 9, p.P95_R102Del in 4), SF3B1 (p.K700E in 11, p.R625C in 4), and U2AF1 (p.Q157P in 6, p.S34F in 4). Patients remained on treatment from 7 to 819 days; 25 patients (30%) had time on treatment greater than 180 days, 20% more than 1 year and 2% over 2 years. The median therapy duration for LR-CMML/MDS, HR-CMML/MDS, and AML patients were 216, 62, and 47 days respectively. Most observed treatment related treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common treatment-related (as judged by the investigator, >10% frequency) TEAEs in the patients treated on schedule I were diarrhea (75%), nausea (37%), fatigue (28%) and vomiting (27%). The most common treatment-related TEAEs in the patients treated on schedule II were diarrhea (68%), vomiting (42%), QTc prolongation (21%), nausea (16%), and fatigue (16%). The most common dose limiting toxicity was prolongation of the QTcF interval >500 msec (n=2, 40 mg on schedule I and n=1, 20 mg on schedule II, all ≥Grade 3) and bradycardia without other arrhythmias (n=1, 14 mg on schedule II, ≥Grade 3). No ophthalmic AEs were observed; 1 patient (LR-MDS) experienced durable marrow aplasia. The maximum tolerated dose (MTD) has not been confirmed for either Schedule I or Schedule II. PK analysis indicates that H3B-8800 is rapidly absorbed and exhibits dose-proportional increase in plasma exposure. Consistent dose-dependent target engagement (i.e., alteration in mature mRNA transcripts) was observed in blood mononuclear cells from patients enrolled in the 2 mg up to 40 mg dose cohorts on both schedules. Despite this splicing modulation, no objective complete responses (CR) or partial responses (PR) meeting International Working Group criteria were observed. One patient with CMML had a durable platelet response that began in Cycle 1 and persisted through Cycle 13. Nine red blood cell (RBC) transfusion-dependent patients with MDS or CMML and 2 patients with AML did not require RBC transfusions for ≥8 weeks (up to 28 weeks) while on study. One platelet transfusion-dependent patient with LR-MDS did not require platelet transfusions for ≥8 weeks. Conclusion: Results from this first-in-human multicenter prospective clinical trial of a splicing modulator in myeloid neoplasms demonstrate dose-dependent target engagement and predictable PK profile of H3B-8800, and safety even with prolonged dosing. Although no objective CR or PR were achieved, decreased RBC or platelet transfusion requirements were observed in 12 (14%) of enrolled patients. Disclosures Steensma: H3 Biosciences: Other: Research funding to institution, not investigator.; Pfizer: Consultancy; Aprea: Research Funding; Stemline: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Astex: Consultancy; Onconova: Consultancy. Wermke:Novartis: Honoraria, Research Funding. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Font:Celgene: Consultancy, 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komrokji:Agios: Consultancy; JAZZ: Speakers Bureau; DSI: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; celgene: Consultancy; pfizer: Consultancy. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Brunner:Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Ades:Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Coombs:H3 Biomedicine: Research Funding. Foran:Agios: Honoraria, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Micol:AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Perez De Oteyza:Celgene: Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buonamici:H3 Biomedicine: Employment. Kim:H3 Biomedicine: Employment. Gourineni:H3 Biomedicine: Employment. Marino:H3 Biomedicine: Employment. Rioux:H3 Biomedicine: Employment. Schindler:H3 Biomedicine: Employment. Smith:H3 Biomedicine: Employment. Yao:H3 Biomedicine: Employment. Yuan:Eisai: Employment. Yu:H3 Biomedicine: Employment. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: H3B-8800 (experimental, unapproved)

Introduction The best strategy for the follow-up of patients with Hodgkin Lymphoma (HL) in complete remission (CR) after the first line of treatment is not established. The NCCN guidelines recommend follow-up computed tomography scan (CT) at 6, 12 and 24 months after the end of treatment. Several clinical trials of relevance require the follow-up with quarterly CT during the first year after treatment, and every 6 months thereafter. However, these recommendations are based on expert opinion rather than evidence. The aim of our study is to evaluate the different follow-up strategies after 1st line of treatment in patients with diagnosis of LH who achieved CR, and to identify the best follow-up strategy. Materials and methods This is a multicenter, retrospective study. We analysed 604 patients from 11 GELTAMO group centers, diagnosed with HL between 2007 and 2016 that had positron emission tomography-computed tomography scan (PET-CT) for initial staging, and at the end of induction treatment. Patients were grouped according to the different follow-up strategies in: 1) only clinical (clinical history, blood test (BT) and physical examination), 2) CT 3) PET-CT. The study was approved by the ethics committee of the Gregorio Marañón hospital. Medians, ranges and percentages were used for the descriptive analysis and the X2 test, Fisher's test and the Mann-Whitney U test for the comparison of variables. Results: Patients and disease characteristics and treatment information are included in Table 1. Table 2 shows the number of radiological images performed, the number of visits and the suspicion of relapse according to the used strategy. The median follow-up was 64 months (24-180). Of 90 suspicions, 59 relapses were confirmed. Relapse was identified in 64% of the patients by some clinical data that suggested it, 17% of patients had only symptoms, 25% had only abnormal physical examinations, 2% had only abnormal BT and 20% presented a combination of all the clinical variables. Regarding laboratory assessment at relapse time, 62% of the patients had a normal blood test at the time of relapse, 18% had elevated ESR, 8% elevated LDH and 9% abnormal blood count. Regardless of the strategy, 55% of relapses had at least one accessible lesion on physical examination. Comparing the used strategy, the median time to relapse was 19 months (p25-75 = 8-39) for the clinical follow-up, 18 months (p25-75 = 9-41) with CT follow-up and 13 months (p25-75 = 2-23) with PET-CT, with not statistical significance differences among them (p = 0.57) (Figure 1). Overall survival was not different using any of the strategies (Figure 2). Conclusions: In our study, the use of CT and PET-CT for the follow-up of patients with HL does not significantly reduce the time to identify the relapse and has no impact on survival. In addition, these strategies expose patients to radiation and have a high cost with not clear benefit. Our next step is to confirm this results with a prospective study. Disclosures Vidal Maceñido: GILEAD SCIENCES: Research Funding. Perez De Oteyza:Celgene: Speakers Bureau.

Background Acute myeloid leukemia (AML) blasts and leukemic stem and progenitor cells typically express higher levels of CD123 than their normal hematopoietic stem cell counterparts, making CD123 an attractive target. Leukemic CD123 expression is associated with poor prognosis, high-risk disease, and increased risk of induction failure (Vergez et al 2011). Single-agent flotetuzumab, an investigational CD123 x CD3 bispecific DART protein, has shown evidence of clinical activity in a Phase 1 study of relapsed/refractory (R/R) acute myeloid leukemia (AML). In this study, flotetuzumab led to T-cell activation which in turn was associated with PD-1 induction on T lymphocytes, enhanced IFNɣ secretion, and upregulation of PD-L1 expression by AML blasts (ASH 2018 Rutella, ASH 2018 Uy). In vitro studies have shown synergistic T-cell mediated cytotoxicity of an AML cell line (KG1A) with flotetuzumab in the presence of PD-1/PD-L1 axis blockade compared to flotetuzumab alone. MGA012, also known as INCMGA00012, is an investigational anti-PD-1 antibody that has shown clinical activity in a Phase 1 study (SITC 2018 Mehnert). We hypothesize that combined checkpoint inhibition with MGA012 together with redirected T‐cell killing of CD123+ cells with flotetuzumab may show enhanced activity over flotetuzumab alone. Methods This is a Phase 1 dose escalation study designed to characterize the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined), pharmacokinetics, and preliminary anti-leukemic activity of flotetuzumab in combination with MGA012, each administered intravenously (IV) in patients with R/R AML. Response evaluation will be determined by modified ELN 2017 criteria. Activity is measured by complete response (CR) (complete remission [CR], or CR with partial hematologic recovery [CRh], or CR with incomplete hematological recovery [CRi], or morphologic leukemia-free state [MLFS]) rate, relapse-free survival, or mortality rate at 1 and 3 months. The impact of flotetuzumab/MGA012 combination on overall survival and event-free survival will be explored. Eligible patients will consist of adults with relapsed or refractory AML (any subtype except acute promyelocytic leukemia) who have exhausted standard of care options. In Induction Cycle 1, patients will be treated with a step-up lead in dose of flotetuzumab, followed by continuous infusion flotetuzumab, starting at week 2 of Cycle 1 and continuing through each 28-day cycle. MGA012 will be administered every two weeks. Depending on response, patients will transition to either consolidation or second induction. Eligible patients who achieve CR/CRh/CRi can receive maintenance MGA012 alone for up to 12 months. Disclosures Wei: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: 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, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. Fong:Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: 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; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: 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; 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, Other: Research support, Research Funding, Speakers Bureau. Gil:Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Perez De Oteyza:Celgene: Speakers Bureau. Rowe:BioSight: Consultancy. Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Sun:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. McNulty:MacroGenics, Inc.: Employment, Equity Ownership. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Wigginton:Western Oncolytics: Other: clinical advisory board; MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership.

INTRODUCTION Cell free tumor DNA (cftDNA) based targeted next generation sequencing (NGS) is a novel tool that enables accurate and minimally invasive tumor genotyping. MATERIAL AND METHODS Here we have performed cftDNA targeted NGS for the molecular diagnosis of a series of 92 peripheral blood samples obtained at diagnosis in patients included in a phase II randomized clinical trial comparing standard RCHOP versus BRCAP as first line treatment in patients with poor IPI (aaIPI2-3 or aaIPI1 with high b2m, age 18-71, NCT01848132). Centralized histopathological review of diagnostic tissue samples confirmed the diagnosis: 83 DLBCL (68%, 55/81 GCB, 32%, 26/81 non-GCB, according to Hans immunohistochemical algorithm), 4 TCHRBCL, 3 PMBCL, 1 concurrent DLBCL and FL3A, 1 FL 3B. 7 out of 83 cases had DLBCL morphology and DH by FISH (6 MYC/BCL2 and 1 MYC/BCL6, all GCB-type by IHC). A targeted NGS approach using amplicon-based chemistry (Truseq, Illumina) that interrogates exonic regions of 35 relevant genes in DLBCL (1458 amplicons analyzed) was used for library generation from plasma derived DNA. Germline DNA from peripheral blood granulocytes from 89 out of 92 patients was sequenced in parallel and used as control DNA for variant calling. Only somatic variants with a read depth above 100 and Variant Allele Frequency > 5% were considered. RESULTS cftDNA concentration (hGE/mL) was associated with LDH levels (U/mL) at diagnosis. Mean cftDNA concentration was lower in patients with low LDH (U Mann whitney p= 0.005). Somatic mutations were identified in 74% (68 out of 92) patient plasma samples. 242 somatic mutations were considered after filtering. Mean of 3.6 mutations per patient. 10 genes were mutated in >10% of the patients, including: FAT2 (19.6%), ARID1A (18%), NOTCH1 (17.4%), NOTCH2 (15.2%), KMT2D (14.13%), SMARCA4 (14%), ATM (13%), EP300 (13%), EZH2 (13%), PLCG2 (13%). Recurrent mutations were found in EZH2 (2 patients). Mutations in BCR/TLR pathway genes were found in less than 10% of the cases (CARD11, 7.6%; MYD88, 4.4%; CD79A, 5.4%; CD79B, 1%; BTK, 4.4%). NOTCH1 mutations were found preferentially in GCB type DLBCL (12/55 GCB vs 1/26 nonGCB, Chi square p value DISCUSSION cftDNA targeted NGS captures the mutational profile in a significant fraction of DLBCL patients and enables tumor genotyping in the clinical trial setting. In contrast with previously published data mutations in NOTCH pathway, including NOTCH1, NOTCH2 and SGK1 were relatively frequent in our series of poor IPI patients, outnumbering the frequency of mutations in BCR/TLR pathway. NOTCH pathway mutations were also preferentially found in GCB-type DLBCL-NOS, PMBCL and 1 case of TCHRBCL. In summary cftDNA genotyping based on targeted NGS can provide potentially useful information for therapy selection in DLBCL patients. Disclosures Martín: Roche: Consultancy, Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses. Gonzalez-Barca:Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; Celtrion: Consultancy. Montes-Moreno:TAKEDA: Consultancy; Roche: Consultancy.

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.

Introduction: Disease control at five years would be a desirable endpoint for elderly multiple myeloma (MM) patients; however, the percentage of cases reaching this objective as well as the biomarkers to predict it, are not well defined. Objective and design: In order to gain further insight about long-term disease control (>5 years progression-free) in elderly MM we have analyzed a homogeneous population of 435 newly-diagnosed transplant-ineligible (TNE) patients enrolled in two consecutive Spanish clinical trials (GEM2005MAS65, GEM2010MAS65), that included both proteasome inhibitors and immunomodulatory drugs. Results: Amongst the 435 patients included in this post-hoc study, only 18.8% remained alive and progression-free after five years of initiating treatment. Noteworthy, in these patients the overall survival (OS) rate at 10-years was 69.4%, as compared to 11.4% for those patients progressing during the first five years (p< 0.001). Baseline variables significantly associated with long-term progression free survival in the univariate analysis were younger age, ISS 1, R-ISS 1, hemoglobin ≥ 12g/dl, normal LDH, and standard-risk cytogenetic abnormalities and the presence of a monoclonal gammopathy of unknown significance (MGUS)-like immunophenotypic profile in the bone marrow. Complete responses (CR) and minimal residual disease (MRD) negativity were also associated with long-term progression free survival. In the multivariate analysis, an hemoglobin level ≥12g/dl (OR 2.61; 95% CI 1.47 - 4.61, p=0.001) and a MGUS-like immunophenotypic profile in the bone marrow (OR 3.33; 95% CI 1.30 - 8.54, p=0.002) were the two baseline variables significantly and independently associated with a higher probability of long-term disease-free survival. When the depth of response (including MRD) was included in the logistic regression model, Hb level ≥12g/dl (OR 2.18; p=0.010) and the MGUS-like signature (OR 4.99, p Focusing on the 24 patients with an MGUS-like signature (based on the automated immunophenotyping analysis of the relative frequency of BM plasma cells (PCs) plus the percentage of clonal and normal PCs within the whole BM PC compartment), 50% percent of these patients displayed a long-term disease-free survival, as compared to only 17.5% of the remaining MM patients. The median OS for patients with MGUS-like signature was 90.2 months as compared to 62.6 for the MM-like patients. Most MGUS-like patients (90.5%) achieved a favorable response (10 complete response (CR) and 9 very good partial response (VGPR)). No differences in outcome were observed between VGPR and CR cases (p-value for OS 0.87) among MGUS-like patients. Conclusions: This study revealed that despite the usage of former novel agents, the probability of disease control at five years is still restricted to a small fraction (18.8%) of transplant-ineligible patients that achieve remarkable rates of long-term OS. Here, we identify that the combination of three biomarkers (normal Hb, MGUS-Like signature and MRD negativity) can help todefine elderly MM patients achieving long-term disease control. Our results highlight the presence of an MGUS-like signature in the bone marrow at diagnoses as the most powerful predictor for long-term disease free survival, and could be incorporated in clinical practice in order toimprove the prognostic information given to our patients. Disclosures Rodriguez Otero: Clínica Universidad de Navarra: Employment; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Research Funding. Mateos:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Ocio:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Puig:Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Oriol:Takeda: 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; Celgene: 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, Speakers Bureau. Bladé:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Lahuerta:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

We have estimated the pharmacological sensitivity and synergism of 125 individual patient samples for all drugs and combination treatments for acute myeloid leukemia in the context of the overall patient population. Each ex vivo pharmacological profile identifies drugs and treatments for which the patient's malignant cells are particularly sensitive or resistant, assisting in the selection of individualized treatments. Background: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. Patients and Methods: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. Results: The sensitivity of single drugs is assessed for standard efficacy (E-MAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. Conclusion: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection.

The tolerability of azacitidine (AZA) allows its administration in elderly patients. The objective of this study was to analyze the clinical and biological characteristics, transfusion independence (TI), overall survival (OS) and toxicity in a series of 107 patients >= 75 years of age from the Spanish Registry of Myelodysplastic Syndromes (MDS) treated with AZA. The median age (range) was 78 (75-90) years. According to the World Health Organization (WHO) classification, 86/102 (84%) had MDS, 10/102 (10%) had mixed myeloproferative/myelodysplastic disorder and 6/102 (6%) had acute myeloblastic leukemia. Regarding MDS by the International Prognostic Scoring System on initiation of AZA, 38/84 (45%) were low-intermediate-1 risk and 46/84 (55%) were intermediate-2-high risk. Ninety-five patients (89%) were red blood cell or platelet transfusion dependent. The AZA schedule was 5-0-0 in 39/106 (37%) patients, 5-2-2 in 36/106 (34%) patients and 7 consecutive days in 31/106 (29%) patients. The median number of cycles administered was 8 (range, 1-30). Thirty-eight out of 94 (40%) patients achieved TI. Median OS (95% confidence interval [CI]) was significantly better in patients achieving TI (n = 38) compared to patients who did not (n = 56) (22 [20.1-23.9] months vs. 11.1 [4.8-17.5] months, p = 0.001). No significant differences were observed in TI rate and OS among the three different schedules. With a median follow-up of 14 (min-max, 1-50) months, the median OS (95% CI) of the 107 patients was 18 (12-23) months and the probability of OS (95% CI) at 2 years was 34% (22-46%). Cycles were delayed in 31/106 (29%) patients and 47/101 patients (47%) were hospitalized for infection. These results show that treatment with AZA was feasible and effective in this elderly population, with 40% achieving TI, having a better OS than patients not achieving it. The schedule of AZA administration did not affect efficacy and toxicity.

and 13 had stable disease. Commonly reported adverse events (AEs) in MEDI-551 pts were infusion-related reactions (IRRs; 62%), nausea (23%), pyrexia (23%), and neutropenia (23%) in the 26 ph 1/2 pts; in the 29 ph 2 pts, they were nausea (62%), IRRs (31%), pyrexia (28%), chills (28%), and fatigue (28%). 11 pts had ≥ grade 3 AEs in the ph 1/2 study and 16 in the ph 2. Common treatmentrelated AEs: IRRs (58%) and nausea (12%) in the ph 1/2; nausea (52%), IRRs (28%), chills (24%), and fatigue (24%) in the ph 2. Three treatment-unrelated AEs of general health deterioration (ph 1/2), subarachnoid hemorrhage (ph 1/2), and sepsis (ph 2), resulted in death. Conclusions MEDI-551 as a single agent demonstrated B-cell depletion, increased serum BAFF levels, clinical activity, and an acceptable risk-benefit profile in relapsed/refractory CLL pts. Preliminary results of the ongoing ph 2 study of MEDI-551+bendamustine demonstrated an acceptable safety profile.

Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (CA) has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Background: Survival of DLBCL patients with high IPI treated with RCHOP immunochemotherapy is poor. In this population, the combination of RCHOP with new drugs is an attractive approach, along with performing an evaluation with PET/CT after 2 to 4 cycles to change the therapy if an early complete response is not achieved. Methods : We performed a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib 1.3 mg/m2 sc days 1, 8, and 15 of a 21-day cycle. Pre-phase therapy was permitted for patients who could not wait the results of the screening procedures to start therapy due to the aggressiveness of the disease. (ClinicalTrials.gov Identifier: NCT01848132). Patients younger than 71 yrs diagnosed with DLBCL and an age-adjusted IPI (aaIPI) 2-3 or aaIPI 1 with increased beta2microglobulin were eligible. The primary endpoint was the proportion of patients who survives free of event at 2 years. Centralized anatomopathology review was performed in all cases; samples were classified as germinal center B-cell-like (GCB) vs non-GCB subtypes by immunohistochemistry according to the Hans algorithm. PET/CTs were performed baseline, after 2, 4 and 6 cycles (PET2, PET4, and PET6), and were reviewed at real time by at least 3 experts of a central panel. Response at the end of therapy was analyzed following the visual method with the Deauville scale, and response after PET2 and PET4 was evaluated using the semiquantitative method. Persistent disease at PET4 was considered as failure of therapy and these patients were removed from trial treatment. EFS was calculated from diagnosis until event defined as death from any cause, relapse, progression or need of salvage therapy (defined as PET4 or PET6 positive). Overall survival (OS) was calculated from diagnosis until death for any cause. We present here a preliminary analysis of results. Results: One hundred and twenty-one patients were included; data on 113 are presented (diagnosis not confirmed in 6, data missing in 2). Median age was 57.1 yrs (range 23-70), 57 (50.4%) were males. Characteristics at diagnosis were: non-GCB subtype 32/87 (36.8%), immunohistochemical co-expression of myc/bcl2 56/82 (77.8%), stage III-IV 107 (94.7%), ≥2 extranodal locations 55/76 (72.5%), ECOG 2-3 36 (32.1%), increased LDH 88 (77.9%), increased beta 2 microglobulin 73 (64.6%), aaIPI 3: 32 (28.3%). No differences were found between treatment arms. Fifty-five patients were treated in the experimental arm (EA) and 58 in the control arm (CA). Twenty-eight (28.3%) out of 99 patients required of pre-phase treatment. The mean relative dose intensity for bortezomib was 88.3%. Data about the most frequent toxicity are shown in table 1. Twenty-nine (30.2%) out of 96 patients who have finished 4 cycles had a positive PET4 according to central review and were withdrawn to receive salvage therapy. Complete remission (CR) at the end of therapy (PET4-/PET6-) was observed in 44 (45.8%) patients. After a median follow-up of 9 months, estimated 12-mo EFS was 36.6%, and 12-mo OS was 82.9% in the whole series. Data of the subgroup analysis according the immunohistochemistry subtypes by Hans algorithm are show in table 2. Conclusions: In the present preliminary analysis, no significant differences were found between RCHOP and BRCAP in terms of CR and EFS in this very high-risk population of young DLBCL patients. However, in the subgroup analysis of patients with non-GCB disease, we found a significantly better CR rate in patients treated with BRCAP. A longer follow-up is needed to evaluate the real impact of this therapy on survival. Disclosures González-Barca: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Martín:Sevier: 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; Janssen: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Sancho:Gilead: 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, Speakers Bureau; Celltrion, Inc: Research Funding; Sanofi: 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. López-Jiménez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Velgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: 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; MundiPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. López-Guillermo:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MundiPharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramírez:Bristol-Myers-Squibb: Honoraria; Novartis: Honoraria; Roche: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Conde:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees.

Background Spleen tyrosine kinase (SYK), a nonreceptor kinase with a key role in B-cell receptor signaling-driven tumorigenesis, is a viable target for inhibition in B-cell malignancies. SYK is also a key regulator of FMS-like tyrosine kinase 3 (FLT-3), which is mutated in 30% of pts with acute myeloid leukemia (AML; Puissant et al. Cancer Cell 2014;25:226-42). TAK-659, a selective, reversible, potent SYK/FLT-3 inhibitor demonstrated inhibition of SYK activity and cell proliferation in vitro and inhibited dose-dependent tumor growth in vivo in lymphoma xenograft models. The TAK-659 maximum tolerated dose (MTD) is 100 mg daily (QD) based on phase 1 data (NCT02000934; Petrich et al. Blood 2015;123:2693). Here we present updated safety and efficacy data from the expansion phase of this study. Methods Adult pts with advanced solid tumors/lymphoma, with no standard effective treatment available, received oral TAK-659 QD in 28-d cycles: 60-120 mg during dose escalation or 100 mg during dose expansion. AEs were assessed per NCI-CTCAE v4.03. Responses per RECIST v1.1 (solid tumors) or IWG modified criteria (lymphoma) were assessed between d22 and d29 (predose) of C2 (both phases), then during C4, C6, and every 3 cycles (escalation) or every even numbered cycle until C12, then every 4 cycles (expansion). During dose escalation, blood samples for plasma PK were collected predose and at multiple times postdose on d1 and d15 of C1; urine samples were collected on d15 of C1, 0-8 hrs postdose. Next-generation sequencing and NanoString analyses are planned to identify mutations correlating with clinical response and to classify lymphoma pts by cell of origin using Lymph2Cx signature. Results At data cut-off (April 27, 2016), 54 pts had received TAK-659. During dose escalation, 35 pts (18 solid tumor; 17 lymphoma [12 DLBCL; 4 FL, 1 MCL]) received TAK-659 QD at 4 dose levels: 60 mg (n=10), 80 mg (n=4), 100 mg (n=14), and 120 mg (n=7). During expansion, 19 lymphoma pts (18 DLBCL; 1 CLL) received TAK-659 QD at 100 mg (MTD). Median age for the overall population was 60.5 years (range, 23-82); 70% were male. Baseline characteristics for the 36 lymphoma pts are shown in Table 1. Of 30 DLBCL and 4 FL pts, 24 and 3, respectively, were response-evaluable as of June 9, 2016 (received ≥1 dose of TAK-659; had ≥1 post-treatment response assessment). By local assessment, 14 pts were de novo (7 GCB, 4 non-GCB, 3 unknown) and 10 were transformed (8 GCB, 2 non-GCB). There were 5 dose-limiting toxicities (DLTs): at 120 mg, 2 pts had increased lipase levels (1 gr 3; 1 gr 4), 1 pt had gr 3 generalized edema, and 1 had gr 3 mucositis; 1 pt at 60 mg had gr 3 increased AST. DLTs related to laboratory changes were asymptomatic. LDH levels were increased from baseline in most pts (significance unknown). Drug-related AEs are shown in Table 2. Drug-related serious AEs (per investigator) were reported for 17 (31%) pts; most common were pneumonia (5 [9%]), pyrexia (3 [6%]), and pneumonitis (2 [4%]). Dose reductions due to AEs occurred in 4 pts (3 from 100 to 80 mg; 1 from 120 to 60 mg). Nine pts discontinued due to AEs; 3 were considered related to TAK-659 (1 sepsis, 2 pneumonitis). There were 10 on-study deaths; 1 was considered possibly related to TAK-659 (sepsis). Preliminary plasma and urine PK data showed that TAK-659 was absorbed quickly (median Tmax 2-3 hrs), with moderate variability in steady-state exposures (40-50% CV for DN-AUCtau), mean peak/trough ratio of 3.2-4.2, and mean accumulation of 2.1- to 2.6-fold after 15 d QD dosing. Renal clearance (CLr) of unchanged drug accounted for 30-34% of apparent oral clearance, suggesting a CLr contribution of ≥30-34% to TAK-659 systemic clearance. Of 24 response-evaluable DLBCL pts, 11 (46%) achieved an objective response; (7 [29%] CR, 4 PR); all 3 response-evaluable FL pts achieved PR; 10/14 responders are ongoing on the study (Figure). Median treatment duration for responders was 138 days for DLBCL (range 54-688) and 237 days for FL (range 185-464). Responses were seen in both de novo and transformed DLBCL pts and appeared to be independent of cell-of-origin classification. No solid tumor pts achieved an objective response. Conclusions Oral TAK-659 has an acceptable PK and safety profile in pts with solid tumors or lymphoma, supporting continuous oral QD dosing. There are early signs of clinical activity in DLBCL and FL pts. Enrollment of pts with additional lymphoma subtypes is ongoing; safety and efficacy will be further investigated. Disclosures Kaplan: Janssen: Research Funding; Seattle Genetics: Research Funding. Gordon:Northwestern University: Patents & Royalties: Patent for gold nanoparticles pending. Infante:Millennium: Research Funding. Popat:Takeda: Honoraria. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. de Oteyza:Takeda: Research Funding. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: 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; Gilead: 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. Faucette:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sheldon-Waniga:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Williams:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Stumpo:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bosch:Hoffman La Roche: Consultancy, Honoraria, Research Funding; Millennium: Research Funding.

Next-generation sequencing (NGS) has revealed new insight into the complexity of clonal and subclonal architecture of multiple myeloma (MM). The introduction of targeted studies allows the detection of mutations with very low allele frequencies at affordable price. However, there is few information about the prognostic impact of this mutational profile in series of homogeneously treated MM patients. In this study, we analyzed the most frequently mutated genes in MM from patients included in a randomized clinical trial applying the highest read depth to date. We performed a correlation study between our results and cytogenetics aberrations and clinical outcomes. We used Ampliseq Library Kit 2.0 to target 77 genes (M3Pv2.0 panel) related to critical pathophysiological pathways, associated to drug resistance or targetable with molecular drugs in MM. We sequenced DNA (15ng) from CD138+ purified plasma cells from 80 MM patients at diagnosis included in GEM2010MAS65 clinical trial. We sequenced at an average read depth of 1500X and using Ion Proton sequencer (Thermo Fisher, USA, PaloAlto, CA). We used Ion Reporter software applying in-house modifications in call variants process. We also sequenced DNA from CD138 negative population in 30% of patients in order to filter out potential artifacts and stablish conditions for excluding germline variants. We first fitted a cox-proportional hazard model to predict survival and a second approach using a penalized regression LASSO. We identified 137 gene mutations in the 80 patients analyzed, 54 mutations were predicted pathogenic by Shif and Poliphen and 65 have been described in COSMIC database. 85% of patients harbored at least 1 mutation. The most frequently mutated genes were KRAS (16%), DIS3 (15%), NRAS (13%), BRAF (6%), and TP53 (5%), accounting for the 54% of the total number of mutations. The most frequently mutated pathways were RAS and NFKB in 34% and 28% of patients respectively. Mutational allele frequency for KRAS, BRAF and TP53 was, in all cases, lower than 50% while DIS3 showed mutations in a broad range (from 2 to 85%). Only one patient presented one mutation in NRAS at 73 % of allele frequency. For patients with more than one mutation, two different scenarios have been found. Some patients showed several genes mutated in a similar allele frequency values. On the contrary, a complex subclonal structure was confirmed in 3 patients, with mutations at very different clonal frequency. CD138 negative fraction was sequenced to confirm that these mutations were exclusive of plasma cells. The first of them had two mutations in DIS3 at 8 and 53% of allele frequency, second in KRAS and DIS3 at 13 and 63% respectively and the third in NRAS and IFNGR2 at 5 and 37% respectively. We found no differences in the survival based on pathway, mutational allele frequency or number of mutations. We also investigated pairwise associations between events and we not found significant correlations (Figure 1). Cox-proportional hazard model only showed a negative impact in survival of patients with TP53 mutations. This ultra-deep targeted sequencing strategy is able to detect mutations in most of patients, at very low allele frequency and using a minimal amount of DNA. Despite of its huge capacity to detect mutations, we have not identified new prognostic factors in MM patients treated with highly efficient therapies. However, this study again confirms the complexity of the genomic landscape of MM and the great heterogeneity between patients. The role of theses mutations at relapse as well as in the subsequent treatment effectiveness remains unknown and should be preferably investigated in larger cohorts of homogeneously treated MM patients. Figure 1 Figure 1. Disclosures Martínez-López: Novartis: Honoraria, Speakers Bureau. Oriol:Janssen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:celgene: Consultancy.

e18510Background: The aim of this study is to determine the ability of Vivia's novel test (based on studying the ex-vivo sensitivity to drugs) to predict the complete remission (CR) rates after ind...

Purpose Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. Methods Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50–315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg. Results A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested. Conclusions A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.

Background: survival of young patients with high IPI DLBCL treated with RCHOP chemotherapy needs to be improved. In this poor risk population the combination of RCHOP with new drugs is an attractive approach, along with performing an early evaluation with PET/CT after 2 to 4 cycles and change induction therapy if a complete response is not achieved. Bortezomib has been combined with RCHOP [1]. We present preliminary data of patients treated in a clinical trial comparing 6 cycles of RCHOP vs 6 cycles of BRCAP, a modified RCHOP regimen changing vincristine by bortezomib at a dose of 1.3 mg/m2 sc days 1, 8, and 15 of every 21 days cycle (NCT01848132). Methods: patients younger than 70 yrs diagnosed of DLBCL with aIPI 2-3 or aIPI 1 with elevated beta2microglobulin were eligible. The main objective was to evaluate the proportion of patients who survives free of event at 2 years. Central pathology review was performed in all cases, and samples were classified as GC vs non-GC subtypes by IHC (Hans algorithm). PET/CTs were performed at diagnosis, after 2, 4 and 6 cycles (PET2, PET4 , and PET6), and were reviewed by at least 3 experts of a central panel at real time. Response was analyzed following the visual method with the Deauville scale, and for PET2 and PET4 the semiquantitative method was used. Patients with persistent disease after 4 cycles were considered a failure of therapy and were dropped out from the trial. Results: data from the first 76 patients were analyzed. Diagnosis of DLBCL was confirmed in all except 3 pts, 36 pts were treated in the experimental arm and 37 in the control arm. Median age was 58.2 yo (range 23-70), 37 (50.7%) were males. Characteristics at diagnosis were: non-GC subtype 18/46 (39.1%), C-myc expression 35/43 (81.4%), bcl2 expression 43/49 (87.7%), double expression cmyc/bcl2 30/42 (71%), stage III-IV 64 (87.6%), ≥2 extranodal locations 27 (42.2%), ECOG 2-3 24 (33%), elevated LDH 43 (62.3%), elevated beta 2 microglobulin 47 (75.8%), aIPI 2: 42 (57.5%), aIPI 3: 21 (28.8%). Among 160 cycles of BRCAP chemotherapy, 5 (3.1%) on day 8, and 22 (13.7%) on day 15, were given without bortezomib due to a neutrophil count below 0.5 /L. The most common toxicities are shown in table 1 without significant differences between both arms. Twenty-one (32.8%) out of 64 patients had a positive PET2. Fifteen (26.8%) out of 56 patients who have finished the 4 cycles had a positive PET4 according to central review and were withdrawn of the trial. Table 1. Episodes of treatment-related adverse events Control arm: RCHOP n=166 Experimental arm: BRCAP n=160 Any grade Grade 3-4 Any grade Grade 3-4 Anemia 6 0 22 9 ( 5.6%) Neutropenia 31 26 (15.6%) 47 37 (23.1%) Thrombocytopenia 9 4 ( 2.4%) 16 5 ( 3.1%) Febrile neutropenia - 6 ( 3.6%) - 10 ( 6.2%) Fever 8 1 ( 0.6%) 8 0 Infection 4 1 ( 0.6%) 7 1 ( 0.6%) Nausea/vomiting 12 0 19 0 Peripheral neuropathy 7 1 ( 0.6%) 7 1 ( 0.6%) Diarrhea 4 0 8 0 Constipation 7 0 4 0 Hepatotoxicity 6 0 6 0 Conclusions: BRCAP regimen with bortezomib sc d1, 8, and 15 is feasible. Its main toxicity is hematological, and some patients cannot receive some doses of bortezomib due to neutropenia. Grade 3-4 non-hematological toxicity is rare, including peripheral neuropathy, and do not differ from RCHOP toxicity. 1.Ruan J et al, JCO 2011;29:690-7 Disclosures Sancho: CELLTRION, Inc.: Research Funding. Lopez-Guillermo:Roche, Celgene, Mundipharma, Gilead, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: MM usually affects elderly patients and although novel agents-based combinations have substantially improved MM outcome, it is possible that this benefit would be particularly relevant for the "youngest-elderly" patients (65-80y). According to the frailty score published by IMWG, the chronological age ≥80 years identifies itself a frail patient population with poor outcome and we have here evaluated the efficacy, safety and outcome of patients included in the GEM2010 trial according to the age to identify the group of patients who benefit most of this total therapy approach. Patients and methods: 242 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). One hundred and fifteen patients (49%) were between 65-75 years, 69 patients (30%) were aged between 75-80 years and 49 patients (21%) were older than 80 years. The allocation in both sequential and alternating arms was well balanced. There were not significant differences in the baseline characteristics of the three subgroups of patients. The ORR was similar in both patients aged 65-75 and 75-80 (80% and 83%), but significantly lower in patients older than 80 years (68%) (p=0.007). The CR rate was also almost identical in patients between 65-75 (45%) and 75-80 (49%), but significantly lower in those aged over 80 years (10%) (p The median PFS was 35 m and 32 m in the group of patients aged between 65-75 and 75-80, respectively (p=NS), but PFS was only 25 months in patients older than 80 (p=0.02). In terms of OS, 75% of the patients between 65-75 years remained alive at 4 years, 60% of patients between 75-80 years (p=0.05), as compared to only 30% of patients older than 80 years (p=0.003). There were no significant differences between the sequential and alternating arms. Hematological and non-hematological toxicity was not different in the different groups according to the age, but it is important to note that 63% of patients older than 80 years early discontinued the trial due to toxicity or informed consent withdrawal, while this occurred in only 30% of patients aged 65-75 and 75-80. Sixty-eight percent and 59% of the patients aged 65-75 and 75-80, respectively, completed the 18 planned cycles, as compared to only 36% of patients aged over 80 years. The median cumulative dose of bortezomib and lenalidomide was significantly higher in the group of patients aged 65-75 (44 mg/m2 for bz and 4410 mg for len) and 75-80 (41 mg/m2 for bz and 4078 mg for len) compared to patients over 80 years (33 mg/m2 for bz and 1783 mg for len). These differences were maintained in both sequential and alternating arms. Conclusions: The present therapeutic approach, based on VMP and Rd for newly diagnosed elderly MM patients probably represents the optimal therapeutic option for elderly patients between 65 and 80 years in a sequential or alternating approach. By contrast, further optimization for the patient population over 80 years is still required. Disclosures Mateos: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ocio:Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Janssen: Honoraria. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:Celgene: Consultancy; Binding Site: Consultancy; Millenium: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; EngMab AG: Research Funding; BD Bioscience: Consultancy; Onyx: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Sanofi-Aventis: Honoraria; Bristol-Myers Squibb: Honoraria; Millennium: Honoraria; Onyx: Honoraria.

Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow dysplasia and ineffective hematopoiesis. Zhou et al. showed that transforming growth factor-beta (TGF-β) signaling was constitutively activated in MDS CD34+ cells and that this over-activation and subsequent myelosuppression was based on reduced expression of SMAD7, the natural inhibitor of TGF-β, in MDS CD34+ cells (Zhou L et al. Cancer Res 2011;71:955-963). Galunisertib specifically inhibited the kinase activity of the TGF-β receptor type I (TGF-βRI) also known as ALK5 and its downstream signaling pathway theoretically replaced the SMAD7 function. Galunisertib reversed hematopoietic suppression in human MDS bone marrow assays, and in a murine model of TGF-β derived bone marrow failure. Based on these preclinical studies that demonstrate hematological improvement (HI) in MDS models following galunisertib treatment, a single-arm phase 2 part of a phase 2/3 proof-of-concept study in very low-, low-, and intermediate-risk patients with MDS was conducted. Methods: The primary objective of this study was to estimate the HI rate based on International Working Group (IWG) 2006 criteria in patients with very low-, low-, and intermediate-risk MDS by Revised International Prognostic Scoring System (IPSS-R), treated with galunisertib. Eligible patients were treated with galunisertib 300 mg/day (150 mg BID) orally for 14 days, followed by 14 days off, constituting a cycle of 28 days. Eligibility criteria permitted any prior therapy, all of which were required to be discontinued at least 28 days prior to initiation of galunisertib. Supportive therapies including ongoing transfusions were allowed. Eligibility criteria included confirmed diagnosis of MDS, anemia with hemoglobin ≤10.0 g/dL, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Safety was assessed and summarized using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Descriptive statistics were used to report baseline characteristics and response rates. Results: In this phase 2 study, 41 patients received galunisertib orally (N=39, 150 mg BID and N=2, 80 mg BID for PK comparison). Patients were 62% males. The median age was 71 years (range: 52-84), the majority of patients were classified as refractory cytopenia with multilineage dysplasia (66.7%) or refractory anemia with ringed sideroblasts (20.5%) based on WHO MDS classification. ECOG PS was 0/1 in 53.8%/46.2% of patients. Sixty-two percent of the patients received ≥6 cycles of treatment. Among the 39 patients receiving 150 mg BID, a total of 15 (38%) patients discontinued from the study within 6 cycles; one due to AE and 9 due to patient/physician decision. The most common possibly related any grade treatment-emergent adverse events (TEAEs) included fatigue (20.5%), diarrhea (15.4%), pyrexia (10.3%), vomiting (10.3%), anemia (7.7%), nausea (7.7%), urinary tract infection (7.7%), neutrophil count decreased (5.1%), and platelet count decreased (5.1%); 12 (30.8%) patients had grade 3/4 TEAEs, 4 (10.3%) were drug-related. One of the 39 patients was protocol ineligible and was removed from the efficacy analysis. Among the 38 evaluable patients in the ITT population, 14 of whom required fewer than 4 units of transfusion per 8 weeks, 10/38 (26%) patients achieved HI, defined as at least a continuous 8-week response with at least a 4-unit reduction in transfusion requirement from baseline or hemoglobin increase by at least 1.5 g/dL per 8-week period. Of these 10 patients, 4 became transfusion-independent, and 5 had transfusion reduction. In a subgroup of 24/38 patients who had a transfusion requirement of at least 4 units every 8 weeks at baseline, 9 (38%) of these patients achieved a transfusion reduction of at least 4 units. No apparent correlation between cytogenetics or MDS subtype including ringed sideroblasts and response was identified; however, only 14 patients had abnormal cytogenetics. No platelet or neutrophil responses were observed. Conclusion: Galunisertib is well tolerated in this MDS population where this ALK5 inhibitor was investigated for the first time. Patients most commonly discontinued from study treatment due to patient/physician decision and not for toxicity. The clinical endpoint of HI was observed in 26% of the ITT population, and no specific response sub-group was identified. Disclosures Valcarcel: GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: 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, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Díez-Campelo:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding. Schlenk:Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Gaidano:MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding. Perez de Oteyza:Eli Lilly and Company: Research Funding. Cleverly:Eli Lilly and Company: Employment, Equity Ownership. Chiang:Eli Lilly and Copany: Employment. Lahn:Eli Lilly and Company: Other: Former employee. Desiaih:Eli Lilly and Company: Employment. Guba:Eli Lilly and Company: Employment, Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Pharmacylics: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Research Funding.

Background: We have overcome the limitations of 40 years of ex vivo testing. The aim of this study is to determine the ability of Vivia's novel test to predict the complete remission (CR) rates after induction chemotherapy with cytarabine (Ara-C) and idarubicin (Ida) in 1st line AML. Material and Methods: Bone marrow samples from adult patients diagnosed with de novo AML in Spanish centers from the PETHEMA group were included. Whole marrow samples maintaining their Native Environment were incubated for 48h in well plates containing Ara-C, Ida, or their combination. Pharmacological responses are calculated using population models. Induction response was assessed according to the Cheson criteria (2003). Patients attaining a CR/CRi were classified as responders and the remaining as resistant. Results: 390 patient samples were used to calculate the dose response (DR) curves for Ara-C alone, Ida alone, and their synergism. For clinical correlation we used 142 patients with median 56 years. The strongest clinical predictor was the Area Under the Curve (AUC) of the DR of Ara-C, and the AUC of IDA. The GAM models revealed a significant relationship between the AUC of the concentration-effect curves of both, idarubicin and, particularly, Ara-C, with greater values associated to higher probabilities of post-induction resistance. The fitted Generalized Additive Method predictions of expected values for each patient were in turn related to overall survival when a discrimination value to define positive and negative test results that prioritized specificity over sensitivity was chosen based on equaling positive and negative predictive values (Fig 1A). Prioritizing specificity over sensitivity reflects the higher cost of false positive over false negative decisions: only in very rare instances, an effective treatment would be erroneously negated to a sensitive patient at the expense of overlooking a number of resistant patients. However, the later patients could take their chances on re-induction therapy. While for diagnostics sensitivity and specificity should both be optimized, for Personalized Medicine the positive and negative predictive values should be optimized preferentially because they define the patient response correlation. Fig 1B shows a table illustrating the correlation between clinical outcome (columns) and the test predictions (lines). From a diagnostic criteria (columns), clinically resistant patients (1st column) are not well predicted with a Sensitivity of 51%, while clinically sensitive patients (2nd column) are very well predicted with a Specificity of 94%. From a Precision Medicine criteria (Lines), patients predicted resistant (1st line) and well predicted with 80% positive predictive value, similar to patients predicted sensitive (2nd line) well predicted with 79% Negative Predictive Value. The test does not properly identify 23/142 that are clinically resistant and the test predicts as sensitive (bottom left quadrant right panel). This mismatched subgroup mimics the problems from molecular markers where a resistant clone present in a minority of leukemic cells cannot be detected yet drives the patient response. However, this group mismatch does not prevent a good correlation with the test predicted outcomes. Flow cytometry identified 2 clones in 75% of these 23 samples, and we revised all samples analyzing each of 2 clones separately whenever they were present. Results did not change by this clonal analysis, suggesting flow cytometry may not identify resistant clones. Future improvements of the test adding 16 concentrations to the dose response curves may be able to detect the presence and parameters of these resistant clones driving patient response. Conclusions: This novel test is able to predict the clinical response to Ida + Ara-C induction with overall correlation and predictive values of 80%, higher than ever achieved. It is significantly higher than the current clinical response rate of 66.7%. Thus this novel test may be valuable information to guide 1st line patient therapy. Figure 1. ROC curve and clinical correlation Figure 1. ROC curve and clinical correlation Disclosures Ballesteros: Vivia Biotech: Employment. Cordoba:Celgene: Research Funding. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria. Gaspar:Vivia Biotech: Employment. Gorrochategui:Vivia Biotech: Employment. Rojas:Vivia Biotech: Employment. Gomez:Vivia Biotech: Employment. Hernández:Vivia Biotech: Employment. Robles:Vivia Biotech: Employment.

Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. Bortezomib-based combinations have shown to improve the outcome of patients with high-risk CA but they do not completely overcome their adverse prognosis. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). There weren't differences in the rates of CA according to the treatment arm. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 37 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 36 months, p=0.01, HR 2.2, 95% IC 1.1-4.2) and this also translated into a significantly shorter 4-years OS (27% vs 72%, p=0.006, HR 3.3, 95% IC 1.4-7.7). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (32 months vs 30 months) and 4-years OS (64% vs 60%). This effect was observed only in the sequential arm applied to either t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (33 months vs 30 months) and 4-years OS (58% vs 65%) in the whole series and no differences were observed in the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:BD Bioscience: Consultancy; Binding Site: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Millennium: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

Background The role of human leukocyte antigen (HLA)-DPB1 as a transplantation antigen is controversial. A higher incidence of acute graft-versus-host disease (aGVHD) has been described after unrelated donor bone marrow transplant when both HLA-DPB1 alleles were mismatched. Methods We investigated the impact of a single HLA-DPB1 mismatch after HLA-A-B-DRB1 identical sibling donor transplantation on aGVHD. We analyzed 627 adult patient-donor pairs and identified 30 pairs without HLA-DPB1 identity (4.78%). In 17 cases, the patient had an allele that was not shared by the donor. Results The cumulative incidence of grades II-IV aGVHD was higher in the HLA-DPB1 mismatched group (66.7% vs. 35.7%, p=0.012). The HLA-DPB1 mismatch was identified by multivariate analysis as an independent risk factor for aGVHD (p=0.020, RR=2.68, 95% CI: 1.73-3.62). Conclusions HLA-DPB1 can mediate alloreactive responses. A single HLA-DPB1 mismatch increases the risk of aGVHD after sibling donor stem cell transplantation.