ALBERT

Description: Background: Acute myeloid leukemia (AML) is a highly heterogeneous malignancy and risk stratification based on genetic and clinical variables is standard practice. However, current models incorporating these factors accurately predict clinical outcomes for only 64-80% of patients and fail to provide clear treatment guidelines for patients with intermediate genetic risk. A plethora of prognostic gene expression signatures (PGES) have been proposed to improve outcome predictions but none of these have entered routine clinical practice and their role remains uncertain. Methods: To clarify clinical utility, we performed a systematic evaluation of eight highly-cited PGES i.e. Marcucci-7, Ng-17, Li-24, Herold-29, Eppert-LSCR-48, Metzeler-86, Eppert-HSCR-105, and Bullinger-133. We investigated their constituent genes, methodological frameworks and prognostic performance in four cohorts of non-FAB M3 AML patients (n= 1175). All patients received intensive anthracycline and cytarabine based chemotherapy and were part of studies conducted in the United States of America (TCGA), the Netherlands (HOVON) and Germany (AMLCG). Results: There was a minimal overlap of individual genes and component pathways between different PGES and their performance was inconsistent when applied across different patient cohorts. Concerningly, different PGES often assigned the same patient into opposing adverse- or favorable- risk groups (Figure 1A: Rand index analysis; RI=1 if all patients were assigned to equal risk groups and RI =0 if all patients were assigned to different risk groups). Differences in the underlying methodological framework of different PGES and the molecular heterogeneity between AMLs contributed to these low-fidelity risk assignments. However, all PGES consistently assigned a significant subset of patients into the same adverse- or favorable-risk groups (40%-70%; Figure 1B: Principal component analysis of the gene components from the eight tested PGES). These patients shared intrinsic and measurable transcriptome characteristics (Figure 1C: Hierarchical cluster analysis of the differentially expressed genes) and could be prospectively identified using a high-fidelity prediction algorithm (FPA). In the training set (i.e. from the HOVON), the FPA achieved an accuracy of ~80% (10-fold cross-validation) and an AUC of 0.79 (receiver-operating characteristics). High-fidelity patients were dichotomized into adverse- or favorable- risk groups with significant differences in overall survival (OS) by all eight PGES (Figure 1D) and low-fidelity patients by two of the eight PGES (Figure 1E). In the three independent test sets (i.e. form the TCGA and AMLCG), patients with predicted high-fidelity were consistently dichotomized into the same adverse- or favorable- risk groups with significant differences in OS by all eight PGES. However, in-line with our previous analysis, patients with predicted low-fidelity were dichotomized into opposing adverse- or favorable- risk groups by the eight tested PGES. Conclusion: With appropriate patient selection, existing PGES improve outcome predictions and could guide treatment recommendations for patients without accurate genetic risk predictions (~18-25%) and for those with intermediate genetic risk (~32-35%). Figure 1 Disclosures Hiddemann: Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Metzeler:Celgene: Honoraria, Research Funding; Otsuka: Honoraria; Daiichi Sankyo: Honoraria. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beck:Gilead: Research Funding.

Description: Key Points AML patients with isolated trisomy 13 have a very poor clinical outcome Isolated trisomy 13 in AML is associated with a high frequency of mutations in SRSF2 (81%) and RUNX1 (75%)

Description: Abstract 327 Introduction: Older patients (≥ 60 years) with acute myeloid leukemia (AML) display a dismal prognosis with only half of the patients reaching a complete remission after intensive induction therapy. The decision whether or not to use intensive chemotherapy is often difficult given the limited number of known markers that might predict the chance to achieve a complete remission. The aim of this study was to establish a risk score for therapy-failure based on clinical variables for older but medically fit AML patients. Patients and Methods: 1379 patients ≥ 60 years of age with AML evaluable for an induction result after treatment with an intensive induction regimen (randomized standard-dose cytarabine containing TAD or high-dose cytarabine (1g/sqm × 6) containing HAM, with a second induction course HAM in case of blast persistence after the first course) within the AMLCG1999 study of the German AML Co-operative Group were evaluated. The following parameters were evaluated for risk prediction in an exploratory analysis: Age, sex, de novo versus secondary leukemia, performance status, body mass index, body temperature, presence of extramedullary manifestations, spleen size, presence of lymph node enlargement, hemoglobin, peripheral blood leukocytes, platelets, blast percentage in peripheral blood and bone marrow, total protein in serum, alanine aminotransferase (ALT), alkaline phosphatase (AP), bilirubin, lactate dehydrogenase (LDH), FAB classification, prothrombin time (PT) and fibrinogen. Since cytogenetics and molecular markers are often not available at the time of decision making, these data were not included. Results: Within this cohort of patients, 744 (54 %) achieved a complete remission. Among the analyzed parameters, age, de novo versus secondary leukaemia, body mass index, body temperature, hemoglobin, peripheral blood leukocytes, platelets, bone marrow and peripheral blood blasts, ALT, AP, LDH, PT and fibrinogen were significantly associated with a CR (p 36°C – 38°C, 〉 38°C), hemoglobin (≤ 10.3 g/dl versus 〉 10.3 g/dl), platelets (≤ 28,000, 〉 28,000 - 53000, 〉 53,000 – 103,000, 〉 103,000 per μl), AP (≤ 89 U/l versus 〉 89 U/l), PT (≤ 75 %, 〉 75 – 87 %, 〉 87 – 98 %, 〉 98 %) and fibrinogen (≤ 150 mg/dl versus 〉 150 mg/dl). Based on these parameters, the predicted remission rates were: minimum, 18.3 %; 1st quartile, 43.9 %; median, 54.4 %;3rd quartile, 64.3 %; maximum: 88.1 %. The observed remission rates were: 1st quarter, 35.7 %; 2nd quarter, 50.3 %; 3rd quarter, 60.2 %; 4th quarter, 69.8 %. Conclusions: Taken together, this risk prediction score based on pre-treatment values predicted the remission probability in patients ≥ 60 years of age with AML receiving an intensive induction therapy. This score may be useful for the determination of the therapy strategy in elderly patients with AML. Disclosures: No relevant conflicts of interest to declare.

Description: The Armadillo repeat-containing X-linked protein 1 (ARMCX1)gene encodes a member of the ALEX family of proteins and is located on the X chromosome. We found this gene aberrantly expressed in acute myeloid leukemia (AML) cells. We analyzed ARMCX1 expression in a cohort of 508 AML patients who received intensive chemotherapy within AMLCG clinical trial. Expression levels of ARMCX1 were determined in pretreatment bone marrow or peripheral blood samples by using oligonucleotide microarrays (GSE37642). High transcript levels (dichotomized at the median expression) of ARMCX1 were predictors for inferior overall survival (OS) (p=0.0027, Log-Rank test) and a lower rate of complete remission (CR) (p=0.0017). Older patients (≥ 60 years) showed an elevated incidence of high ARMCX1 expression compared to younger patients (

Description: Background: Dose intensity is considered one of the prime determinants of antileukemic efficacy in induction treatment of acute myeloid leukemia (AML) - as demonstrated by the superior long-term results of double induction versus conventional induction. In an attempt to further pursue this historically successful strategy an ongoing phase II study of the AML-CG pilots the feasibility of the S-HAM regimen (HD-AraC 3g/m2/12h d1,2,8,9; Mitoxantrone 10mg/m2 d3,4,10,11) in first-line treatment of de-novo AML. In this regimen the interval between the two induction cycles is reduced from 17 days (double induction) to a minimum of 3 days (S-HAM) - thereby increasing dose-intensity more than 2-fold in the critical early phase of treatment. Results: In the past 18 months 99 patients have been recruited into the trial with a median age of 52 years (range 18 – 78). Of 93 patients evaluable for response the following results were achieved: CR 62%, CRp 24%, PL 6%, ED 8% - resulting in an overall response rate (ORR) of 86%. The early death rate (ED) of 8% and the toxicity profile compared favourably with a historical control group within the AML-CG 1999 study (subgroup: de-novo AML, age less than 60 years, HAM-HAM double induction) with an ED rate of 14% (ORR 68%, persistent leukemia (PL) 18%). The high antileukemic efficacy of S-HAM was also demonstrated by the fact that 88% of patients had a bone marrow blast count of 〈 10% one week after therapy as compared to less than 48% of patients of the HAM-HAM double induction group. If patients had an adequate blast clearance on day 18 pegylated G-CSF was applied every 10 days until neutrophil recovery. The median time to neutrophil recovery was 30 days after start of treatment with S-HAM which was substantially shorter than following either TAD-HAM or HAM-HAM double induction in the AML-CG 1999 trial (both with a median of 45 days). Since the S-HAM regimen has proven feasible at the present dose level a dose escalation was performed with an additional day of HD-AraC and Mitoxantrone in the first cycle of the sequential regimen. Conclusion: In the future the appropriate dose level of the S-HAM regimen will then constitute the experimental arm for a randomized comparison of a dose-intensified regimen S-HAM - combining a promising antileukemic activity with significantly reduced duration of critical neutropenia - versus standard double induction for patients younger than 60–70 years in the next generation of the AML-CG studies.

Description: Abstract 1056 Poster Board I-78 Introduction: We previously showed that a prolonged myelosuppressive maintenance chemotherapy was superior to S-HAM as a postremission therapy in patients 〉 16 years of age with AML after a TAD-HAM double induction therapy and TAD consolidation chemotherapy with regard to relapse-free survival (RFS) and borderline significance of the overall survival (OS) in responding patients (Buchner et al., JCO 2003, 21:4496-4504). Here we present long-term follow-up data with a median follow-up of 7.9 years from diagnosis and 7.1 years from the date of complete remission. Patients and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were upfront randomized in the AMLCG1992 study of the German AML Co-operative Group to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age 〈 60 years] or 1 g/m2 [age ≥ 60 years] x 6 (HAM in patients ≥ 60 years only in case of blast persistence on day 16 of therapy) induction, TAD consolidation, and monthly maintenance with cycles of cytarabine combined with either daunorubicin (course 1), 6-thioguanine (course 2), cyclophosphamide (course 3), and again 6-thioguanine (course 4), and restarting with course 1 for 3 years, or to receive TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age 〈 60 years) or 0.5 g/m2 (age ≥ 60 years) x 8 instead of maintenance. Results: A total of 576 patients (69.2%) achieved a complete remission (CR) those were 294 of 429 (68.5%) patients randomized to receive maintenance and 282 of 403 (70.0%) patients randomized to receive intensive consolidation S-HAM (p=n.s.). 190 patients received maintenance therapy as intended and 135 patients received an intensive consolidation therapy as intended. This prolonged follow-up analysis verified the superior relapse-free survival in all patients in the maintenance arm (10-year RFS 30.0 ± 5.6 versus 19.9 ± 6.1 %, p = 0.015). Stratified by age, the 10-year RFS was superior in younger patients 〈 60 years (36.9 ± 7.1 versus 25.2 ± 8.0 %, p = 0.038) and borderline significant in elderly patients (17.2 ± 4.5 versus 6.8 ± 6.2 %, p = 0.075). A subgroup analysis of known risk groups (lactate dehydrogenase (LDH) level 〈 700U/l versus ≥ 700U/l at diagnosis, cytogenetic risk profile, bone marrow blasts on day 16 after the start of the induction therapy) revealed a superior RFS in the subgroup of patients with LDH level 〉 700 U/l at diagnosis (33.5 ± 12.3 versus 18.2 ± 9.5 %, p = 0.043). This superior RFS also translated into a superior 10-year relapse-free interval (RFI) of all responding patients in the maintenance arm (35.7 ± 6.3 versus 27.6 ± 5.9 %, p = 0.015) with borderline significance in younger patients (42.9 ± 7.4 versus 35.0 ± 7.4 %, p = 0.053) and a significant difference in elderly patients (20.6 ± 10.0 versus 8.4 ± 7.5 %, p = 0.043). In this updated analysis, there was a trend, but no significant difference in the OS (maintenance arm: 10-year OS 24.3 ± 4.8, intensive consolidation arm: 19.7 ± 4.7 %, p = 0.148), and we verified a trend for a better OS in responding patients for the maintenance arm (10-year OS in responding patients 33.6 ± 7.5 versus 28.5 ± 6.2 %, p = 0.093). The event-free survival (EFS) also showed a trend towards better EFS in the maintenance arm (10-year EFS 20.7 ± 4.2 versus 14.8 ± 4.1 %, p = 0.082) which was significant in elderly patients (10-year EFS 10.5 ± 5.5 versus 3.9 ± 3.7 %, p = 0.044). Discussion: This updated analysis with a long-term follow-up of median 7.9 years from diagnosis and 7.1 years from CR verified the superior RFS and the trend for enhanced OS in responding patients. These results suggest the superiority of a prolonged monthly myelosuppressive maintenance therapy as compared to intensive consolidation S-HAM after TAD-HAM induction and TAD consolidation. Disclosures: No relevant conflicts of interest to declare.

Description: As a global approach to acute myeloid leukemia the AMLCG started a clinical trial in 1999 with the intention to clarify the influence of baseline characteristics as well as treatment variables on patients’ outcome. The heterogeneity of this disease in mind, all randomization was done stratified for potential risk factors. Furthermore, all randomization was restricted to the single time point up-front of any treatment. Thus, an unbiased intention-to-treat analysis could be provided. Between June 1999 and January 2012, 3370 consecutive patients 16 - 86 (median 61) years of age entered the trial at 57 participating centers. The general up-front randomization comprised (A) repeated G-CSF priming versus no G-CSF, (B) double induction by TAD (thioguanine-araC-daunorubicin) all at standard dose plus HAM (high-dose araC- standard dose mitoxantrone) versus HAM plus HAM, (C) postremission TAD and maintenance versus TAD and autologous stem cell transplantation. For age adaption patients of 60 years and older received reduced intensity double induction (B) and maintenance instead of autologous transplantation (C). The complete remission rate was 57% (65%

Description: Acute myeloid leukemia (AML) with isolated trisomy 13 (AML+13) is rare and frequently associated with FAB M0 morphology. The clinical course is not well characterized but according to the ELN classification of intermediate prognosis. Eighty to one-hundred percent of patients (pts) with AML+13 carry mutations in the RUNX1 gene. Over-expression of FLT3 (located on chromosome 13 [chr 13]) due to the additional gene copy on the third chr 13 was proposed as a mechanism of leukemogenesis in AML+13 (gene dosage hypothesis). We set out to characterize the clinical course of AML+13 pts and elucidate their molecular background using whole exome sequencing, targeted resequencing and gene expression profiling. We identified 23 pts with AML+13 enrolled in a multicenter trial of the German AML Cooperative Group (AMLCG-1999) and compared this group to 386 pts without +13 who were classified in the ELN Intermediate-II genetic category. All pts received intensive induction chemotherapy. There was no significant difference in age, white blood cell or platelet count between the two groups. However, LDH levels were significantly (p=.01) lower in the AML+13 group while bone marrow blast percentage was significantly higher (p=.04). Twelve AML+13 pts (52%) reached complete remission, but all relapsed. Relapse-free and overall survival were inferior in the AML+13 group compared to other ELN Intermediate-II pts (median RFS, 9 vs 15 months, p=.01; median OS, 7 vs. 13 months, p=.03). Remission samples from two AML+13 pts were available as normal control for exome sequencing. Using SureSelect human all exon target enrichment (Agilent) followed by 80bp paired-end sequencing on an Illumina GAIIx platform, we were able to identify non-synonymous leukemia-specific mutations affecting, among others, RUNX1, ASXL1, PTPN11 and CEBPZ. Genes identified by exome sequencing and a panel of genes recurringly mutated in AML were studied by targeted amplicon resequencing in all AML+13 pts with available material (16/23; Figure). As described before, a high incidence of RUNX1 mutations (75%) was identified. In addition, we detected mutations in spliceosome components in 14/16 (88%) of AML+13 pts, including SRSF2 codon 95 mutations in 13/16 pts (81%). One patient without SRSF2 mutation showed a mutation in SF3B1. Moreover, recurring mutations were found in ASXL1 (44%) and BCOR (25%), and were associated with RUNX1 and SRSF2 mutations. Interestingly, both pts without mutations in the splicing machinery had mutations in DNMT3A, which were also mutually exclusive with mutations in RUNX1 or ASXL1. Two pts carried mutations in CEBPZ suggesting that CEBPZ is a novel recurringly mutated gene in AML.FigureMutation frequencies in 16 patients with AML+13Figure. Mutation frequencies in 16 patients with AML+13 To further characterize this genetically homogenous subgroup, we compared gene expression profiles of 9 pts with AML+13 with 509 AML pts without +13. We identified 678 (up-regulated 492; down-regulated 186) probe sets as significantly deregulated. Only 59 (8.7%) of these probe sets were localized on chr 13, but of those, 55 were up-regulated and only 4 were down-regulated. Up-regulated probe sets on chr 13 included FOXO1, FLT3 and RB1. The strongest down-regulated probe set on chr 13 belonged to the tumor suppressor gene SPRY2, which is a negative regulator of receptor tyrosine kinases. Gene set enrichment analysis showed significant deregulation of gene sets associated with regulation of transcription and nuclear transport. In summary, our study is the first to show that AML+13 is significantly associated with inferior OS and RFS compared to other intermediate-risk cytogenetic abnormalities in a homogeneously treated cohort. Furthermore, we present evidence that AML+13 leukemias are a genetically quite homogenous subgroup. AML+13 is not only associated with a high rate of RUNX1 mutations but also with mutations in SRFS2, ASXL1 and BCOR. The incidence of mutations in SRSF2 in AML+13 is the highest of any AML subgroup reported so far. In addition, our gene expression data show a homogenous expression profile associated with AML+13. The striking association of a few recurring mutations in AML+13 suggests a biological relationship with synergistic lesions during leukemogenesis. While mutations in RUNX1, ASXL1 and up-regulation of FLT3 were previously reported as markers of poor prognosis in AML, the combination of these lesions might be responsible for the extremely poor outcome of AML+13. Disclosures: Krebs: Illumina: Honoraria. Greif:Illumina: Honoraria.

Description: Background Internal tandem duplication (ITD) and pointmutations in the tyrosine kinase domain (TKD) of the receptor tyrosine kinase FLT3 occur in about 30% of patients with acute myeloid leukemia (AML). In contrast to the negative prognostic impact of FLT3-ITD in normal karyotype AML, FLT3 pointmutations occurring in the TKD and juxtamembrane (JM) region are less frequent and of unclear clinical impact. Although TKD mutations can induce resistance to tyrosine kinase inhibitors the individual transforming potential of FLT3 pointmutations has not been analysed in detail. In this study we have performed a comprehensive analysis of various FLT3 mutants in a comparative setting in vitro and analyzed gene expression profiles, and clinical outcome with respect to FLT3mutation status. Material and Methods We analyzed relapse and survival in 672 cytogenetically normal AML patients and the FLT3 status at diagnosis and relapse in 156 patients. In the murine Ba/F3 cell model we analyzed the transforming potential, subcellular localization, phosphorylation status and signaling properties of eight different FLT3 mutants. The investigated FLT3 mutations include three ITD of different length and insertion site, V592A in the JM region, common FLT3-TKD mutations D835V and D835Y as well as D839G and I867S in the second TKD. FLT3-D839G and -I867S were recently found in AML patients by our group during routine diagnostics but have not been functionally characterized before. The corresponding remission samples did not express these mutations. Further a gene expression profile analysis with respect to FLT3-ITD and -TKD mutation status and evaluation of differences in activation of predefined STAT5 target gene set was performed. Results In 672 normal karyotype AML patients FLT3-ITD, but not FLT3-TKD mutations were associated with an inferior relapse free and overall survival in multivariate analysis. In paired diagnosis-relapse samples FLT3-ITD showed higher stability (70%) compared to FLT3-TKD (30%). In vitro, FLT3-ITD induced a fully transformed phenotype in Ba/F3 cells, whereas FLT3 pointmutations showed a weaker but clearly transformed phenotype with gradual increase in proliferation and protection from apoptosis. The transforming capacity of the investigated mutants was associated with cell surface expression and tyrosine 591 phosphorylation of the FLT3 receptor. Western blot experiments revealed STAT5 activation only in FLT3-ITD transformed cells, further gene expression profile analyses displayed differences in predefined STAT5 target genes between FLT3-ITD and FLT3-TKD mutations. In contrast, FLT3-non-ITD mutants had an enhanced signal of AKT and MAPK activation. Further differences were found on mRNA level presenting deregulation of SOCS2, ENPP2, PRUNE2 and ART3 expression between FLT3-ITD, FLT3-TKD and FLT3-WT. Conclusion Although apparently divergent in response to treatment all functionally characterized mutants showed a clear gain-of-function phenotype with a wide range of transforming activity associated with clinical prognosis and signaling. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Despite substantial progress in the treatment of newly diagnosed AML, 20% to 40% of patients do not achieve remission with conventional induction chemotherapy. In addition, 50% to 70% of patients with CR1 are expected to relapse within 3 years. Currently, allogeneic HSCT is thought to be the most reliable curative option for patients with relapsed and/or refractory (r/r) disease. Compared to HSCT in CR1 allogeneic HSCT beyond CR1 is associated with lower survival rates. So far, different predictive factors influencing survival in r/r AML have been identified. However, pretransplantation variables delineating prognostic subgroups after allogeneic HSCT beyond CR1 are less well known and the total number of patients in trials addressing this issue has been limited. Methods We analyzed the outcome after allogeneic HSCT in non-APL-AML patients transplanted with either subsequent 2nd complete remission (CR2), r/r AML or with persisting cytopenia (PC, including patients with hematologic complete remission with incomplete hematologic recovery and patients with persisting bone marrow hypoplasia) after induction or salvage therapy. Of 3989 patients who enrolled into a multicenter clinical trial (AMLCG1999; NCT00266136) of the German Acute Myeloid leukemia Cooperative Group (AMLCG) we identified 498 subjects aged 17 to 74 years who underwent allogeneic HSCT beyond first CR. Before transplantation, all patients received first line treatment either with 6-Thioguanine, cyararabine, daunorubicin (TAD) and high-dose cytarabine, mitoxantrone (HAM) or HAM/HAM. After induction failure (n=97) or relapse (n=401) patients either received salvage chemotherapy (n=299) or directly underwent allogeneic HSCT (n=199). Overall survival (OS) and relapse free survival (RFS) after allogeneic HSCT were the main endpoints for this analysis. Kaplan-Meier analysis was performed to estimate survival probabilities in subgroups. Log-rank tests were used to compare survival groups. Relative hazard rates and differences in subgroups were calculated using cox regression analysis. Results At a median follow-up of 6.5 years for surviving patients, OS and RFS rates were 32% (95% CI 28-36%) and 30% (95% CI 26-34%), respectively. Subgroup analysis revealed an OS of 49% in 128 patients with allogeneic HSCT in CR2. In comparison, 73 patients who underwent allogeneic HSCT with PC after induction (n = 42) / salvage treatment (n = 31) and 297 patients with refractory disease (RD) exhibited an OS of 39% and 23%, respectively (Figure 1). The corresponding cumulative incidences (CI) at 1/6.5 years for death in remission after allogeneic HSCT were 25%/31% for patients transplanted in CR2, 29%/41% for patients transplanted with PC and 30%/46% for patients transplanted with RD, respectively. The cumulative incidence of relapse (CIR) after 6.5 years was 58% for patients transplanted with RD compared to 34% for patients transplanted in CR2 and 31% for patients with PC. Main prognostic factors for survival outcome were remission status prior to allogeneic HSCT and cytogenetic risk category at diagnosis. By contrast, patient age, donor, graft source, remission status after induction therapy and CMV status had no significant impact on survival outcome. Conclusions Long-term OS rates after allogeneic HSCT for patients with r/r AML are considered to range between 20 and 40%. Our analysis indicates that a substantial fraction of patients who received similar first line treatment within one prospective trial is able to achieve long term survival when transplanted beyond CR1. In addition, remission upon salvage therapy prior to allogeneic HSCT might be a relevant prognostic factor for patients with r/r AML. However, whether remission induction prior to HSCT can provide an overall survival benefit in patients with r/r disease is still elusive and is currently being evaluated in a prospective randomized clinical trial (ETAL3-ASAP; NCT02461537). Disclosures Beelen: Medac: Consultancy, Other: Travel Support. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Lenz:Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria. Hiddemann:Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stelljes:MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.