Additional Gene Mutations Refine the 2017 European Leukemianet (ELN) Classification of Adult Patients (Pts) with De Novo Acute Myeloid Leukemia (AML) Aged <60 Years: An Analysis of Alliance for Clinical Trials in Oncology (Alliance) Studies

Abstract The ELN recommendations for diagnosis and management of AML in adults, authored by a panel of international experts, have become an important tool to assess pts' prognosis and guide treatment decisions. Following advances in our understanding of the molecular landscape of AML, several gene mutations were added as criteria for assigning pts to genetic risk categories in the 2017 ELN classification. The aim of our study was to apply the 2017 ELN risk groups to a large cohort of 864 AML pts aged <60 years who were similarly treated with intensive cytarabine/daunorubicin based chemotherapy on Cancer and Leukemia Group B/Alliance protocols. In addition, we sought to identify novel gene markers that could refine the ELN classification. Using the 2017 ELN genetic risk-stratification criteria, we assigned 49% of pts to the Favorable-risk group, whereas 22% and 29% of pts belonged to the Intermediate- and Adverse-risk groups, respectively. The complete remission (CR) rate of Favorable-risk pts was 92%, compared with 77% and 48% CR rates of Intermediate-risk and Adverse-risk pts. Fifty-two percent of Favorable-risk pts were disease-free and 63% were alive 3 years after diagnosis, compared with the respective 3-year rates of 22% and 32% for pts belonging to the Intermediate-risk group, and only 10% and 19%, respectively, for pts classified in the Adverse-risk group. Using a targeted 80-gene sequencing panel, we detected 2,354 mutations, with a median of 3 per pt. The frequencies of specific mutations differed between the ELN risk groups. We performed multivariable outcome analyses for the achievement of CR, disease-free (DFS) and overall (OS) survival within each of the ELN groups. Within the Favorable-risk group MVA analyses, the presence of WT1 mutations associated with lower CR rates (P=0.02). Mutations in BCOR (P=0.02), IDH1 (P=0.04), KIT (P<0.001), PTPN11 (P=0.01) and SETBP1 (P=0.02) associated with a shorter DFS; mutated BCOR (P=0.02), IDH1 (P=0.006), SETBP1 (P=0.004), WT1 (P<0.001) and ZRSR2 (P=0.002) associated with a shorter OS. In the Intermediate-risk group MVA analyses, mutations in WT1 associated with lower CR rates (P=0.02). Mutations in DNMT3A and WT1 associated with shorter DFS (DNMT3A, P<0.001; WT1, P=0.01) and OS (DNMT3A, P<0.001; WT1, P=0.005). In the Adverse-risk group MVA analyses, IDH2 mutations associated with lower CR rates (P=0.05). NRAS mutations associated with shorter DFS (P<0.001) and OS (P=0.008). In addition, IDH2- (P=0.03) and TET2-mutated pts (P=0.009) had shorter OS than pts without these mutations. Among FLT3-ITDlow pts, those harboring NPM1 mutation had higher CR rates (P<0.001) and longer OS (P=0.001), but not DFS (P=0.16), than pts with wild-type (wt) NPM1. Within the FLT3-ITDhigh cohort, pts with an NPM1 mutation had higher CR rates than those without (P<0.001). However, there was no difference in either DFS or OS between NPM1 mutated and NPM1 wt pts, indicating that the negative prognostic impact of FLT3-ITDhigh may outweigh the positive prognostic impact of NPM1 mutations with respect to those survival endpoints. We also noted that the negative prognostic impact of WT1 mutations was worsened by co-occurring NPM1 mutations. Similarly, the impact of IDH1 mutations within the Favorable group was influenced by NPM1 mutations, with IDH1/NPM1 co-mutated patients having inferior survival. Based on the results of our multivariable analyses, as well as co-occurring mutations, we provide a possible refinement of the ELN genetic risk stratification in Table 1. DFS and OS of the re-classified pts were comparable to DFS and OS of the original ELN groups (Figure 1). Importantly, the re-classification also changed the percentages of AML patients assigned to specific risk groups, reducing the Favorable-risk group from 49% to 39% and increasing the Adverse-risk group from 29% to 38%, with the Intermediate-risk group remaining almost the same (23% vs 22%). In summary, our study provides a comprehensive analysis of genetic prognostic markers in younger AML pts treated with standard chemotherapy within the framework of the ELN risk classification. Furthermore, we identified several combinations of co-occurring mutations with prognostic significance. Our results provide a refinement of the 2017 ELN risk classification, and identify additional pts that may need more intensive treatment early on. Support: U10CA180821, U10CA180882, U10CA180861, U24CA196171; ClinicalTrials.gov Disclosures Mims: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Kolitz:Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Mutation Landscape and Prognostic Correlates of ASXL1 Variants in Primary and Secondary Myelofibrosis

Blood ◽

10.1182/blood-2021-148685 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2578-2578

Author(s):

Giacomo Coltro ◽

Paola Guglielmelli ◽

Giada Rotunno ◽

Carmela Mannarelli ◽

Chiara Maccari ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Risk Group ◽

Risk Groups ◽

High Risk Group ◽

Prognostic Impact ◽

Driver Genes ◽

Advisory Committees ◽

Risk Of Death ◽

Significant Difference

Abstract Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocytemia, is characterized by a complex and partially undeciphered molecular architecture. Besides mutations in driver genes (JAK2, CALR, MPL), somatic mutations in selected myeloid-associated genes have been shown to impact prognosis of MF patients (pts). Among these, ASXL1 mutations (ASXL1MTs) are associated with poor outcomes in myeloid malignancies including PMF, where they are included in the category of "high molecular risk" (HMR) mutations along with EZH2MTs, IDH1/2MTs, and SRSF2MTs (Vannucchi AM, Leukemia 2013). However, a recent study (Luque Paz D, Blood Adv 2021) questioned the value of ASXL1MTs in MF. The current study aimed at further characterizing the prognostic role of ASXL1MTs in MF. Methods: After IRB approval, pts with WHO-defined MF were included in the study. Mutational analysis by targeted NGS was performed as previously described (Guglielmelli P, JCO 2017). All deposited variants were manually curated to assess pathogenicity. In this study, we also used the molecular model proposed by Luque Paz et al. that identifies 4 genetic groups: TP53MT; High-risk (≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1/2); ASXL1MT-only; and "Others". Results: A total of 525 pts were included in the study, including 331 (63%) PMF and 194 (37%) SMF. Median age at diagnosis was 89 (18-90) years, 314 (60%) were male. The median follow-up time was 80 (98% CI, 68-90) months. Overall, 324 (62%) pts were JAK2MT, 126 (24%) CALRMT, 24 (5%) MPLMT, 40 (8%) triple negative (TN), and 11 (2%) double mutated. Among non-driver genes, ASXL1MTs were found in 158 (30%) pts, EZH2MTs in 45 (9%), SRSF2MTs in 37 (7%), NRASMTs in 30 (6%) U2AF1MTs in 27 (5%), TP53MTs and CBLMTs in 25 (5%) each, IDH1/2 MTs in 18 (3%), and KRAS MTs in 15 (3%). Pts in the HMR category were 125 (38%) in PMF and 63 (32%) in SMF. According to the above model, distribution of pts was as follows: TP53MT n=25 (5%), High-risk n=137 (26%), ASXL1MT-only n=64 (12%), and Others n=299 (57%). Pts in the TP53MT and ASXL1MT-only groups were more likely to be diagnosed with SMF compared to pts in the High-risk and Others groups (44% and 48% vs 28% and 38%, respectively). In addition, the High-risk group was enriched in TN pts (16%), while CALRMTs were more common in the ASXL1MT-only and Others compared to the TP53MT and High-risk groups (25% and 27% vs 12% and 18%, respectively). In univariate analysis, the TP53MT and High-risk groups were associated with the worst overall survival (OS), with median values of 38 (14-110) and 55 (45-85) months (P=.0039), respectively (Fig 1A). Albeit remarkably better, the OS of pts in the ASXL1MT-only group was inferior compared to pts in the Others group (median 124 [91-156] vs 193 [142-NR] months; P=.0118) (Fig 1A). We then analyzed separately PMF and SMF cohorts. In the former, the TP53MT and High-risk groups remained associated with the worst OS (median 58 [20-126] vs 55 [36-85] months), although with no significant difference, likely due to the low frequency (4%) of TP53MTs mutations in PMF (Fig 1B). Concurrently, the negative prognostic impact of the ASXL1MT-only group was confirmed in comparison to the Others group (median 103 [78-NR] vs 320 [178-NR] months; P=.0170). In pts with SMF, while the TP53MT group (6%) had by far the worst OS (median 13 [6-NR] months), the OS of the ASXL1MT-only group (median 141 [56-171] months) was comparable to that of the Others group (median 131 [106-NR] months; P=.5188) and not different from the High-risk group (median 58 [45-174] months; P=.3606) (Fig 1C). In a further analysis including only pts in the High-risk group, ASXL1MTs were found in 62% and 63% of patients with PMF and SMF, respectively. In survival analysis, the presence of ASXL1MTs was associated with an increased risk of death only in PMF (median OS 47 [31-73] vs 102 [34-317] months; P=.0240), unlike in SMF (median OS 90 [47-174] vs 25 [16-338] months; P=.3296) (Fig 1D-E). Conclusion: In the current study, we critically re-addressed the prognostic impact of ASXL1MTs by applying a genetic model recently developed by Luque Paz et al. to our cohort of molecularly annotated, WHO-defined MF pts. Overall, our results confirm that ASXL1MTs -even in the absence of other co-occurring high-risk mutations- harbor a negative prognostic impact mainly in PMF. These findings also reinforce the idea that PMF and SMF represent two different biological entities. Figure 1 Figure 1. Disclosures Vannucchi: Incyte: 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Outcomes of Patients with Relapsed or Refractory Acute Myeloid Leukemia Receiving Hypomethylating Agent and Venetoclax

Blood ◽

10.1182/blood-2019-128958 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1357-1357 ◽

Cited By ~ 2

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

Initial Therapy ◽

Intermediate Risk ◽

Advisory Committees ◽

Significant Difference ◽

Frontline Therapy ◽

Refractory Aml

Background: Patients with acute myeloid leukemia (AML) have dismal overall outcomes and survival is exceptionally poor in patients who experience relapse or are refractory (R/R) to frontline therapy. Since December 2018, combination therapy with hypomethylating agents (HMA) and venetoclax (HMA+Ven) has become standard frontline therapy for older patients or younger unfit patients. Moreover, it has been routinely utilized in patients experiencing relapsed or refractory AML yet response and outcome data is limited in patients with R/R disease. Thus, we investigated outcomes after HMA+Ven in patients with relapsed or refractory AML. Methods: We retrospectively annotated 72 patients who received treatment with HMA+Ven at Moffitt Cancer Center and Memorial Healthcare System between 2017 and 2019. Patients were divided into two subgroups: 1) initial remission therapy and 2) salvage therapy. Clinical and molecular data were abstracted in accordance with the Institutional Review Board approved protocol. Overall response rate (ORR) included patients achieving complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Patients achieving CR, CRi, or MLFS were termed as responders (RES) and patients without CR, CRi, or MLFS were nonresponders (NRES). Fisher's Exact method was used to determine significance for categorical variables. Kaplan-Meier analysis was performed to determine median overall survival (mOS) and log-rank test was utilized to determine significance. All p-values are two-sided. Results: Out of 72 patients, 41 received HMA+Ven as initial therapy and 31 received it in the R/R setting. Baseline characteristics are outlined in Table 1. Median age was 63 years for patients with R/R AML with 58% female. In the R/R cohort, ORR was 34.5% with 0 (0%) patients achieving CR, 8 (27.6%) patients achieving CRi, and 2 (6.9%) achieving MLFS (Table 2). When compared to patients receiving HMA+Ven as initial therapy, ORR was significantly lower in the R/R cohort (64.1% vs. 34.5%, p=0.03). Among 31 patients in the R/R cohort, 6.5% (n=2) proceeded to allogeneic stem cell transplant (allo-SCT) after achieving CRi. European LeukemiaNet (ELN) risk stratification was known in 22 patients in the R/R cohort and ORR were similar in patients in the favorable/intermediate risk group (n=8) compared to adverse risk group (n=14) (37.5% vs. 28.6%, p=1.0). When compared to HMA+Ven used as initial therapy, ORR among the R/R cohort were not different among adverse risk groups (58.3% vs. 28.6%, p=0.10); however, ORR were significantly lower among patients with favorable/intermediate risk (100% vs. 37.5%, p=0.009). At a median follow-up of 7.6 months (mo), mOS was 4.9mo in the R/R cohort with mOS among RES superior to NRES (not reached vs. 2.4mo, p=0.0009) (Figure 1). Moreover, mOS was inferior in R/R patients compared to initial therapy (4.9mo vs. 13.8mo, p=0.0013) (Figure 2). A total of 15 (48.4%) patients had HMA exposure prior to receiving HMA+Ven without apparent impact on mOS (3.7mo (prior HMA) vs. 4.9mo (no prior HMA), p=0.97). The median duration of CR/CRi was 5.2mo and the median time to CR/CRi was 2.4mo. Based on ELN risk groups, mOS was not statistically different among patients with favorable/intermediate risk disease compared to adverse risk disease (8.6mo (fav/int) vs. 2.8mo (adverse), p=0.07). Responses were also analyzed based upon somatic mutations (Figure 2). In patients with isocitrate dehydrogenase 1 and 2 mutations (IDH1/IDH2) compared to patients without IDH1/2, ORR were 60% vs. 25%, respectively (p=0.28) with no significant difference in mOS (7.2mo (IDHmut) vs. 3.1mo (IDHwt), p=0.38). Comparing patients with TP53 mutation to those without TP53 mutations, no significant difference in ORR (25% vs. 33%, p=1.0) or mOS (4.4mo vs. 6.9mo, p=0.0.84) was noted. Conclusion: Although combination therapy with HMA+Ven has yielded impressive responses as frontline therapy, response rates with this combination in the salvage setting are less encouraging with the possible exception of those patients with IDH1/IDH2 mutations. Nevertheless, responders to salvage HMA+Ven had a significant survival benefit compared to nonresponders, suggesting that this combination is a reasonable salvage option in patients with relapsed or refractory AML. Disclosures Padron: Incyte: Research Funding. Kuykendall:Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria; Janssen: Consultancy; Abbvie: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:JAZZ: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. OffLabel Disclosure: Venetoclax is approved in combination with hypomethylating agents (azacitidine or decitabine) or low dose cytarabine for treatment of newly diagnosed AML in adults aged 75 years or older, or those who have comorbidities that preclude the use of induction chemotherapy.

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Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽

10.1182/blood.v124.21.1992.1992 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1992-1992 ◽

Cited By ~ 1

Author(s):

Eugen Tausch ◽

Christina Galler ◽

Richard Schlenk ◽

Peter Hillmen ◽

Fritz Offner ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Gene Mutations ◽

Phase Iii ◽

Response To Treatment ◽

Prognostic Impact ◽

Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Combining Information Regarding Chromosomal Aberrations t(4;14), Del(17p13) and the Copy Number of 1q21 with the International Staging System Classification Allows Stratification of Myeloma Patients Undergoing Autologous Stem Cell Transplantation: Results From the HOVON-65/GMMG HD4 Trial

Blood ◽

10.1182/blood.v118.21.332.332 ◽

2011 ◽

Vol 118 (21) ◽

pp. 332-332

Author(s):

Kai Neben ◽

Henk M. Lokhorst ◽

Anna Jauch ◽

Uta Bertsch ◽

Thomas Hielscher ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Risk Group ◽

Staging System ◽

Risk Groups ◽

Low Risk ◽

Advisory Committees ◽

International Staging System

Abstract Abstract 332 PURPOSE : In Multiple Myeloma (MM), the combination of serum beta-2-microglobulin level with serum albumin concentration has been proposed as an outcome predictor in the International Staging System (ISS). More recently, subgroups of MM defined by genetic and cytogenetic abnormalities have been associated with unique biologic, clinical, and prognostic features. PATIENTS AND METHODS: We analyzed the prognostic value of 12 chromosomal abnormalities by fluorescent in situ hybridization (FISH) in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Patients with newly diagnosed MM were randomized to receive either three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). All patients underwent autologous stem cell transplantation (ASCT) followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. In addition, a second cohort of patients was analyzed as a control group (n=462), undergoing ASCT at the University of Heidelberg between September 1994 and December 2010. RESULTS: For the entire group of patients treated within the HOVON-65/GMMG-HD4 trial, we identified 233 patients with 2 copies (67.7%), 95 patients with 3 copies (27.6%) and 16 patients (4.7%) with more than three copies of the chromosomal region 1q21. In addition to del(17p13) and t(4;14), we added +1q21 (>3 copies) to the group of high-risk aberrations, since the outcome of these patients was almost as poor as it was observed for patients with del(17p13). Subsequently, we analyzed whether combining the ISS score with information on the presence of high-risk aberrations could improve the prognostic value with regard to patients' outcome. A combination of the presence or absence of del(17p13), t(4;14), or +1q21 (>3 copies) with the ISS score allowed patients to be stratified into three distinct groups: low-risk [absence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS I], high-risk [presence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS II/III], and intermediate-risk (all remaining patients). Most of the patients belonged to the low- (33%) and intermediate-risk (49%) groups, whereas 18% were allocated to the high-risk group. The median PFS times for the low-, intermediate-, and high-risk groups were 41.9 months, 31.1 months (HR=1.7; p=0.0018) and 18.7 months (HR=3.6; p<0.0001), respectively. The 3yr-overall survival (OS) decreased from 94% in the low-risk group to 80% (HR=4.6; p=0.0001) and 43% (HR=12.8; p<0.0001) in the intermediate- and high-risk groups, respectively. These results were confirmed in the independent cohort of patients: From date of first ASCT, the median PFS times for the low-, intermediate-, and high-risk groups were 43.3 months, 23.0 months (HR=1.5; p=0.015) and 13.8 months (HR=2.4; p=0.0003), respectively. The 4yr-OS decreased from 84% in the low-risk group to 71% (HR=2.1; p=0.0043) and 49% (HR=3.84; p<0.0001) in the intermediate- and high-risk groups, respectively. CONCLUSION: In our series, the ISS/FISH-based score/algorithm predicted PFS and OS much better than the ISS alone. Our results with molecular cytogenetic techniques may already have implications for the risk-adapted clinical management of patients with MM particularly in younger patients. Disclosures: van de Velde: Ortho Biotech Oncology Research & Development: Employment. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Clinical relevance of high–intermediate risk endometrial cancer according to European risk classification

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2020-001693 ◽

2020 ◽

Vol 30 (10) ◽

pp. 1528-1534

Author(s):

Agnieszka Rychlik ◽

Ignacio Zapardiel ◽

Laura Baquedano ◽

María Ángeles Martínez Maestre ◽

Denis Querleu ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Endometrial Cancer ◽

Lymph Node ◽

European Society ◽

Risk Group ◽

Risk Groups ◽

Intermediate Risk ◽

Nodal Metastases ◽

Disease Free

ObjectiveRisk models in endometrial cancer define prognosis and indicate adjuvant therapy. One of the currently used classifications was designed in 2016 in collaboration with the European Society of Medical Oncology (ESMO), the European Society of Gynecologic Oncology (ESGO), and the European Society of Radiotherapy (ESTRO). A high–intermediate risk group was introduced within the intermediate risk group. The purpose of this study was to evaluate the clinical relevance of this subclassification.MethodsA multicenter retrospective study was carried out at five international tertiary institutions. Patients diagnosed with intermediate risk endometrial cancer on the basis of definitive pathology findings were included. Patients were stratified into intermediate and high–intermediate risk groups. Incidence of nodal metastases, and disease free and overall survival were compared between the two risk groups in univariate and multivariate analysis.Results477 patients were included: 325 (68%) patients were identified as intermediate and 152 (32%) as high–intermediate endometrial cancer patients. Nodal metastases were found in 18 patients (11.8%) in the high–intermediate risk endometrial cancer group and 16 patients (4.9%) in the intermediate risk group. Lymphovascular space invasion was found to be a strong predictive factor of lymph node involvement. High–intermediate risk was found to be an independent factor of disease free survival (hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00 to 3.08; p=0.050) and overall survival (HR 1.99; 95% CI 1.10 to 3.60; p=0.022) in the multivariate analysis.ConclusionsThe study validates the clinical significance of the intermediate risk endometrial cancer subclassification. Prognosis for high–intermediate risk endometrial cancer was significantly poorer. The prevalence of lymph node metastases was higher in this group of patients.

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Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽

10.1182/blood-2019-125967 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 48-48 ◽

Cited By ~ 1

Author(s):

H. Moses Murdock ◽

Haesook T. Kim ◽

Bryan Hambley ◽

Pankit Vachhani ◽

Nathan Denlinger ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

Gene Mutations ◽

Genetic Alterations ◽

Advisory Committees ◽

Genetic Characteristics ◽

The Impact ◽

Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p<0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p<0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate > 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: 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; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. 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. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

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High CRP-Albumin Ratio Predicts Poor Prognosis in Transplant Ineligible Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-144832 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3388-3388

Author(s):

Hajime Senjo ◽

Masahiro Onozawa ◽

Daisuke Hidaka ◽

Shota Yokoyama ◽

Satoshi Yamamoto ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Risk Group ◽

Intermediate Risk ◽

Newly Diagnosed ◽

High Group ◽

Advisory Committees ◽

Intermediate Group

Abstract Introduction. Older patients aged over 65 with acute myeloid leukemia (AML) are often ineligible for hematopoietic stem cell transplantation (HSCT) and generally have a poor prognosis. The personalized strategy for appropriate treatment for these patients has not yet been completely established. While C-reactive-protein (CRP) to albumin ratio (CAR) based on serum level of CRP and albumin (Alb) predicts prognosis of patients with hematological malignancies treated with HSCT (Miyashita E, BBMT. 2019), the prognostic significance of this inflammatory and nutritional assessment in transplant-ineligible elderly patients with AML remains to be clarified. Methods. Hokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG). In this study, we focused on older (≥65 years) patients with newly diagnosed AML treated without HSCT and investigated cytogenetic and molecular abnormality of leukemic cells including FLT3-ITD, NPM1, CEBPA, and KIT. We stratified the patients into favorable, intermediate, and adverse risk group based on NCCN 2017. Based on the result of blood sample test, we assessed CAR [CRP (mg/dL) / Alb (g/dL)] at diagnosis for each patient. Since the median CAR at diagnosis was 0.52 in this cohort, we defined CAR < 0.52 and ≥ 0.52 as CAR low and CAR high, respectively. We evaluated the impacts of NCCN 2017 and CAR on overall survival (OS) in these patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. In total, 197 patients with newly diagnosed AML patients aged 65 or older enrolled in HLN between April 2010 and March 2019. Nine patients undergone HSCT were excluded, and 188 patients were reviewed (Age 65-93, median 72; male 119, female 69). In this cohort, classification based on NCCN 2017 successfully divided the prognosis of the patients for 2-year and 5-year OS [2-year OS; favorable group, 58.1%; intermediate group, 29.4%; adverse group, 12.6%, 5-year OS; favorable group, 33.7%, intermediate group, 8.74%; adverse group, 9.44%, P=0.000079, Figure A]. OS in patients with CAR 0.52 or more was significantly lower than the low score group [2-year OS; CAR low group, 43.4%; CAR high group, 21.5%; 5-year OS; CAR low group, 21.0%; CAR high group, 9.96%, P=0.00013, Figure B]. In a univariate analysis, higher age, adverse group in NCCN 2017, high CAR, and not reached complete remission (CR) after first induction chemotherapy were associated with poor 2-year OS. A multivariate analysis demonstrated that adverse group in NCCN 2017 and high CAR were independently associated with poor 2-year OS (adverse group in NCCN 2017; HR, 1.671; 95% CI, 1.157 to 2.421, P=0.007, high CAR; HR, 1.572; 95% CI, 1.093 to 2.276, P=0.01618; log-rank). Combined with NCCN 2017, while there were no significant prognostic impacts of CAR at diagnosis in patients with favorable or adverse risk groups (Figure C, E), we found that in intermediate risk group the patients with high CAR had poorer prognosis than patients with low CAR [2-year OS; CAR low group, 43.7%; CAR high group, 15.9%, P=0.0000658; Figure D]. Altogether, we demonstrated that high CAR predicts poor prognosis in the transplant-ineligible elderly patients with newly diagnosed AML and improves risk stratification of the patients with NCCN 2017 intermediate risk group. Conclusion. CAR is a simple and easily evaluable parameter for predicting outcomes of transplant-ineligible elderly patients with newly diagnosed AML, independently from NCCN disease risk classification. Moreover, CAR can further stratify the prognosis of patients with NCCN 2017 intermediate risk group and improve the predictive risk stratification for elderly AML patients. Figure 1 Figure 1. Disclosures Kondo: SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Teshima: Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria; Fuji pharma CO.,Ltd: Research Funding; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; TEIJIN PHARMA Limited: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Sanofi S.A.: Research Funding.

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Gene Mutations Detected by Whole-Exome Sequencing and Recurrent Cytogenetic Abnormalities Are Independent Events in Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.1816.1816 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1816-1816

Author(s):

Hervè Avet-Loiseau ◽

Graham R Bignell ◽

Cheng Li ◽

Florence Magrangeas ◽

Thierry Facon ◽

...

Keyword(s):

Multiple Myeloma ◽

Exome Sequencing ◽

Board Of Directors ◽

Whole Exome Sequencing ◽

Risk Group ◽

Gene Mutations ◽

Newly Diagnosed ◽

Advisory Committees ◽

Independent Events ◽

Whole Exome

Abstract Abstract 1816 Multiple Myeloma (MM) is characterized by several recurrent chromosomal abnormalities, some of them driving the outcome of the patients, especially t(4;14), del(17p), and hyperdiploidy. On the other hand, recent data based on whole genome sequencing showed that MM is characterized by many gene mutations, some of them being recurrent. In order to try to reconcile these two types of genetic abnormalities, we performed whole exome sequencing (WES) in 53 newly-diagnosed patients characterized by high or low risk at the chromosomal level. We selected 16 patients with del(17p) in at least 60% of the clonal plasma cells, 5 patients with del(12p), including 3 with associated t(4;14), 2 patients with t(14;16), 1 patient with both del(17p), del 12p), and t(4;14), considered as the poor risk group (24 patients), 24 patients with hyperdiploidy (including chromosome 5 gain), and 2 patients with a normal SNParray profile, considered as the good risk group (26 patients, and 3 patients with hyperdiploidy and either del(17p) and/or del(12p), considered as the uncertain risk group. A total of 3621 non-silent mutations were observed through the 53 tumor genomes. The median number of mutations per patient was 79 (31–462). We did not observe differences in the number of mutations according to cytogenetic risk. Regarding specific gene mutations, 376 genes presented 2 mutations, and 128 genes presented at least 3 mutations (3–16). Comparison with recently published sequencing data (Chapman, Nature, 2011) revealed only a few common mutated genes (NRAS 26%, KRAS 23%, TP53 13%, BRAF 11%, and FAM46C 10%). In contrast, many recurrently mutated genes were identified in this series, but not in the published one. This could be related to the relatively low number of sequenced cases in both series. Very interestingly, quite a high number of strictly identical mutations involving many genes were observed in different patients (139 cases), suggesting that those mutations are more probably driver rather than passenger events. To conclude, in this large comprehensive study, we did not find any significant correlation between recurrent chromosomal changes and gene mutations, suggesting that these two events occur independently. We cannot address the issue of the prognostic value of the gene mutations because of the low number of patients sequenced so far. This question will definitely have to be addressed in future larger series on newly diagnosed patients with MM. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: 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; Onyx: Membership on an entity's Board of Directors or advisory committees.

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Adverse Impact of DNA Methylation Regulatory Gene Mutations on the Prognosis of AML Patients in the 2017 ELN Favorable Risk Group, Particularly Those Defined by NPM1 Mutation

Diagnostics ◽

10.3390/diagnostics11060986 ◽

2021 ◽

Vol 11 (6) ◽

pp. 986

Author(s):

James Yu ◽

Jingxin Sun ◽

Yuan Du ◽

Rushang Patel ◽

Juan Carlos Varela ◽

...

Keyword(s):

Dna Methylation ◽

Risk Group ◽

Regulatory Gene ◽

Gene Mutations ◽

Risk Groups ◽

Npm1 Mutation ◽

Group A ◽

The Impact ◽

Favorable Group

The 2017 ELN risk stratification has been widely adopted, but some studies have suggested the outcomes are heterogenous within the ELN risk groups and may be affected by other co-existing genetic mutations. This study evaluated the impact of DNA methylation regulatory gene (TET2, IDH1/2, DNMT3A, SETBP1) mutations (DMRGM) evaluated by NGS in the outcome of AML patients in each ELN risk group. A total of 114 patients were analyzed with a median follow-up of 12 months. Overall, 30.7% (35/114) of patients had DMRGM. DMRGM status had no impact on CR rate in each ELN risk group. The OS, however, was significantly shorter in patients with DMRGM compared to those without DMRGM (median OS: 12 vs. 33 months, p = 0.0053). Multivariate analysis showed DMRGM status was an independent unfavorable factor for OS (HR: 2.704, 95% CI: 1.451–5.041, p = 0.0017). The adverse OS impact of DMRGM was only observed in the ELN favorable group (7 months vs. not reached, p = 0.0001), but not in the intermediate or adverse group. Among the favorable group with DMRGM (n = 16), DMRGM occurred predominantly in cases with mutated NPM1 (15/16, or 93.8%). Our results suggest that DMRGM adversely impact the outcomes of ELN favorable group patients, particularly those with mutated NPM1. Further studies are warranted to confirm our observations.

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Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup

Blood ◽

10.1182/blood-2020-137032 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Norbert Vey ◽

Corentin Orvain ◽

Christian Recher ◽

Arnaud Pigneux ◽

Marc Bernard ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Risk Groups ◽

Advisory Board ◽

Intermediate Risk ◽

Phase 2 ◽

Phase 3 ◽

Eligibility Criteria ◽

Advisory Committees ◽

Consolidation Phase

In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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