PTPN11 mutations and Outcomes in Adult Patients with Acute Myeloid Leukemia

Background: Mutations in the protein tyrosine phosphatase gene PTPN11 (also known as SHP2) are found in approximately 10% of adult patients with acute myeloid leukemia (AML). A recent study reported that mutated PTPN11 associates with inferior response rates and shorter survival among intensively treated AML patients, independently of the ELN prognostic groups (Alfayez et al., Leukemia 2020). Earlier analyses of the genomic landscape of AML did not uncover a similar prognostic relevance of PTPN11 mutations. Therefore, our aim was to clarify the prognostic relevance of mutated PTPN11 variants in AML patients receiving intensive front-line therapy. Patients and Methods: We studied 1116 AML patients enrolled on two subsequent multicenter phase III trials of the German AML Cooperative Group (AML-CG 1999, NCT00266136; and AML-CG 2008, NCT01382147) who were genetically characterized by amplicon-based targeted next-generation sequencing (Herold et al., Leukemia 2020). All patients had received induction chemotherapy containing cytarabine and daunorubicin or mitoxantrone. Results: We identified 146 PTPN11 mutations in 114 of 1116 patients (10%). Mutations clustered in two hotspot regions (5': codons 52-79; n=108 and 3': codons 491-512, n=38) as previously reported. Associations of PTPN11 mutations with baseline clinical and genetic patient characteristics are shown in Figure A. PTPN11 mutations were most frequent in the European LeukemiaNet (ELN) "favorable" genetic risk group, and associated with higher leukocyte counts. Patients with mutated PTPN11more commonly had mutated NPM1, IDH1 and DNMT3A, and less frequently had FLT3-ITD, IDH2 and TP53 mutations, compared to patients with wild-type PTPN11. With regard to treatment outcomes, the rate of complete remission was similar among patients with mutated and wild-type PTPN11 (65% vs. 59%, P=.25). In univariate analyses, PTPN11-mutated patients had significantly longer relapse-free survival (RFS; 5-year estimate, 55% vs 33% for PTPN11-wild type patients; P=.001; Figure B) and tended to have longer overall survival (OS; 5-year estimate, 43% vs 32%; P=.06; Figure C). However, in multivariable models adjusting for age, sex, leukocyte count, AML type (de novo/sAML/tAML) and ELN-2017 genetic risk group, mutated PTPN11 no longer associated with RFS (hazard ratio [HR], 0.89, 95% confidence interval [CI], 0.63 - 1.27; P=0.53) or OS (HR, 1.03; 95% CI, 0.80 - 1.33; P=.79). Moreover, PTPN11 mutations did not significantly associate with RFS or OS within any of the ELN genetic risk groups. Finally, we detected no significant differences in baseline characteristics or outcomes between patients with PTPN11 mutations affecting the 5' hotspot region (n=82), the 3' hotspot region (n=21), or mutations at both hotspots (n=11). Conclusion: In our cohort of newly diagnosed and intensively treated AML patients, mutations in PTPN11 occurred in 10% and associated with prognostically favorable genetic characteristics such as mutated NPM1 and absence of FLT3-ITD and TP53mutations. Consequently, PTPN11 mutations were most commonly found within the ELN-2017 favorable risk category. While patients with PTPN11 mutations had relatively favorable survival outcomes, multivariable models suggest this observation is confounded by the frequent co-occurrence of known favorable genetic markers. Our data are in disagreement with a recently published study on 880 newly diagnosed patients that found an unfavourable prognostic impact of mutated PTPN11, particularly among the 410 patients who received intensive treatment. Possible explanations for these discrepant results include differences in treatment regimens between the two cohorts, as well as the play of chance when studying a relatively rare gene mutation in medium-sized cohorts. In summary, our data do not support a role of PTPN11 mutations as an adverse prognostic biomarker in newly diagnosed, intensively treated adult AML patients. Figure Disclosures Metzeler: Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Honoraria. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Morphosys: Research Funding; Seattle Genetics: Research Funding; Roche AG: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; 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; Incyte: Research Funding; 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; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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Prospective Identification of Acute Myeloid Leukemia Patients Who Benefit from Gene-Expression Based Risk Stratification

Blood ◽

10.1182/blood-2019-129519 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1397-1397

Author(s):

Diego Chacon ◽

Ali Braytee ◽

Yizhou Huang ◽

Julie Thoms ◽

Shruthi Subramanian ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Genetic Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Groups ◽

High Fidelity ◽

Improve Outcome ◽

Acute Myeloid

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.

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Survival Improvement Of Secondary Acute Myeloid Leukemia Over Time: Experience From 962 Patients Included In 13 EORTC-Gimema-HOVON Leukemia Group Trials

Blood ◽

10.1182/blood.v122.21.829.829 ◽

2013 ◽

Vol 122 (21) ◽

pp. 829-829 ◽

Cited By ~ 3

Author(s):

Safaa M. Ramadan ◽

Stefan Suciu ◽

Marian J.P.L. Stevens-Kroef ◽

Roelof Willemze ◽

Sergio Amadori ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Malignant Disease ◽

Risk Group ◽

Toxic Exposure ◽

Secondary Acute Myeloid Leukemia ◽

History Of ◽

Over Time ◽

Acute Myeloid

Abstract Background Secondary acute myeloid leukemia (sAML) describes patients (pts) with a history of malignant or non-malignant disease or AML secondary to environmental, occupational or therapeutic exposures. They are generally associated with poor outcome despite the use of intensive treatments. The impact of clinical features and type of treatment on pts' outcome is still not well established. In the current analysis we evaluated sAML pts who were treated in 13 EORTC collaborative trials conducted between May 1986 and January 2008. sAML pts in the database were pooled to characterize clinical features of the disease and evaluate changes in survival over these years (yrs). Method Main selection criteria were AML with bone marrows blasts ≥20% and documented history of prior malignancy, non-malignant disease and/or toxic exposure. AML-M3 and MDS without confirmed diagnosis ≥2 months before AML were excluded. All pts were eligible for standard treatment. Induction regimens were anthracycline and AraC based: 7+3, including etoposide, intensified with high dose (HD)-AraC randomized to standard doses (SD) in younger (AML12) or gemtuzumab ozogamicin in elderly pts. Consolidation regimens were age adapted. In mid-1980s, autologous transplant was tested vs a 2nd consolidation cycle (AML8A) in pts ≤45 yrs and thereafter used systematically in pts ≤60 yrs without available donor. Allogeneic transplant (Allo-SCT) was offered to pts ≤46 yrs with HLA-compatible sibling since mid-1980s and expanded in the last decade to pts up to 59 yrs. Selected pts were divided into 3 sAML cohorts, cohort A after MDS, cohort B after other malignant diseases and cohort C after non-malignant conditions and/or toxic exposure. Results Of 8858 pts enrolled in the 13 evaluated studies, 962 were sAML. Median age was 63 yrs (range 16-85), 413 were young (≤60 yrs) and 549 were elderly (≥61 yrs); 54% were males. Cohort A consisted of 509 pts (median age 64 yrs), cohort B of 362 pts (median age 59 yrs) and cohort C of 91 pts (median age 61 yrs). In cohort B, breast cancer (24%) and lymphoma (14%) were the most frequent primary tumors. Autoimmune diseases represented 22% of non-malignant conditions. In young pts, complete remissions (CR/CRi) rate was 59%; 55% in SD-AraC vs 89% in HD-AraC treated pts. Allo-SCT in CR1 was performed in 21% of all pts. The Allo-SCT rate increased from 5% before 1990, 20% in 1990-1999 to 25% from 2000 (20% in SD-AraC vs 31% of HD-AraC treated pts). CR/CRi was achieved in 45% of elderly pts. Median follow-up was 6 yrs. Median overall-survival (OS) was 14.5 months in young and 9 months in elderly pts. The 5-yr OS was 28% and 7% respectively. Five-yr OS was 11% in cohort A and 22% in both cohort B and C. Treatment outcome of younger pts according to disease features and treatment type over time in cohort A and B are detailed in table 1 & 2. Using Cox model stratified by cohort age, gender, WBC, risk group, year of treatment and HD-AraC were independent prognostic factors for OS. In the AML12 study, compared to denovo pts, sAML pts ≤45 yrs had worse outcome if treated with SD-AraC whereas a better OS was seen if treated with HD-AraC. In elderly pts only the good/intermediate risk group of cohort B had a relatively better 5-yr OS (15%). Conclusions The outcome of sAML in younger pts has improved over the yrs in parallel with HD-AraC introduction in induction of remission. HD-AraC should be considered for younger pts with sAML. Disclosures: Ramadan: Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Suciu:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. Meert:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other. de Schaetzen:Alwaleed Bin Talal Foundation : A research funding is under advanced negotiation with the foundation Other Other.

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Racial Variations in Mutational Profile in Newly Diagnosed Acute Myeloid Leukemia Patients

Blood ◽

10.1182/blood-2020-143329 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Tahsin Anwar ◽

Mohammed Mian ◽

Mahran Shoukier ◽

Achuta K Guddati ◽

Moinul Hossain ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Suppressors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cohesin Complex ◽

Newly Diagnosed ◽

Mutational Burden ◽

Epigenetic Modifiers ◽

Kinase Pathway ◽

Acute Myeloid

Background: Increasing evidence shows the impact of mutational burden in acute myeloid leukemia (AML) and impact on clinical response. Classifying these mutations into exclusive sub-types that are mutually exclusive was recently attempted. We sought to identify differences in mutational burden in AML patients based on race. Methods: We retrospectively reviewed the patient charts to distinguish the mutational markers of AML that substantially impact the outcome of AML. We categorized the mutations in seven functional groups with mutually exclusive mutations Signaling and kinase pathway (FLT3, KRAS, NRAS, KIT, PNPN1, JAK2, CBL), Epigenetic modifiers (DNMT3A, IDH1, IDH2, TET2, ASXL1, EZH2, and MLL/KMT2A), Nucleophosmin (NPM1), Transcription factors (CEBPA, RUNX1, and GATA2), Tumor suppressors (TP53), Spliceosome complex (SRSF2, U2AF1, SF3B1, and ZRSR2), and Cohesin complex (RAD21, STAG1, STAG2, SMC1A, and SMC3). For estimating racial distribution, we included only Whites and African Americans (AA) in the study as they represent 95% of the total population at our Cancer Center. Remission and relapse were defined per standard guidelines. We compiled data of all newly diagnosed AML patients treated at our institution between 2016 to the end of 2019. Both next generation sequencing (NGS) and Polymerase Chain Reaction (PCR) methods of genetic marker recognition techniques were included in the study. Results: 159 patients with AML were included in the analysis. We excluded seven patients of different race, including Asian (n=2), Hispanic (n=3), and unknown (n=2). The median age of the patients at diagnosis were 47 years (range 14 - 84 years), 73.3 % were white Caucasian, and 52.8% were female. The median age for white and African American (AA) patients was similar (47 vs 42 year respectively, p=0.55659), however, AAs have more female than Whites (65.9% vs. 47.8%, p=0.04164). In descriptive analysis of genetic marker mutation distributions between Whites and AA we observed signaling and kinase pathway 26.9% vs 25%, p=0.80231; epigenetic modifiers 14.8% vs 25%, p=0.13144; nucleophosmin 14.8% vs 13.6%, p=85460; transcription factors 5.2% vs 6.82%, p=0.69686; tumor suppressors 7.8% vs 0%; spliceosome complex 6.1% vs 2.3%, p=0.32647 and cohesin complex 1% vs 0%, respectively. Overall, 32.2% achieved complete remission (CR), 21.5% complete remission with incomplete hematologic recovery (CRi) and 45.6% Refractory. The CR + CRi rates of Whites and AA were not statistically significant (54.8% vs 52.3% respectively, p=0.77699). The median number of induction required for CR in both races was the same (2 and 2, respectively). We did not find any differences in number of induction for achieving CR by race. However, the rate of relapse was higher in white patients than in AA (49.1% vs 31.8%, respectively) (p=0.05039). Conclusion: This analysis suggests that there might be variations in functional categories of mutations markers in AML patients by race, tumor suppressors (TP53) found more frequently in whites and epigenetic modifiers in AA. This might be at least in part the reason for a higher relapse rate among whites. Additional studies and larger cohorts are needed to further explore the correlation between race, molecular markers and outcomes for AML. Figure Disclosures Cortes: Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding;BioPath Holdings:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Research Funding;Pfizer:Consultancy, Research Funding;Telios:Research Funding;Jazz Pharmaceuticals:Consultancy, Research Funding;Merus:Research Funding;Immunogen:Research Funding;BiolineRx:Consultancy, Research Funding;Bristol-Myers Squibb:Research Funding;Arog:Research Funding;Amphivena Therapeutics:Research Funding;Novartis:Consultancy, Research Funding;Sun Pharma:Research Funding.Kota:Novartis:Consultancy;Pfizer:Consultancy.

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WT1 Monitoring of Minimal Residual Disease (MRD) in Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.3695.3695 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3695-3695 ◽

Cited By ~ 1

Author(s):

Michele Malagola ◽

Crisitina Skert ◽

Enrico Morello ◽

Francesca Antoniazzi ◽

Erika Borlenghi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Myeloid Leukemia ◽

Research Funding ◽

Residual Disease ◽

Newly Diagnosed ◽

End Of Treatment ◽

Minimal Residual ◽

Acute Myeloid

Abstract Background: Although a complete remission (CR) can be achieved in 70-80% of newly diagnosed acute myeloid leukemia (AML) patients, relapses occur in up to the 50% of cases. Thus, minimal residual disease (MRD) monitoring is a major issue for early detection of patients at high-risk of treatment failure and relapse. Aim: to dynamically evaluate WT1 pan-leukemic molecular marker of MRD in patients with AML. Matherial and methods: 107 newly diagnosed AML patients consecutively treated between 2010 and 2013 were monitored with quantitative WT-1 from bone marrow (BM) and peripheral blood (PB) at baseline, after induction, after the first consolidation course, before allogeneic stem cell transplantation (allo-SCT), at the 3rd and the 6th month after transplantation Results: At diagnosis, 104/107 (97%) had increased PB and BM WT1 levels assessed according to the ELN assay. Eighty-eight out of 107 patients (82%) achieved a complete remission (CR) after induction, 30/88 (34%) relapsed during follow up and 24/107 (22%) were addressed to allogeneic stem cell transplantation (allo-SCT). By univariate analysis, PB-WT > 50x10^4/ABL and BM-WT1 > 250x10^4/ABL after induction (PB: p=0.02; BM: p=0.04), after consolidation (PB: p=0.003), at the end of treatment (PB and BM: p=0.001), at 3rd month of follow up (PB and BM: p=0.005) and at 6th month of follow up (PB: p=0.005) were associated with a reduced overall survival (OS). By multivariate analysis, a BM-WT1 > 250 x 10^4/ABL at the end of treatment was significantly associated with a reduced OS. In order to adapt the cut-off of WT1 in our series of patients, we considered WT1 levels as continuous variables and categorized them at approximately the 25th, 50th, and 75th percentile. A cut-off of PB-WT1 > 25x10^4/ABL and BM-WT1 > 125x10^4/ABL at the end of the treatment program was identified as correlated with reduced leukemia-free survival (LFS) and OS (p=0.001). Similarly, and restricting the analysis on the 24 patients allo-transplanted in CR, 8/11 (73%) with pre-transplant PB-WT1 ≥ 5 and 4/13 (31%) with PB-WT1 < 5 relapsed, respectively (p=0.04). The incidence of relapse was higher in AML patients with PB-WT1 ≥ 5 measured at 3rd (56% vs 38%; p=0.43) and 6th month (71% vs 20%; p=0.03) after allo-SCT. Interestingly, 5/5 (100%) patients with pre-transplant PB-WT1 ≥ 5 who never reduced this level at 3rd or 6th month after allo-SCT experienced a disease recurrence. Conclusions: our data, although retrospectively collected, show that WT1 monitoring may be useful to predict the relapse in AML patients. Acknowledgments: This work was supported in part by Banca di Credito Cooperativo di Pompiano e Franciacorta and Lions Club Bassa Bresciana Association. Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy.

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Outcome of Newly Diagnosed Acute Myeloid Leukemia with Hyperleukocytosis: Retrospective Study of JALSG AML201

Blood ◽

10.1182/blood.v128.22.1616.1616 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1616-1616

Author(s):

Kenji Matsumoto ◽

Shin Fujisawa ◽

Maki Hagihara ◽

Sumihisa Honda ◽

Shigeki Ohtake ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Leukocyte Count ◽

Early Death ◽

Brain Hemorrhage ◽

Newly Diagnosed ◽

Chugai Pharmaceutical ◽

Pre Treatment ◽

Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) with hyperleukocytosis is considered to have a poor prognosis due to a high early death rate secondary to complications such as disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. The usefulness of pre-treatment reduction of leukemic cells is controversial. We reviewed the clinical characteristics and outcome of adult patients with newly diagnosed AML with or without hyperleukocytosis registered to the Japan Adult Leukemia Study Group (JALSG) AML201study and examined whether early death in induction therapy for this AML subtype influenced the outcome. Methods: We retrospectively reviewed the records of 1,022 patients enrolled in the JALSG AML201 study, which was a phase 3 clinical trial for AML newly diagnosed from December 2001 to December 2005. The JALSG AML201 study administered cytarabine from day 1 to 7 as the induction therapy combined with idarubicin or daunorubicin (Ohtake S, et al. Blood. 2011, 24;117:2358-65.). None of the patients received pre-treatment with oral hydroxyurea or leukapheresis. Patients with performance status (PS) of 4 or severe comorbidities such as septic shock were excluded. Patients' characteristics and outcomes such as rate of early death (defined as death occurring within the first thirty days of treatment), achievement of complete remission (CR), overall survival (OS) rate and cumulative incidence of recurrence (CIR) were compared between patients with hyperleukocytosis and those without hyperleukocytosis. Result: We analyzed retrospectively the records of 1,057 patients with AML registered with the JALSG AML201 study and excluded 35 patients whose leukocyte count or outcome was not recorded. We found 113 AML patients with an initial leukocyte count greater than 100 × 109L−1 (HiLC group). There were 66 males and 47 females, and the median age was 45 years (range: 16-64). Median of leukocyte count before treatment was 160 × 109L−1 (range: 102-382 × 109L−1). According to the French-American-British (FAB) classification, there were four as M0, thirty-four as M1, fifty-six as M2, thirty as M4, and nineteen as M5. Cytogenetic analysis was performed in 107 patients. Eight patients had favorable karyotype, 90 had intermediate karyotype, and nine had unfavorable karyotype. Fifteen percent of patients with hyperleukocytosis had PS of two or greater. We compared the outcome of this AML subset with 909 patients with a leukocyte count lower than 100 × 109L−1 (median count: 10,900, range: 0.77-99.5× 109L−1) who received the same induction chemotherapy as the JALSG AML201 protocol (LoLC group). There was no significant difference between the two groups for age and sex; median age of the patients in LoLC group was 47 years (range: 15-64) with 542 males and 367 females. The frequency of the patients with a favorable karyotype or PS of 0 or 1 was lower in HiLC group than in LoLC group, whereas the rate of FAB M4 or M5 was higher in HiLC as compared to LoLC group. Eighty-two patients (72.5%) in HiLC group and 714 patients (78.5%) in LoLC group achieved CR. Sixty (53%) and twenty-two (19.5%) achieved CR after one and two cycles of treatment, respectively. In contrast, 577 (63%) and 137 (15%) in LoLC group achieved CR after one and two cycles of chemotherapy, respectively. The rate of CR was not significantly different between two groups (p=0.118). However, 5 year OS was significantly lower in HiLC as compared to LoLC group (26.9% vs. 49.4%, p < 0.001). Interestingly, the rate of early death was not different between the two groups (1.65% vs. 1.77%, p = 1.0), although the rate of severe complications, such as DIC, was higher in HiLC compared to LoLC group (32% vs. 10%, p < 0.001). The frequency of brain hemorrhage (1% vs. 1%, p = 1.0) and gastrointestinal hemorrhage (4% VS. 3%, p = 0.294) was not different between two groups. One patient died of brain hemorrhage and one of DIC in HiLC group, whereas five patients died of brain hemorrhage, four of sepsis, and three of pneumonia in LoLC within the first thirty days of treatment. CIR was higher in HiLC (64.7%) as compared to LoLC group (51.6%) (p = 0.0048). Conclusion: We conclude that hyperleukocytosis on presentation did not significantly affect the rate of early mortality during the induction phase of the treatment. It is considered that intensive chemotherapy without pre-treatment would be possible if appropriate supportive cares were given to manage fatal complications such as DIC. Disclosures Kiyoi: MSD K.K.: Research Funding; Alexion Pharmaceuticals: Research Funding; AlexionpharmaLLC.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Phizer Japan Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding. Naoe:Amgen Astellas BioPharma K.K.: Honoraria; CMIC Co., Ltd.: Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties.

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A Phase II of Combination Daunorubicin and Cytarabine (Ara-C) and Nilotinib (TASIGNA) (DATA) in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Expression: Final Results

Blood ◽

10.1182/blood-2018-99-118552 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1443-1443

Author(s):

Aref Al-Kali ◽

Raoul Tibes ◽

Jeanne Palmer ◽

Hassan B. Alkhateeb ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Liver Failure ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

White Blood Count ◽

Newly Diagnosed ◽

Relapse Rates ◽

Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with a wide range of response and relapse rates using standard chemotherapy combining anthracycline plus cytarabine (7+3). The stem cell receptor tyrosine kinase KIT is expressed on more than 10% of blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of ≥ 20% on myeloblasts by flow cytometry. KIT mutations were allowed. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction, while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts (Al-Kali, ASH 2015) recommended to continue study accrual. Results: i)- Demographics: Thirty four pts were enrolled from July 2013 to June 2017. Median age was 59 years (range 24-69) with 71% being male. Median laboratory findings include hemoglobin of 8.8 gm/dL, platelets of 56 x109/L, white blood count of 3.3 x109/L (0.4-125), and peripheral blood blasts 17 %(0-94%). Cytogenetics were normal in 43% of the pts and favorable cytogenetics were seen in 6%(inv 16). FLT3 gene testing was done on 26 pts and was positive in 13%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed pathogenic mutation in 1/28 cases (4%). ii)- Clinical outcome Out of all 34 pts enrolled on the study, 18 (53%) achieved CR (or CR with incomplete platelet recovery) with a median CR duration of 21.8 months. Of 26 evaluable pts, the overall CR rate was 69%. 4 of the 18 pts (22%) who achieved remission needed a second induction. One pt died due to liver failure (had only one dose of nilotinib and toxicity was attributed to daunorubicin). 13 (38%) pts proceeded to allogeneic stem cell transplant (HSCT), 12 of whom are alive and none were able to initiate nilotinib maintenance. Only 6 (1 had HSCT) out of 34 (18%) pts relapsed after achieving CR. Median DFS was 45.8 months, while median OS was 42.4 months. 2-year DFS and OS were 58% and 72%, respectively. iii)- Safety Thirty four pts were evaluated for adverse events (AE). Fourteen pts had G4 non-hematological AEs, including fourteen G4 AEs related to infection, 2 with electrolyte imbalances, 1 heart failure, 1 elevated bilirubin, 1 elevated lipase, and 1 jejunal hemorrhage. One patient had G5 liver failure. Most common (>20%) G3 non-hematological AEs were febrile neutropenia (56%), hypophosphatemia (21%), elevated ALT (21%) and hypertension (21%). Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Final results show an acceptable safety profile with most common AE being infection. Thirty day mortality was low (3%). DATA regimen has comparable CR rates of 53% (intent to treat) and 69% in evaluable pts. Relapse rates were very low at 18% with durable responses and encouraging survival rates. Figure. Figure. Disclosures Al-Kali: Novartis: Research Funding. Tibes:Novartis: Research Funding. Palmer:Novartis: Research Funding.

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Updated Results of a Randomized Phase II Trial of Idarubicin and Cytarabine with Clofarabine or Fludarabine in Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.1067.1067 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1067-1067

Author(s):

Nicholas J. Short ◽

Farhad Ravandi ◽

Xuelin Huang ◽

Jorge E. Cortes ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Cell Transplant ◽

Newly Diagnosed ◽

Historical Cohort ◽

To Receive ◽

Acute Myeloid

Abstract Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in acute myeloid leukemia (AML). We sought to evaluate the relative safety and efficacy of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FAI) in adult patients (pts) with newly diagnosed AML. Methods: Adult pts ≤60 years of age with newly diagnosed non-APL AML were randomized using a Bayesian adaptive design to receive either CIA or FAI. All pts received induction with idarubicin 10 mg/m2 IV daily on days 1-3 and cytarabine 1000 mg/m2 IV daily for on days 1-5. Pts in the CIA arm also received clofarabine 15 mg/m2 IV daily on days 1-5; pts in the FAI arm received fludarabine 30 mg/m2 IV daily on days 1-5. Responding pts could receive up to 6 cycles of consolidation with attenuated doses of the same drug combination. The primary endpoint was to compare the event-free survival (EFS) of CIA and FAI. Secondary endpoints included the CR/CRp rates, overall survival (OS) and the safety of the regimens. Results: Between 8/2011 and 6/2016, 182 pts have been randomized to receive either CIA (n=106) or FAI (n=76). Baseline characteristics of the 2 arms were well-balanced and are summarized in Table 1. Response rates are summarized in Table 2. Of the 180 pts evaluable for response, the CR/CRp rate was similar in the CIA and FAI arms (80% and 81%, respectively). However, the rate of MRD negativity by multiparameter flow cytometry at the time of CR/CRp was significantly higher in pts who received CIA than in those who received FAI (80% vs. 64%, respectively, P<0.05). Rates of stem cell transplant (SCT) in first remission were similar in the two arms (35% vs. 38%, respectively). The median duration of follow-up was 27 months. The median EFS and OS for the entire cohort were 12 months and 39 months, respectively. The median EFS was similar in the CIA and FAI arms (13 months and 12 months, respectively, P=0.91). The imbalance in sample size between these two arms was caused by better performance of the CIA arm during the initial period of the trial, although the difference largely disappeared after further follow-up. There was also no difference in OS between the two regimens; the 2-year OS rates were 51% and 57%, respectively (P=0.24). No difference in survival was observed if pts were censored at the time of SCT. Overall, treatment was safe with 8-week mortality rates of 4% in the CIA arm and 1% in the FAI arm. When compared to a historical cohort of pts treated with idarubicin and cytarabine (IA) alone, the triplet regimen (pooled population of CIA + FAI) resulted in improved EFS and OS among a subgroup of patients <40 years of age. In this group of younger patients, the median EFS for CIA/FAI (n=38) and IA (n=16) were 25 months and 9 months, with a 2-year EFS rate of 52% and 33% respectively (P=0.27). There was also a strong trend towards superior OS in the CIA/FAI compared to the IA groups (median OS: not reached vs. 20 months; 2-year OS rate 68% vs. 47%; P=0.08). Conclusions: In adult pts with newly diagnosed AML, CIA and FAI resulted in similar rates of CR/CRp and had similar EFS and OS. Compared to a historical cohort of pts treated with IA alone, the addition of a nucleoside analogue appears to result in superior EFS and OS in younger pts. Disclosures Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Daver:Ariad: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Jain:Novimmune: Consultancy, Honoraria; Infinity: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding. DiNardo:Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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Prognostic Index for Older Adult Patients with Newly Diagnosed Acute Myeloid Leukemia: The Edouard Herriot Hospital Experience.

Blood ◽

10.1182/blood.v110.11.4352.4352 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4352-4352

Author(s):

Claudiu Plesa ◽

Quoc-Hung Le ◽

Youcef Chelghoum ◽

Mohamed Elhamri ◽

Isabelle Tigaud ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Risk Group ◽

Prognostic Score ◽

Prognostic Index ◽

Disease Free Survival ◽

Newly Diagnosed ◽

Co Morbidity ◽

Acute Myeloid

Abstract The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.

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Idarubicin and Cytarabine Combined with Clofarabine or Fludarabine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia: Interim Result of a Phase II Clinical Trial

Blood ◽

10.1182/blood.v126.23.2508.2508 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2508-2508

Author(s):

Paul B. Koller ◽

Koji Sasaki ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Susan O'Brien ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Patient Characteristics ◽

Interim Result ◽

Newly Diagnosed ◽

Younger Patients ◽

Award Recipient ◽

Acute Myeloid

Abstract Background: The combination of 7+3 with a purine nucleoside analogue improved overall survival (OS) in patients with acute myeloid leukemia (AML). We randomized patients to receive either clofarabine (CIA) or fludarabine (FIA) combined with idarubicin and cytarabine. Methods: Patients who were diagnosed with non-CBF AML or non-APL AML were eligible and were randomized using a Bayesian design to one of the following two induction chemotherapy regimens: CIA (clofarabine 15 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily for 5 days) or FIA (fludarabine 30 mg/m2 IV daily for 5 days, idarubicin 10 mg/m2 IV daily for 3 days, cytarabine 1,000 mg/m2 IV daily x 5 days). Patients could proceed to up to 6 cycles of consolidation with the same drugs according to an attenuated schedule. Results: One-hundred-fifty-eight patients (97 patients, CIA; 61 patients, FIA) were treated so far. Patient characteristics and outcome are summarized in Table 1. Median age is 53 years (range, 20-66) in CIA and 49 years (range, 18-66) in FIA. All patients were evaluable for response. Responses are summarized in Table 1. MRD negativity was observed in 43 (74%) patients treated with CIA and in 19 (35%) patients treated with FIA (p=0.049). Median follow up is 21 months and 16 months for patients treated with CIA and FIA, respectively. Treatment was well tolerated with 8-week mortality rates of 1% and 2%, for patients treated with CIA and FIA respectively. The overall median EFS and OS for the whole population were 12 months and 25 months, respectively. Median EFS for patients treated with CIA and FIA was 14 months and 11 months, respectively (p=0.81). No difference in OS between CIA and FIA was observed: the 2-year OS rates were 48% and 53% (p=0.45), respectively. Furthermore, there was no difference in survival whether patients were censored or not at the time of transplantation. Compared to IA regimen in similar patients population, the triplet (FIA and CIA) showed an improvement in 2-year EFS (60% vs 34%; p=0.05) and a trend for better survival (40% vs 32%; p=0.5) in younger patients (40 years and younger). Conclusions: The combination of clofarabine or fludarabine to idarubicin and cytarabine is safe and effective with high CR and negative MRD rates in patients with newly diagnosed AML. Particularly in younger patients, CIA or FIA can lead to a superior outcome compared to 3+7. Table 1. Patient characteristic and outcome CIA N= 97 (61%) FIA N= 61 (39%) P Median age, y 53 [20-66] 49 [18-66] NS PS ≥ 1 79 (81) 48 (79) NS Hemoglobin, g/dL 9.4 [7.3-13.1] 9.2 [7.8-11.4] NS Platelets x 109/L 37 [1-1069] 40 [5-399] NS WBC x 109/L 3.6 [0.6-103.0] 4.1 [0.5-59.4] NS blast (PB) 11 [0-92] 10 [0-94] NS blast (BM) 52 [1-96] 50 [11-96] NS Creatinine, mg/dL 0.79 [0.34-1.35] 0.79 [0.49-1.72] NS LDH, IU/L 819 [325-11952] 684 [231-12042] NS Bilirubin, mg/dL 0.6 [0.2-1.9] 0.5 [0.2-1.5] 0.03 Cytogenetic # evaluable 97 61 NS Diploid 46 (47) 26 (43) -5/-7 or complex 25 (26) 19 (31) Misc 26 (27) 16 (26) FLT3-ITD, # evaluable 94 61 NS Mutated 20 (21) 11 (18) NPM1, # evaluable 90 55 0.05 Mutated 28 (31) 9 (16) Response # evaluable 97 61 0.347 ORR 82 (85) 48 (79) CR 70 (72) 41 (67) CRp 9 (10) 6 (10) PR 1 (1) 1 (2) MRD Negativity 43/58 (74) 19/35 (54) 0.049 Overall MRD Negativity 54/64 (84) 24/37 (65) 0.024 CR/CRp > SCT 33/79 (42) 23/47 (49) 0.435 Death (on study) 2 (2) 1 (2) NS 4-week mortality 0 (0) 1 (2) NS 8-week mortality 1 (1) 1 (2) NS Median F/U (m) 21.3 [0.9-44.7] 16.3 [4.3-42.0] NS Events, # evaluable 97 61 NS Events 51 (53) 31 (51) Primary failure 15 (15) 13 (21) Relapse 26/82 (32) 13/48 (27) Death in CR 6 (9) 4 (7) Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:LFB: Consultancy, Honoraria; Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient.

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