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By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p &lt, 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p &lt, 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Introduction Patients with secondary acute myeloid leukemia (sAML) after myelodysplastic (MDS) or myeloproliferative neoplasms (MPN) treated with chemotherapy show poorer outcomes compared with de novo AML; consequently, these cases should be allocated to allogeneic stem cell transplant (alloSCT) whenever possible (Döhner H, Blood 2017). Some recent evidence suggested the potential of molecular characterization for implementing the current WHO definition (Arber DA, Blood 2016), since chromatin-splicing mutations have been reported to be highly specific for sAML (Lindsley RC, Blood 2015). However, this molecular signature has also been recognized in some clinically defined de novo AML cases (Papaemmanuil E, NEJM 2016). Based on this background, we assessed the clinical impact of chromatin-splicing mutational signature in clinically defined de novo AML patients enrolled into the prospective NILG 02/06 trial [ClinicalTrials.gov Identifier: NCT00495287]. Patients and Methods The trial (Bassan R, Blood Advances 2019) randomized 574 newly diagnosed AML patients to receive induction (standard vs high-dose) followed by consolidative chemotherapy and/or alloSCT. For the present analysis, only patients with de novo AML (n=313) and WHO-defined sAML after MDS or MPN (n=101) with a full genetic characterization have been considered. Studies performed at diagnosis included conventional karyotype (n=412) and molecular analysis (n=414) and/or targeted NGS (this latter performed on 197 patients with normal karyotype). Patients with WHO-sAML were defined by the presence of an antecedent history of MDS or MPN (n=21) and/or cytogenetic WHO criteria of AML with MDS-related changes (n=80). Chromatin-splicing mutational signature defined the molecular-sAML group and comprised ASXL1, STAG2, BCOR, KMT2A-PTD, EZH2, PHF6, SRSF2, SF3B1, U2AF1, ZRS2 and RUNX1, excluding patients with WHO recurrent abnormalities. Results Chromatin-splicing mutations were scored in 55/313 (17.6%) de novo AML patients (hereafter named molecular-sAML). The most frequently reported were KMT2A-PTD (45.5%), RUNX1 (44.4%) and ASXL1 (22.2%), while other mutations in the signature accounted for 5-17.5% of cases. Compared to de novo AML without chromatin-splicing mutations, patients with molecular-sAML and WHO-sAML were older (P Conclusions Chromatin-splicing mutational signature identifies a distinct high-risk group within de novo AML patients, which shows clinical characteristics and outcomes closer to sAML than to de novo AML patients. These data highlight the need to detect this molecular signature at diagnosis and support a molecular definition of sAML. Disclosures Ferrero: Novartis: Honoraria. Corradini:Celgene: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Bassan:Incyte: Honoraria; Amgen Inc.: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Rambaldi:Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support.

Introduction In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287). Patients and Methods Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation. Results The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P Conclusions Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

The prognosis of elderly patients with acute myelogenous leukemia (AML) is usually dismal, while the true survival of older patients not included in clinical trials is not known. We retrospectively evaluated the impact on survival of an aggressive versus a non-aggressive approach in 1005 patients aged60 years registered in the database of the GIMEMA cooperative group.Group A patients (n=621) received aggressive treatment, while group B patients (n=384) underwent non-aggressive therapy. The groups were different for risk factor distribution: the patients in group B had a higher median age, worse performance status (PS) and a higher proportion of previous myelodysplastic disease.The overall median survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At multivariate analysis the following factors were associated with a significantly shorter survival: age71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95% CI=1.24-1.68), white cell count10,000 mL (RR=1.37; 95% CI=1.06-1.75), and heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference in survival was associated with aggressive or non-aggressive treatment (RR=1.1; 95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a white cell count10,000/mL showed a significantly better survival when treated aggressively (median survival 7 vs 3 months, p = 0.011).Despite an obvious selection of patients with a worse prognosis in group B, the difference in survival between the two groups was marginal. Multivariate analysis failed to demonstrate a significant survival benefit in aggressively treated patients. All these considerations indicate that elderly patients with AML are overall unlikely to benefit from aggressive treatment, so that this should be offered only to selected patients.

Histone deacetilase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects. Valproic acid (VPA) has HDCAi activity and synergizes with Ara-C to differentiate AML blasts in vitro. VPA is orally applicable and has a low toxicity prophile. We tried to assess the therapeutic activity of VPA in combination with low-dose Ara-C in elderly/frail AML/RAEB patients. We enrolled in this study 31 patients with Myeloid Pathologies. Fifteen pts had diagnosis of oligoblastic AML (M0:2, M1: 7, M2: 1, M4:1, M5: 4); 13 patients had RAEB (RAEB 1: 2, RAEB 2: 11) with the following IPSS: int-1=2, int-2= 2, high= 6. Three other patients had progression from previous MPS (1 from ET, 2 from LMMC). Median age was 70 yrs (range: 53 to 84). Median time from Diagnosis to treatment was 15 months (range 1 to 79). Clinical status at start of protocol was: at Diagnosis = 13 pts, Resistant after induction =6 pts, Relapsed after CR =11 pts, Relapsed after allogeneic transplant =1 pt). All patients were excluded from conventional chemotherapy for age and multiple comorbidities. In 27 out of 31, these comorbidities required therapy or periodic controls (grade 3), other 2 pts had one of G4 grade (life-threatening). Thirteen patients were defined “frail” because they presented 3 of G3 comorbidities or at least a G4 one. Twenty-nine pts were evaluated for autosufficiency with ADL score, 5 of them didn’t reach the score of 6, showing impairment in their autosufficiency. Assessing functional autonomy, IADL score showed deficiency in 17 of 29 patients. In our protocol, VPA was administered in continuum to reach serum concentration of 50–100μg/ml. Ara-C was given in cycles of 8 days, 40 mg/day. Ammonium and valproic acid serum level was routinely checked. Bone marrow examination was done at the enrollement in the study, after sixth cycle of Ara-C and/or if improvement of blood counts were observed. In two patients that were in CR at the end of sixth cycle, VPA was maintained; other six cycles of Ara-C were given monthly and thereafter every third month until relapse. Six patients received the treatment for at least 6 cycles, the other patients had a median of 2 cycles, (range 1 to 4). Ten patients are still in treatment, 17 dropped out for progression/death, one patient underwent reduced intensity allotransplant while in remission. From the start of protocol, median overall survival was 4 mths, range 1 to 33 mths. Fifteen pts are alive now. Overall, 11 of 31 patients (35%) had hematological improvement (according to IWG, 2008), including 7 CR (22%) with clearing of blasts in the marrow and normalization of blood counts. The median cycle of improvement was 2 (range 1 to 4) and the median duration of improvement was 2 months (range 1 to 23 months), including two pts that lasted in CR for 10 and 23 months; 3 pts are still in CR at 5,8 and 10 mths from the starting of response, one patient is in Hematological Improvenment at 2 mths. Hematological toxicity requiring platelet transfusion was seen in 17 patients, while 10 pts required red cell transfusion. Transient hyperammoniemia was seen in one patient; liver toxicity in another patient. Neutropenia-related infections were seen in 3 pts. Adding VPA to low-dose Ara-C, some complete responses and some improvements in peripheral cytopenias can be achieved without a significant increase in toxicity. Therefore this therapeutic protocol is feasible for elderly/frail oligoblastic AML/RAEB patients who cannot have aggressive therapy.