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Risk stratification; Acute myeloid leukemia Estratificació del risc; Leucèmia mieloide aguda Estratificación de riesgo; Leucemia mieloide aguda The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and postremission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, whereas it recommends allogeneic stem cell transplantation (alloSCT) as a postremission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%), and 245 (36%) patients allocated to the favorable-, intermediate-, and adverse-risk group, respectively. The 2- and 5-year overall survival (OS) rates were 77% and 70% for favorable-risk patients, 52% and 46% for intermediate-risk patients, and 33% and 23% for adverse-risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype, and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol based on alloSCT after remission for nonfavorable ELN subgroups and identifies a genetic subset with a very poor outcome that warrants investigation of novel strategies. This study was supported (in part) by Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III (ISCIII) grants PI16/01027, PI19/1476, and PI20/01621; Health Research and Innovation Strategic Plan (PERIS) grant SLT002/16/00433 and research group support SGR 1395 and SGR 1655 from Generalitat de Catalunya; resident award “Emili Letang” 2019 (Hospital Clínic de Barcelona); and “Beca de Investigación FEHH 2019” (Fundación Española de Hematologia y Hemoterapia).

// Marta Cabezon 1, 2 , Joan Bargay 3 , Blanca Xicoy 1 , Olga Garcia 4 , Josep Borras 3 , Mar Tormo 5 , Silvia Marce 1 , Carme Pedro 6 , David Valcarcel 7 , Maria-Jose Jimenez 1 , Ramon Guardia 8 , Laura Palomo 4 , Salut Brunet 9 , Ferran Vall-Llovera 10 , Antoni Garcia 11 , Evarist Feliu 1 and Lurdes Zamora 1 ; On Behalf of the CETLAM Group 1 Hematology Service, ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autonoma de Barcelona, Badalona, Spain 2 Departament de Medicina, Universitat Autonoma de Barcelona, Badalona, Spain 3 Hematology Service, Hospital Son Llatzer, Mallorca, Spain 4 Josep Carreras Leukemia Research Institute, Campus Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain 5 Hematology Service, Hospital Clinic de Valencia, Valencia, Spain 6 Hematology Service, Hospital del Mar, Barcelona, Spain 7 Hematology Service, Hospital Vall d’Hebron, Barcelona, Spain 8 Hematology Service, ICO Girona-Hospital Josep Trueta, Girona, Spain 9 Hematology Service, Hospital de Sant Pau, Barcelona, Spain 10 Hematology Service, Hospital Mutua de Terrassa, Terrassa, Spain 11 Hematology Service, Hospital Arnau de Vilanova, Lleida, Spain Correspondence to: Lurdes Zamora, email: lzamora@iconcologia.net Keywords: myelodysplastic syndromes; secondary acute myeloid leukemia; targeted deep sequencing; prognostic factors; 5-azacytidine Received: December 06, 2017 Accepted: March 05, 2018 Published: April 10, 2018 ABSTRACT Myelodysplastic syndromes (MDS) are stem cell disorders caused by various gene abnormalities. We performed targeted deep sequencing in 39 patients with high-risk MDS and secondary acute myeloid leukemia (sAML) at diagnosis and follow-up (response and/or relapse), with the aim to define their mutational status, to establish if specific mutations are biomarkers of response to 5-azacytidine (AZA) and/or may have impact on survival. Overall, 95% of patients harbored at least one mutation. TP53, DNMT3A and SRSF2 were the most frequently altered genes. Mutations in TP53 correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS) in univariate analysis. Patients with SRSF2 mutations were associated with better OS and PFS. Response rate was 55%; but we could not correlate the presence of TET2 and TP53 mutations with AZA response. Patients with sAML presented more variations than patients with high-risk MDS, and usually at relapse the number of mutations increased, supporting the idea that in advanced stages of the disease there is a greater genomic complexity. These results confirm that mutation analysis can add prognostic value to high-risk MDS and sAML patients, not only at diagnosis but also at follow-up.

Minor histocompatibility antigen (miHA) mismatches have been related to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but this association remains controversial due to the lack of consistency in the results obtained by different groups. The CTLA-4 genotype of the donor has been reported to be relevant in the appearance of acute GVHD. We explored the effect of the donor's CTLA-4 genotype in the incidence of acute GVHD associated with HA-1, HA-8, or H-Y miHA mismatches in a large cohort of 1295 patients receiving an allogeneic transplant from an HLA-identical sibling donor. The incidence of acute GVHD was higher if the donor and recipient were mismatched for HA-1, HA-8, or H-Y, but only when the donor had the CTLA-4 rs231775 AA genotype (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.75; P=.005; HR, 2.11, 95% CI, 1.06 to 4.18; P=.033; and HR, 1.50; 95% CI, 1.05 to 2.15; P=.025, respectively). In contrast, this increased risk of developing acute GVHD was not found when the donor presented the CTLA-4 rs231775 AG or GG genotypes. We conclude that the immune response to specific miHA mismatches is modulated by the CTLA-4 genotype of the donor., Supported in part by grants PI11/01690 and PI14/01646 from the Fondo de investigaciones sanitarias, Institute de Salud Carlos III, FEDER (Fondo Europeo de desarrollo regional), and grant MTV3/120210 from the Fundacio la Marato de TV3.

Background Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph+ ALL. Design and Methods This was a phase II study of patients with newly diagnosed Ph+ ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease. Results Of the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by Sow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplant-related causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of disease-free and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively. Conclusions These results confirm that imatinib is an effective first-line treatment for adult Ph+ ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.

[Background]: The EVI1 gene (3q26) codes for a zinc finger transcription factor with important roles in both mammalian development and leukemogenesis. Over-expression of EVI1 through either 3q26 rearrangements, MLL fusions, or other unknown mechanisms confers a poor prognosis in acute myeloid leukemia. [Design and Methods]: We analyzed the prevalence and prognostic impact of EVI1 over-expression in a series of 476 patients with acute myeloid leukemia, and investigated the epigenetic modifications of the EVI1 locus which could be involved in the transcriptional regulation of this gene. [Results]: Our data provide further evidence that EVI1 over-expression is a poor prognostic marker in acute myeloid leukemia patients less than 65 years old. Moreover, we found that patients with no basal expression of EVI1 had a better prognosis than patients with expression/over-expression (P=0.036). We also showed that cell lines with over-expression of EVI1 had no DNA methylation in the promoter region of the EVI1 locus, and had marks of active histone modifications: H3 and H4 acetylation, and trimethylation of histone H3 lysine 4. Conversely, cell lines with no expression of EVI1 have DNA hypermethylation and are marked by repressive trimethylation of histone H3 lysine 27 at the EVI1 promoter. [Conclusions]: Our results identify EVI1 over-expression as a poor prognostic marker in a large, independent cohort of acute myeloid leukemia patients less than 65 years old, and show that the total absence of EVI1 expression has a prognostic impact on the outcome of such patients. Furthermore, we demonstrated for the first time that an aberrant epigenetic pattern involving DNA methylation, H3 and H4 acetylation, and trimethylation of histone H3 lysine 4 and histone H3 lysine 27 might play a role in the transcriptional regulation of EVI1 in acute myeloid leukemia. This study opens new avenues for a better understanding of the regulation of EVI1 expression at a transcriptional level., This work was supported by a grant of Ministerio Educación y Ciencia (SAF2005/06425), Ministerio Ciencia e Innovación (PI081687), AECC, Departamento Salud del Gobierno de Navarra (14/2008), Generalitat de Catalunya (2009-SGR-1246), Fundación Cellex, SACYL (355/4/09), ISCIII-RTICC (RD06/0020/0078, RD06/0020/0101, RD06/0020/0006, RD06/0020/0031), and Fundación para la Investigación Médica Aplicada y UTE (Spain).

Introduction Patients with intermediate-risk cytogenetic AML (IR-AML) have a heterogeneous prognosis, and are currently further stratified based on determined gene mutations. However, the optimal post-remission therapy, especially in younger patients, is unclear. Recently, miR-3151, a novel microRNA (miRNA) located in intron 1 of the BAALC gene, has been identified. High miR-3151 expression –either alone or in combination with high BAALClevels– independently correlates with poor prognosis in patients ≥ 60 years with normal cytogenetics AML (CN-AML) (Eisfeld AK, et al. Blood 2012). However, the prognostic value of miR-3151 in younger patients (≤60 years) with IR-AML has not been examined. We hypothesized that miR-3151 expression could also be a prognostic marker in younger patients. Aim To analyze whether miR-3151 expression – either alone or in combination with BAALC– improved prognostic assessment in younger patients (up to 60 years) with IR-AML and to characterize in this subset of patients the miRNA signature associated with high miR-3151 expression. Methods Samples were available from two separate cohorts of patients with IR-AML who had received intensive therapy: a training set of 76 patients from a single institution and a validation set of 108 patients from several centers who had been treated within the CETLAM AML-2003 protocol. Information on NPM1, FLT3-ITD and CEBPA was available for both patient cohorts. The expression levels of 670 miRNAs had previously been analyzed in the 76 patients in the training set. In the present study, the expression of miR-3151 and BAALC was analyzed using TaqMan® MicroRNA Assay and TaqMan® Gene Expression Assay (Applied Biosystems), respectively. Expression levels of miR-3151 and BAALC –both alone and in combination – were correlated with patient outcome. Statistical analyses were performed with SPSS v.15.0.1, R software v.2.9.0 and TIGR MultiExperiment Viewerv4.0. Results In the training set, higher expression of miR-3151(dichotomized by its median value of normalized expression) correlated with a shorter 5-year overall survival (OS) (32%±17% vs. 61±17%, p=0.029) and 5-year leukemia-free survival (LFS) (29%±17% vs. 58±17%, p=0.036) in patients ≤ 60 yrs. When the analysis was restricted to patients with CN-AML, miR-3151 expression retained its prognostic significance (p= 0.016). In addition, increased BAALCexpression was associated with shorter OS (28%±20% vs. 58±14%, p=0.054) and LFS (17%±18% vs. 55±14%, p=0.039). In the multivariate analysis for OS and LFS, including age, WBC, NPM1mut, FLT3-ITD, BAALC and miR-3151 expression levels as covariates, miR-3151 showed independent prognostic significance for OS (p=0.016; HR=2.52, 95% CI: 1.2-5.4),and a statistical trend for LFS (p=0.09). Patients with low expression of both miR-3151 and BAALC had better prognosis (OS: 66%±18% vs. 34±16%, p=0.027; LFS: 67%±20% vs. 27±16%, p=0.009).Interestingly, the combination of both miR-3151 and BAALC retained a significant prognostic value for LFS within the favorable molecular subgroup/ ELN favorable subgroup (patients harboring NPM1mut without FLT3-ITD or biallelic CEBPAmut; LFS: 44%±30% vs. 100%, p=0.017) and showed a trend in the unfavorable molecular subgroup/ELN Intermediate I&II subgroups (patients lacking both NPM1 and CEBPA mutations and/or harboring FLT3-ITD; OS: p=0.064 and LFS: p=0.072). In the validation set, miR-3151 overexpression confirmed its prognostic impact in patients in the univariate analysis for OS (45%±12% vs. 26±19%, p=0.039) and LFS (51%±14% vs. 30±24%, p=0.034) and in the multivariate analysis for OS (OS: p=0.038; HR 1.88, IC 95%: 1.06-3.34) and LFS (p= 0.014; HR 2.411 (1.198-4.855) Finally, a supervised analysis revealed that samples exhibiting high levels of miR-3151 expression had a distinctive miRNA signature including miR-509, miR-135a, miR-100*, miR-186*, let-7a* and miR-501. Conclusion miR-3151 is an independent prognostic marker in patients with IR-AML. The study of miR-3151 refines the molecular prognostic stratification of these patients and hence could be of help to guide therapy. Acknowledgments Marina Díaz-Beyá is supported by Fundación Española de Hematologia y Hemoterapia. This research is supported by Sociedad Española de Hematologia y Hemoterapia and by grants from Fondo de Investigaciones Sanitarias FIS-PI080158. Disclosures: No relevant conflicts of interest to declare.