ALBERT

Description: Introduction Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is the best curative option for many patients with Acute Myeloid Leukemia and related malignancies, mostly due to the antileukemic activity of immune cells contained in the graft. Although in most of the cases HSCT can accomplish apparent disease eradication, frequently residual leukemic cells are able to evade elimination, eventually outgrowing and resulting in clinical relapse. Apparently indistinguishable from disease at diagnosis, relapses commonly display a more aggressive behavior, and most of the available therapeutic options are ineffective. Next-generation sequencing provides the opportunity to track specific alterations and disease subclones during the clinical history of patients, and from this information to identify mechanisms by which leukemic cells evade elimination. Methods Serial disease samples collected longitudinally during the complex clinical history of a patient with high-risk myelodysplastic syndrome were analyzed by genomic HLA typing and by high-depth exome sequencing (minimum depth of coverage 70x). Patient fibroblasts and mononucleated peripheral blood cells harvested at remission served as reference for germline HLA typing and exome sequence. Whenever possible, leukemic blast were FACS-purified. Sequencing data were aligned to the reference genome using the BWA aligner and analyzed using the tools developed from the Cancer Genome Analysis group at the Broad institute to identify newly acquired mutations, clonal segregation of novel and pre-existing mutations and quantitative clonal dynamics. Results A 54 year old patient with high-risk refractory anemia with excess blasts (pancytopenia, blasts 19%, adverse cytogenetics) underwent unmanipulated T cell-repleted HLA-haploidentical HSCT in the presence of active disease. After one year of remission a first relapse occurred. HLA typing of the leukemic blasts harvested at relapse demonstrated the selective genomic loss of the mismatched HLA haplotype targeted by donor T cells, a frequent mechanism of leukemia immune evasion after haploidentical HSCT, first described by our group (Vago et al, N Engl J Med, 2009). The patient was re-transplanted from a different haploidentical donor mismatched for the HLA alleles retained by the mutated variants; accordingly, T cells from this donor were expectedly alloreactive against the relapsed leukemia. The patient re-obtained complete remission, which was maintained for five years, before the occurrence of a second relapse. Unexpectedly, at this relapse leukemic cells had lost the HLA molecules mismatched with the second donor, and expressed those that had gone amiss at first relapse. Since at both relapses HLA haplotype loss was due to a stable genomic alteration, chromosome 6p acquired uniparental disomy (aUPD), any linear relation between the first and second relapse could be ruled out (Figure 1). Leukemic samples at diagnosis, first relapse and second relapse were further characterized by high-depth exome sequencing, revealing that most of the mutations present in each of the three samples were not found in the other two: only a minute fraction of the mutations could be identified in all three disease presentations, possibly comprising the “driver mutations” harbored by the original leukemic stem cell clone. Amongst these shared mutations we are currently validating the functional and epidemiological relevance of missense alterations in the TP53 tumor suppressor gene, in the NHEJ1 gene (related to chromosomal instability), and in the BTNL8 gene, encoding the costimulatory receptor B7-H5, which may putatively play a role in leukemia recognition by T cells. Conclusions Our results demonstrate that antileukemic immunity has a profound impact on leukemia clonal evolution, driving the selection of immuno-privileged subclones. Importantly, the genetic alterations shared between the leukemic variants that emerged at years of distance during the clinical history of our patient suggest the long-term persistence of a reservoir of leukemic stem cells which are resistant to, or in stable equilibrium with, the immune pressure that sculpted their progeny. Finally, the longitudinal approach adopted in this study holds promise for the identification of leukemia “driver” mutations, to provide new insights into leukemogenesis and new rationales for targeted eradicating therapies. Disclosures: Bordignon: MolMed SpA: Employment. Bonini:MolMed SpA: Consultancy.

Description: Background: According to the WHO classification, secondary acute myeloid leukemia (s-AML) includes cases occurring in patients (pts) receiving prior antineoplastic treatments as well as cases developing in pts with a history of previous hematology disorders, such as a myelodysplastic syndrome (MDS) or a chronic myeloproliferative disease (MPD). Outcomes for this large group of pts, which has a high median age and a high frequency of unfavourable cytogenetics, has been traditionally considered very poor, compared to AML developing “de novo”, and treatment with intensive chemotherapy (iCT) is not standardized in elderly pts. Indeed pts with s-AML have been excluded from molecular and cytogenetic prognostic stratification defined by the ELN criteria. Aim: Since patients with s-AML actually represent an heterogeneous subgroup of pts a multicenter retrospective study was performed to analyse their outcome in relationship to age, fitness and ELN risk stratification, in order to potentially identify subgroups at different prognosis. Patients and Methods: We evaluated 127 pts, representing 35% of a population-based series of elderly AML, aged 〉 65 years (y), diagnosed at five Hematology Centers of the Hematological Network of Lombardy in Northern Italy from January 2008 to May 2014. Thirteen pts (10%) had t-AML and 114 (90%) had AML secondary to previous hematological disorders (89 MDS and 25 MPD). Median age was 74 y (range 65-94 y). Performance status (PS) was evaluable in 122 pts (96%) and PS ECOG was 〉3 in 32 pts (26%). According to “fitness criteria”, (Ferrara et al, Leukemia, 2013), 126 pts (99%) were evaluable: 54 pts (42.5%) were fit to i-CT (FIT), 55 (43.3%) unfit to i-CT (UNFIT), 17 (13.4%) unfit to ni-CT (FRAIL). Intensive CT was given to 34 (27%), ni-CT (low-dose arac, azacytidine or experimental non-myelotoxic drugs) to 26 (20%) and best supportive care (BSC) to 67 pts (53%). Overall concordance between the fitness and the treatment actually received was 78%.The ELN prognostic criteria were applicable in 69 pts (54%), because of lack of complete molecular and cytogenetic data in the others. Six pts (8.5%, all NPM1+) were at low, 14 (20%) at intermediate-1, 11 (16%) at intermediate-2 and 38 (55%) at high risk. Results: The median OS according to fitness was 9,6, 4 and 3 months (ms), in FIT, UNFIT and FRAIL pts, respectively (p=0.0021) (Figure 1). Both the treatment received (i-CT or ni-CT vs BSC) and the risk ELN classification were related to OS (p〈 0.0001 and p=0.0089, respectively). In FIT pts the median OS was 8 ms in pts treated with i-CT, 11 ms with ni-CT, and 3 ms with BSC (p

Description: Atypical Chronic Myeloid Leukemia (aCML) is a clonal disorder belonging to the Myeloproliferative/Myelodysplastic (MPN/MDS) group. The molecular lesions responsible for the onset of aCML remained unknown until 2013 when recurrent somatic mutations of SETBP1 were identified. However, the frequency of SETBP1 mutations in aCML does not exceed 25-30%, which suggests that other lesions may play a role in the remaining cases. To gain further insight into the somatic variants responsible for the onset of aCML, we generated whole-exome and transcriptome sequencing data on 15 matched case/control aCML samples. A total of 151 non-synonymous and 42 synonymous single-nucleotide somatic variants were identified. Of these, 140 were transitions and 53 transversions. Of the non-synonymous mutations, 141 were missense and 10 nonsense mutations. In 2/15 (13.3%) samples we identified the presence of missense, single-nucleotide somatic variants occurring in the ETNK1 gene affecting two contiguous residues: H243Y and N244S. Sanger sequencing confirmed the presence and the somatic nature of the variants. Targeted resequencing of 383 clonal hematological disorders showed evidence of mutated ETNK1 in 7/70 aCML (10.0%, 95% C.I. 4.6-19.5%) and in 2/77 chronic myelomonocytic leukemia samples (CMML; 2.6%, 95% C.I. 0.2-9.5%) %), while no ETNK1 mutations were identified in the remaining hematological disorders. All the variants were heterozygous and clustered in the same, highly conserved region within the kinase domain (1/9 H243Y and 8/9 N244S). Somatic, heterozygous ETNK1 variants have been also recently reported in 10% of Systemic Mastocytosis (SM) cases and in 22% of SM with associated hypereosinophilia (Lasho T et al., Abstract 4062, EHA2014); strikingly, there is a large overlap between the variants that we identified in aCML and CMML and those described for SM (3 N244S and 2 G245A), which suggests that the common hotspot region may play a critical and yet unknown functional role. The hitherto described data suggest that ETNK1 variants are restricted to a limited subset of hematological disorders. This is further supported by the lack of somatic ETNK1 mutations in 60 paired whole-genome and over 600 exomes, comprising 276 paired tumor/germline primary samples and 344 cancer cell lines (http://cancer.sanger.ac.uk/cancergenome/projects/cell_lines/). In 2/6 ETNK1 mutated aCML cases (33%, 95% C.I. 9%-70%), we detected the presence of a coexisting somatic SETBP1 variant. The fraction of SETBP1 mutations identified in this group is perfectly in line with the overall frequency of SETBP1 mutations in aCML, suggesting that mutations occurring in ETNK1 and SETBP1 are not mutually exclusive. To discriminate if ETNK1 and SETBP1 mutations occur in different or in the same clone, we performed colony assay experiments, revealing the coexistence of the two somatic mutations within the same clone. Liquid Chromatography – Mass Spectrometry experiments revealed that in ETNK1 mutated cells the intracellular levels of phosphoethanolamine are over 5-fold lower than in the wild-type counterpart (p 〈 0.05), suggesting that ETNK1 mutations may impair the physiological catalytic activity of the kinase. Taken globally these data identify ETNK1 somatic mutations as a new oncogenic lesion in aCML and CMML, two overlapping MDS/MPN neoplasms. They also show that ETNK1 variants apparently cause a loss-of-function effect, leading to a decrease in the intracellular levels of phosphoethanolamine. Disclosures Campbell: 14M Genomics Limited: Consultancy, Equity Ownership.

Description: Introduction: in acute myeloid leukemia (AML) the response to treatment is evaluated upon full recovery of peripheral blood counts by bone marrow (BM) assessment using morphology and cytogenetics, if appropriate number of metaphases is obtained. Real time quantitative PCR (RQ-PCR) and multiparametric flow citometry (MFC) are sensitive techniques to assess minimal residual disease (MRD) mostly used to refine risk stratification and to guide therapy. Evaluation of response to induction chemotherapy (CT) during aplasia (around day 14 from start of induction) has shown a significant prognostic impact, the presence of residual disease predicting a worse prognosis. All reported studies on early BM blast clearance evaluation rely on morphology as a single technique. Unfortunately, at day 14 BM is often not evaluable for cytology and morphologyc blast count. Unpredictability and intra-observer variability must also be considered when assessing blast count by morphology alone. No studies analysing early BM blast clearance by means of MFC and/or PCR have been published and the correlation between the two assays is unknown in this setting. Moreover, it is to be established if early intensification (around day 15 from start of induction) with a second cycle of CT could increase the CR rate in pts with disease persistence in the BM evaluated at day 14. Matherial and methods: we retrospectively evaluated data of 23 newly diagnosed AML pts who received induction CT at our center between 02/2009 and 05/2014, and for whom analysis of BM both at day 14 and after hematologic recovery (around day 28) was performed. The aim of our study was to define the prognostic value of early MRD quantification by MFC (d14-LAIP) and WT1 quantification by PCR (d14-WT1) in predicting the response to induction. Firstly we compared d14-LAIP and d14-WT1 to identify the more sensitive and specific assay in predicting the response to induction, in particular for cases not evaluable for morphologic blast count. Then we compared the outcome of pts who received or did not receive an early intensification for persistence of disease at d14 BM evaluation. Results: 20 pts received the 3+7 induction regimen, 3 pts the ICE induction regimen. After BM evaluation at day 14, 7 pts received early reinduction CT (FLAG-IDA regimen) starting at day 16 (median), 16 pts did not receive further therapy before BM evaluation at day 28. Overall CR rate was 70% (16 pts), PR/NR 30% (7 pts), TRM 4% (1 pt). At day 14, leukemic blast percentage was not evaluable by morphology in 8 (35%) cases due to marrow aplasia, in 1 (4%) case blasts were 2%; by PCR (17 cases), in 4 (24%) cases WT1 was 90%. Our data confirm the prognostic value of day 14 BM evaluation and suggest that MRD detection, also in aplasia, could drive early reinduction CT which probably could increase the CR rate, without significantly clinical complications. Anyway, this last point must be confirmed with a larger study. Disclosures Bordignon: MolMed S.p.A: Chairman and CEO Other.

Description: Introduction Complex Karyotype (CK), monosomy of chromosome 7 or 5 and Monosomal Karyotype (MK) are associated with a dismal outcome in Acute Myeloid Leukemia (AML) patients (pts). Allogeneic stem cell transplantation (allo-SCT) can be considered the only potentially curative option for these pts. Conventional allo-SCT strategies confer long term Overall Survival (OS) of around 20%. No data are available on the role of haploidentical stem cell transplantation (haplo-SCT) in this high risk setting. We reviewed our experience to address this issue. Patients and methods This retrospective analysis included adult AML pts treated at San Raffaele Hospital. Between November 2001 and April 2014, 33 consecutive pts with poor cytogenetic risk AML with monosomy of chromosome 7 or 5 (12/33 pts), MK (3/33 pts) and CK (18/33 pts) received haplo-SCT. Karyotypes were obtained from diagnostic bone marrow samples with standard methods and in accordance with International System of Human Cytogenetic Nomenclature guidelines. OS and Disease Free Survival (DFS) were calculated using the Kaplan-Meier product-limit method. Results Median age of pts at transplant was 50 years (range, 22 to 65). At the time of haplo-SCT, 10 pts (30%) were in complete remission (8 were in first complete remission), while 23 (70%) had active disease. Patients received a myeloablative conditioning regimen, Treosulfan-based. Twenty seven out of 33 pts received a T-cell repleted haplo-SCT, 6 pts a T-cell depleted haplo-SCT. In those pts who received a T-cell repleted transplant, GvHD prophylaxis was based on Cyclosporin and Methotrexate (7/27 cases) or Rapamycine and Mycophenolate Mofetil (20/27 cases). All 27 pts received Antithymocyte Globulin. Median follow-up after haplo-SCT was 304 days (range, 5 to 2897 days). Of 33 pts, 30 (91%) were in CR at day +30 after transplant, 1 died of sepsis before disease evaluation, 2 had disease persistence. At the last follow-up 11 out of 33 pts (34%) were alive, all of whom in CR, 22 pts (66%) died for the following causes: disease relapse/progression 10 (45%), Graft versus Host Disease 3 (14%), infection 9 (41%). Transplant related mortality (TRM) was 35.2% at 1 year and 35.2% at 3 years after transplant. Extimated DFS from day 30 after transplant was 34.5% at 1 year and 28% at 3 years. Extimated OS for all pts was 45% at 1 year and 22.6% at 3 years. Discussion Our data support haplo-SCT as a potentially curative option for AML pts with high risk cytogenetic abnormalities. Despite a TRM of 35% at 3 years, 1/3 of these pts achieved a long term disease free status. In the setting of a disease with extremely poor therapeutic options, haplo-SCT appears promising and not inferior to other sources of allogeneic stem cell transplantation. Transplantation strategies aimed at reducing transplant related mortality or disease relapse should be explored in order to improve these results and achieve a better outcome. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 2385 Background. Allogeneic haemopoietic stem cell transplantation (HSCT) is the best therapeutic option for high-risk hematological disease (HRHD), particularly acute myeloid and lymphoblastic leukemia (AML/ALL). A widely application of HSCT is limited by lack of availability of a suitable donor for every candidate patients (pts). In order to offer a donor to every candidate pts, several centers had developed in the last decade alternative strategy of HSCT, such as umbilical cord blood (UCB) or family haploidentical HSCT (haplo-HSCT). With the aim to treat high-risk leukemia in the ideal appropriate time by allogeneic HSCT, we adopted a policy relying upon HLA typing at entry of every pts diagnosed with HRHD, followed, in absence of a MRD, by the prompt activation of the MUD search. Patients lacking a MRD or a MUD at the appropriate timing are proposed for haplo-HSCT. Methods. Here we report an intention-to-treat analysis of alternative donor HSCT at our Institution for pts diagnosed with high risk AML or ALL. Data were obtained from local institutional database. Results. Between Jan-2004 and July-2010 241 pts (median age 48y, r 15–72) with diagnosis of ALL (60 pts; median age 33y, r 15–64; male 39) or AML (181 pts, median age 51y, r 19–72; male 83) were defined as “high risk status” and received an indication to HSCT according to EBMT (European Group for Blood and Marrow Transplantation) and Northern Italy Leukemia Group (NILG, www.nilg.it) recommendations. In the ALL group 3 pts died before proceed to HSCT, 5 pts are waiting for the identification of a donor. Overall, 52/60 (86%) pts underwent HSCT, the status of disease at transplant was of complete remission (CR) for 27 pts, persistence of disease (PD) for 25. In the AML group 6 pts died before proceed to HSCT, 15 pts are waiting for the identification of a donor. Overall, 160/181 (88%) pts underwent HSCT, the status of disease at transplant was of CR for 97 pts, PD 63. Overall 92 pts activated the research of a MUD, 42 proceed to transplant, 7 received a UCB, 26 received a haplo-HSCT due to absence of a suitable donor in the appropriate time frame or failure to met the criteria to engage a MUD donor. The median time from diagnosis to registry activation was 69 days (r 5–876), the median time from activation to transplant 84 days (r 28–348). In the group of pts in CR at transplant, 37 underwent HSCT from a MRD and 36 from a MUD, 4 pts received a UCB and 47 a haplo-HSCT. Seventy-two pts are alive and in CR at last follow-up, 3/72 after a second transplant from a different donor (haplo-HSCT) and 3/72 after chemotherapy and adoptive immunotherapy to treat hematological relapse. Fifty-two pts died and the causes of death were: relapse (27), infection-related (19), graft-versus-host-disease (GvHD; 5), acute myocardial infarction (1). In the group of pts in PD at transplant, 16 underwent HSCT from a MRD and 6 from a MUD, 3 pts received UCB and 63 a haplo-HSCT. Fifteen pts are alive, 14 in CR, 1 pts under adoptive immunotherapy; 1/14 pts received a second transplant from a different donor (haplo-HSCT) to treat hematological relapse. Seventy-three pts died and the causes of death were: relapse (43), infection (23), GvHD (7). Overall, the median survival is 382 days and the median follow-up for pts alive is 548 days. The 1-year overall survival (OS)/transplant related mortality (TRM)/relapse incidence (RI) are 50,76% 26,96% and 40% respectively. For pts transplanted in CR the 1y OS/TRM/RI are 77,2%, 20,01% and 25% respectively. The outcome analysis per donor source (MRD vs MUD vs haplo-HSCT) is comparable (p=ns). For pts transplanted in PD the 1y OS/TRM/RI are 19,7%, 41% and 67% respectively. The outcome analysis per donor source (MRD vs MUD vs haplo-HSCT) shows a trend of lower RI and TRM in the haplo-SCT vs MRD. Conclusion. The policy adopted provided an allogeneic HSCT in 〉 80% of candidate high-risk acute leukemia patients. No significant differences were registered in outcome for patients transplanted from matched-related, unrelated or family haploidentical donors. Further evaluation and a long-term follow-up will add important evaluation in term of long-term disease control and long-term toxicities. Disclosures: Bonini: MolMed: Consultancy. Bordignon: Molmed: Employment.

Description: Introduction Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) represents the best curative option for many patients with high-risk myeloid malignancies, mainly due to its potent immuno-mediated antileukemic effect. Still, post-transplantation relapse remains an unsolved issue. We and others described genomic loss of the mismatched HLA haplotype as a mechanism by which leukemic cells evade donor T cell-mediated immune pressure and cause clinical relapse after partially HLA-incompatible HSCT (Vago et al, N Engl JMed, 2009), but the actual incidence and risk factors of this phenomenon are to date largely unknown. Methods We analyzed retrospectively 224 consecutive partially HLA-mismatched HSCTs performed in our Institute in the last ten years (Unrelated Donor, UD: 60; Mismatched Related Donor, MMRD: 164) in patients affected by myeloid malignancies (Acute Myeloid Leukemia, AML: 173; Myelodisplastic Syndrome, MDS: 27, Myeloproliferative Neoplasms: 17; others: 7). All patients received myeloablative conditioning and infusion of donor T cells, either as part of the graft or as an add-back. Patients’ follow-up included bone marrow genomic HLA typing to identify HLA loss relapses. In selected cases of HLA loss relapse cryopreserved serial serum samples harvested after HSCT were analyzed for the eventual presence of anti HLA Class I or Class II antibodies. Results We documented 77 cases of relapse: 66 after MMRD and 11 after UD HSCT. Out of 77 relapses 21 (27%) were due to genomic loss of the mismatched HLA in leukemic cells. HLA loss occurred in 19 patients with AML, one with MDS and one with myelofibrosis. All the 21 cases of HLA loss occurred after MMRD HSCT (32%), so the analysis for putative risk factors were limited to this subgroup of transplants (n=164), comparing the frequencies of putative risk factors between patients with HLA loss and “classical” relapses (n=21 and 45, respectively). HLA loss relapses occurred significantly later than their classical counterparts (median time to relapse 307 vs 86 days, p

Description: Abstract 4191 Introduction: HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a readily available therapeutic option for patients suffering from high-risk hematological malignancies who lack an HLA-compatible donor or for whom there is no time to find one. To avoid GVHD, haplo-HSCT has been classically performed under conditions of strict T-cell depletion, in the form of CD34-selected (“naked”) grafts. Unfortunately, naked haplo-HSCT is followed by a profound state of immune incompetence, which associates with high non-relapse mortality (NRM) rates, mainly due to opportunistic infections. Over the last decade, different strategies have been developed in order to speed-up immune reconstitution after haplo-HSCT, including the delayed infusion of donor T cells (DLI), the selective depletion of T-cell subsets from the graft or the use of an unmanipulated graft followed by novel strategies of immune suppression. Aim: To analyze in depth the early phenomena of immune reconstitution following haplo-HSCT in order to find early surrogate biomarkers of NRM. Results: From 2004 to 2010, we prospectively studied multiple parameters of T-cell immune reconstitution in 89 pts treated at our Center with haplo-HSCT. Time-points of analysis were pre-transplant, at day 30, day 90 and day 180 post-transplant. Underlying diseases included: high-risk AML 53 pts (60%), ALL 11 pts (12%), CLL 2 pts (2%), tyrosine kinase inhibitors-resistant CML 4 pts (5%), Hodgkin lymphoma 6 pts (7%), NHL 2 pts (2%), MDS with high International Prognostic Scoring System 7 pts (7%), other 4 pts (4%). Eighteen patients (20%) were given prophylactic suicide gene-modified DLI starting at day 30 post-transplant, while 64 patients (80%) received an unmanipulated graft followed by rapamycin until day 100. Overall, the incidence of grade III-IV acute GvHD was as low as 12%. Chronic extensive GvHD developed in 28% of pts. Compared with historical naked haplo-HSCT, the recovery of T-cell counts was accelerated: at day 90, median CD3+ cells were 378 per μL (0–2817), CD4+ 127 (0–804), CD8+ 173 (0–1922). Higher T-cell counts, however, did not clearly associate with lower NRM rates. After the initial expansion of effector memory cells (CD45RA−/CD62L−) in patients given DLI (P

Description: Abstract 1920 Background. Understanding of leukemia biology and advances in the transplant field have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients (pts) affected by acute myeloid leukemia (AML). The trend of growth of HCTs in adult pts with AML can be expected to continue based on acceptance and availability of alternative donor. Few data are available for: i) the reliable estimates of the number of HCT for AML and the total number of AML pts for whom HCT is appropriate, ii) the choice of the different donor sources. A risk-adapted treatment strategy is crucial to improve the outcome of pts with AML. Our policy is to offer a haploidentical HCT to adult pts lacking a matched donor in the appropriate time according to clinical indications (www.leukemianet.org, www.ebmt.org). This policy is integrated in ongoing protocols for primary disease (www.nilg.it). Methods. Here we are reporting the intention-to-treat (ITT) analysis of HCT in all consecutive AML pts referred to our Institution between January 2004 and April 2012. Classification, prognostic evaluation, response criteria and survival outcomes for AML were defined according to the standard recommendation of the European LeukemiaNet (Dohner H et al, Blood. 2010: 115:453–474). Results. Indication to HCT was given to 241 pts (median age 52y, r17-72, 66 pts over-60y; male 138). HCT was performed in 201/241 pts (median time from diagnosis to HCT 222 days, median time from HCT-indication to HCT 80 days), 24/201 pts received a second HCT due to disease relapse. Pts distribution according to ITT algorithm is reported in figure 1. In ITT analysis, 83,4% of candidate pts received an HCT. Characteristic related to pts/disease/transplant are reported in table 1. Noteworthy, pts in 1st complete remission (CR1) are evenly distributed according to donor source (namely HLA-matched sibling donor – MSD, unrelated donor – URD, haploidentical related donor - haplo-HCT). The overall survival (OS) analysis for pts transplanted in CR is 71% at 1y and 56% at 3y, for pts in morphologic leukemia free state (MLFS) 32% and 21%, for pts in relapse 23% and 11% (p

Description: Abstract 4583 Background: the outcome of pts older than 65 with AML is dismal because of the unfavourable characteristics of the disease and the frequent co-morbidities. Intensive chemotherapeutic programs, with or without haematopoietic stem cells transplantation (HSCT), are not usually offered to these pts since they are considered too toxic. If treated with intensive therapeutic programs these pts show initial complete remission (CR) rates around 45% to 55% and 2 years survival of 10–20%. Since 2001 in our institution we have systematically screened AML elderly patients older than 65 yrs for comorbidites and offered to “fit” AML elderly pts an intensive approach aimed at curing the disease. In this single-center retrospective study we describe the outcome of this court of pts. Aim: to evaluate toxicity and survival after intensive treatments in an homogeneous court of AML pts older than 65. Methods: from 10/2001 to 3/2011 we treated 60 pts older than 65, median age 70 (66–77), 30 pts ≤70 yrs (median 68, 66–70), and 30 pts 〉70 (median 73, 71–77). Among AML pts older than 65 years old we considered eligible for intensive chemotherapy those with PS (ECOG) ≤ 2, renal, hepatic and cardiac function parameters within normal ranges. All pts signed informed consent for intensive chemotherapy. Diagnosis (WHO): 33 AML with MDS related changes, 4 AML with minimal differentiation, 6 AML w/o maturation, 8 AML with maturation, 5 AMML, 1 erythrolaeukemia, 1 AML with mutated NPM1, 2 t-AML. Cytogenetics: 43 intermediate risk (33 with normal karytotype), 10 high risk (7 complex, 3 with Monosomal Karyotype), 2 good risk, 5 not evaluable. Induction with one or two of the following chemo cycles was administered to each patient: FLAG-IDA (fludarabine + cytarabine + idarubicin) or 3–7 (cytarabine + daunorubicin, idarubicin or mitoxantrone), high-dose cytarabine (HiDAC). Post-remission treatment: chemotherapy (CHT) 1 patient, HiDAC 12 pts, autologous transplantation (AUTO) 14 pts, allogeneic transplantation (ALLO) 2 pts. Results: overall induction related mortality was 18.3%, 7% in pts ≤70 yrs, 30% in 30 pts 〉70 p=0.041, CR rate was 57% (34 pts), 73% in pts ≤70 yrs, 40% in pts 〉70 p=0.018. Relapse rate was 73.5% (25 pts), 68% pts ≤70 yrs, 83% in pts 〉70. Median OS was 386 days, 2 and 5 yrs OS was 38 and 19%, respectively, median DFS was 397 days and 2 yrs DFS was 22%. In pts ≤70 and 〉70 yrs, median OS and DFS were 574 and 313, 397 and 425 days, respectively, p=ns, 2 and 5 yrs OS was 41% and 27%, 30% and 8%, 2 yrs DFS 27% and 17%, respectively, p=ns. OS of pts who obtained the CR after induction: median 1155 and 790 days for pts ≤70 and 〉70 yrs, respectively, p=ns, 2 yrs OS 51% and 58%, respectively, p=ns. Conclusions: our data suggest that prolonged survival can be achieved in elderly AML who are fit to receive intensive chemotherapy. Data on mortality and remission induction are very promising in pts 66–70 yrs old, whereas early death is an important cause of treatment failure in older pts (〉70), together with disease relapse. However, also older pts, with a median age of 73, who obtain the CR can reach a survival plateau at 2 yrs. Overall, these results i) indicate that selection of elderly AML pts for treatment assignment should be refined by the development of new tools for oncologic-geriatric assessment rather than by PS and vital organ function evaluation ii) prompt to design of prospective trials addressing the role of intensive regimens and transplantation programs in “fit” elderly AML pts. Disclosures: No relevant conflicts of interest to declare.