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Figure S1. EPO and plasma chemokine expression following treatment with ARRY-614 at 1200 mg QD. Figure S2. Comparison of EPO in IWG2006 Responders and Non-Responders.

Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.

Supplemental Table 2. Dose escalation PK parameters for ARRY-614

Supplemental Table 1. Treatment-emergent AEs (safety population)

Background and objective SARS-CoV-2 infection has bimodal distribution in Europe with a first wave in March to June 2020 and a second in September 2020 to February 2021. We compared the frequency, clinical characteristics and outcomes of adults with acute lymphoblastic leukemia (ALL) and infection in the first vs. second pandemic waves in Spain. Patients and Methods In this prospective study the characteristics of ALL and COVID-19 infection, comorbidities, treatment and outcome in the two periods were compared. The study ended when vaccination against SARS-CoV-2 was implemented in Spain. Results Twenty eight patients were collected in the first wave and 24 in the second. The median age was 46.5 years (range 20–83). Patients from the first wave had a trend to more severe ALL (higher frequency of patients under induction or submitted to transplantation or under immunosuppressive therapy). No significant differences were observed in need for oxygen support, intensive care unit (ICU) requirement, days in ICU and time to COVID-19 infection recovery. Seventeen patients (33%) died, with death attributed to COVID infection in 15 (29%), without significant differences in the 100 day overall survival (OS) probabilities in the two waves (68% ± 17% vs. 56% ± 30%). The only prognostic factor for OS identified by was the presence of comorbidities at COVID-19 infection (HR: 5.358 [95% CI: 1.875- 15.313]). Conclusion The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time, providing evidence in favor of vaccination priority for these patients., Microabstract The characteristics and outcome of ALL in adults with COVID-19 infection in the first two waves of the pandemic in Spain were compared. The frequency and mortality of COVID-19 infection were high in adults with ALL, without changes over time. Comorbidities at COVID-19 infection was the only prognostic factor for survival.

Introduction and objective. SARS-CoV-2 pandemic has deeply impacted in Spain. In cancer patients (pts) the lethality has been higher than in normal population, but, little is known on the impact in adults with ALL. Our objective was to analyze the frequency, clinical characteristics and outcome of adult ALL patients infected by SARS-CoV-2. Methods. Between March 1, 2020 and May 31, 2020 (the period of the peak of COVID-19 infection in Spain) two registries from the PETHEMA (Programa Español de Tratamientos en Hematologia) and GETH (Grupo Español de Trasplante Hematopoyético y Terapia Celular) groups were activated to recruit adult patients with ALL and COVID-19 infection confirmed by PCR. The PETHEMA registry was based on ASH proposal (www.ashresearchcollaborative.org/covid-19-registry) and the GETH registry was specifically performed for hematological diseases and COVID-19 infection. Both registries were merged for this study. Eighty-four Spanish centers were contacted and weekly reminds were sent until May 19, 2020. The demographic and clinical characteristics of ALL and COVID-19 infection, the comorbidities, the treatment and outcome were collected. The study was closed for follow in July 10, 2020. Results. Fifty-six of 84 centers answered the survey and 28 patients with ALL and COVID-19 infection were identified in 17 of them, especially on March (n=11) and April (n=15). Median age was 46 (range 20-78) yrs. and 19 were aged over 40 yrs. Fifteen pts were male, 1 was active smoker and 9 showed one or more comorbidities (chronic liver disease [n=2] diabetes [n=1], hypertension [n=5], cardiopathy [n=2], prior malignancy [n=1] and hypogammaglobulinemia [n=1]). ALL was of B-cell precursors in 18 pts (Ph+ in 6) and T in 10. Twenty-six pts were on treatment of LAL (induction [n=10], consolidation [n=3], maintenance [n=1], HSCT [n=5], rescue [n=6], and palliative [n=1]). Eight patients were previously submitted to allogeneic HSCT, CAR T [n=1] or immunotherapy with monoclonal antibodies (inotuzumab, n=4) and 21 were receiving immunosuppressive drugs (corticosteroids in 11, fludarabine in 4, among others). Eleven pts showed neutropenia Conclusion. The frequency of adult patients with ALL and COVID-19 infection can be considered high, given the low incidence of adult ALL. COVID-19 infection was frequent in patients with advanced age and on ALL therapy. The frequency of severe COVID-19 infection and the mortality were high. Supported in part by 2017 SGR288 (GRC) Generalitat de Catalunya and "la Caixa" Foundation. Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau;Pfizer, Amgen:Research Funding.Barba:Amgen, Celgene, Novartis, Pfizer:Speakers Bureau;Amgen, Celgene, Gilead, Jazz Pharmaceuticals, Novartis, Pfizer, Shire:Consultancy.

Two hundred and sixteen consecutive patients with MDS and abnormal karyotype treated with hypomethylating agents between 4/04 and 10/12 were reviewed. Median follow-up was 17 months. Using IWG criteria, best responses were complete response (CR) in 79 patients (37%), partial response (PR) in 4 (2%), and hematologic improvement (HI) in 10 (5%). Cytogenetic response (CyR) was achieved in 78 patients (36%): complete (CCyR) in 62 (29%) and partial in 16 (7%). CyR was achieved in 48 of 79 patients (61%) with CR, 1 of 14 (7%) with PR/HI, and in 29 of the 123 (24%) with no morphologic response. Median overall survival (OS) and leukemia-free survival (LFS) for patients with and without CCyR were 21 and 13 months (P = .007), and 16 and 9 months (P = .001), respectively. By multivariate analysis, the achievement of CCyR was predictive for better OS (HR = 2.1; P < .001). In conclusion, CyR occurs at a rate of 36% (complete in 29%) in patients with MDS treated with HMA and is not always associated with morphological response. The achievement of CCyR is associated with survival improvement and constitutes a major predictive factor for outcome particularly in patients without morphologic response. Therefore, the achievement of CCyR should be considered a milestone in the management of patients with MDS.

Context Recent studies have described the importance of Suppressor of Tumorigenicity-2 (ST2) and Regenerating islet-derived 3a (REG3a) serum biomarkers in allogenic stem-cell-transplantation. Only two studies have focused on haploidentical stem-cell-transplantation with post-transplant-cyclophosphamide (haplo-SCT-PCy). Objective Perform an early weekly analysis of ST2 and REG3a biomarkers after haplo-STC-PTCy and study their association with transplant outcomes. Patients Prospective study of 101 consecutive patients who underwent Haplo-SCT-PTCy between 2012-2019 at University Hospital of Salamanca. Design Serial serum samples were collected on days 0, +3, +7, +14, and +21 in 81 patients. ST2 and REG3a serum concentration was stablished by Luminex XMap. The median luminescence levels between groups were compared using the Wilcoxon-Mann-Whitney test. Cut-off points for each cytokine were estimated using the Cutoff Finder application in R. Multivariate Cox proportional hazard models were performed including the most relevant clinical variables. Results Recipient median age 50 years. 70% were performed with reduced intensity conditioning. With a median follow up of 35 months, cumulative incidence of aGVHD III-IV at +180 was 11% and transplant-related mortality at 1-year (TRM-1y) 25%. Overall survival (OS) and progression-free survival (PFS) at 2 years was 64% and 62%. GVHD-free-relapse-free survival at 2 years (GRFS-2y) was 49%. ST2 levels were higher in patients with aGVHD III-IV (day +14), and were associated with higher TRM at 1 year (+7, + 14), lower PFS-2y (+7, +14, +21), lower GRFS-2y (+7, +14, +21), and lower OS-2y (0, +7, +14, +21). Higher levels of REG3a were associated with higher TRM-1y (+7, +14), aGVHD III-IV (+14), lower GRFS (+14), and lower OS-2y (+7). In multivariate analysis for TRM, higher levels of ST2 (+7, +21) and REG3a (+14, +21), prior auto-SCT, and HCT-CI ≥ 3 were statistically significant, while OS was independently related to ST2 (+7, +14) levels and HCT-CI ≥ 3. ST2 (+14) and REG3a (+14) levels were the only variables independently associated to aGVHD III-IV, PFS, and GRFS. Conclusions Our results confirm the significant role of ST2 and REG3a in haplo-SCT-PTCy outcome. We demonstrate, for the first time, its prognostic impact on days +7 and +14. Confirmation in prospective and larger series is required.

Grupo Español de Trasplante Hematopoyético (GETH) and Grupo Español de Linfoma y Trasplante Autólogo (GELTAMO)., We performed a retrospective multicenter study including 140 patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) from March 1995 to November 2018. Our objective was to analyze long term outcomes. Seventy-four percent had received a previous auto-SCT (ASCT) and the median number of lines pre-allo-SCT was 3 (range 1–9). Three year-event free survival (EFS) and overall survival (OS) were 38% and 44%, respectively. Non-relapse mortality (NRM) at day 100 was 19%. Cumulative incidence of grade III–IV acute graft versus host disease (GVHD) at day 100 was 16% and moderate/severe chronic GVHD at 3 years 34%. Active disease at allo-SCT (HR 1.95, p = 0.039) (HR 2.19, p = 0.019), HCT-CI ≥ 2 (2.45, p = 0.002) (HR 2.33, p = 0.006) and donor age >37 years (HR 2.75, p = 0.014) (HR 1.98, p = 0.043) were the only independent variables both for PFS and OS, respectively. NRM was significantly modified by HCT-CI ≥ 2 (HR 4.8, p = 0.008), previous ASCT (HR 4.4, p = 0.048) and grade III–IV acute GVHD on day 100 (HR 6.13, p = 0.016). Our data confirmed that allo-SCT is a curative option for patients with R/R DLBCL, displaying adequate results for fit patients with chemosensitive disease receiving an allo-SCT from a young donor.

Background (or Purpose) Inflammation has an essential role in the pathogenesis of myelodysplastic syndromes (MDS). Its expression is controlled by phosphodiesterase 4 (PDE4). Thus, PDE4 inhibitors might be useful therapeutic targets for MDS. Patients (or Materials) and Methods We evaluated the expression of each isoform of PDE4 (A, B, C, and D) using transcriptomic profiling and examined the potential impact on the outcome of patients with MDS in terms of survival and response to hypomethylating agents. Total RNA was extracted from CD34+ bone marrow hematopoietic cells from healthy individuals (n = 10) and patients with MDS (n = 24) or chronic myelomonocytic leukemia (n = 19). Results The study cohort had a median follow-up period of 21.2 months (range, 0.2-68 months) and a median overall survival of 17.6 months (95% confidence interval, 9.6-25.6). The main finding of the present study was that PDE4 mean expression was generally higher in patients with MDS than in healthy individuals. Also, upregulated PDE4 expression seemed to have a possible negative effect on survival (P > .05). Moreover, lower, compared with higher, mean PDE4A and PDE4C expression is indicative of a response to a hypomethylating agent (0.09 and 0.03 vs. 0.54 and 0.49, respectively; P > .05). Conclusion These results should be confirmed in a larger patient cohort. PDE4 expression could be an effective potential prognostic factor and therapeutic target for patients with MDS and chronic myelomonocytic leukemia. The role of PDE4 inhibitors should be explored in vitro against MDS cell lines and in preclinical mouse models of MDS.

INTRODUCTION: Infection complications are important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT), even in HLA-identical sibling donors. Although there are many studies associating single nucleotide polymorphisms (SNPs) and allo-SCT evolution, these are mainly related with graft versus host disease (GVHD) and/or transplant related mortality (TRM), with few focused on post-allo-SCT infections. This multicentric study analyzes the potential implication of SNPs with cytomegalovirus (CMV) reactivation and fungal infection (FI) development in allo-SCT with reduced intensity conditioning (RIC). MATERIALS AND METHODS: We included paired recipient-donor samples from 247 RIC allo-SCT for patients diagnosed of AML (35%), NHL (21%), MDS (16%), MM (10%), CLL (7%), HL (6%), or others (5%) in four centers in Spain. Flu-Bu conditioning was used in 55% of the transplants while Flu-Mel in 42%. A total of 52 SNP were analyzed from 44 different gene loci and genotyping was carried out by Sequenom Mass ARRAY platform. Allele frequencies were estimated by direct counting and compared between groups using Fisher's test. P-value RESULTS: Patient's characteristics are shown in Table 1. The median follow up for patients was 28 months (1-175), overall survival at 5 years was 45%, while the event-free survival at 5 years was 57%. Cumulative incidence of CMV reactivation at 3 years was 34% and of FI 11%. Transplant related mortality was 17%, and infection related mortality 14%. In univariate analysis, patients with genotype A/A in rs3093023 (CCR6) showed a lower incidence of CMV reactivation (table 2), along with acute GVHD were the variables associated in multivariate analysis. Regarding to FI, recipient genotype A/A in rs1494555 (IL7R), donor C/C in rs1800795 (FAS), and donor G/G in rs2302217 (MAdCAM-1) were associated with higher FI incidence (table 2), being the only variables related in multivariate analysis. CONCLUSION: This data suggest an association between rs3093023 (CCR6), rs1494555 (IL7R), rs1800795 (FAS) and rs2302217 (MAdCAM-1) polymorphisms with higher incidence of post-allo-SCT opportunist infection. Confirmation in larger series is required. FUNDING: RD12/0036/0069, CB16/12/00233 and 00480, PI12/02361 and ERDF, Innocampus; CEI-2010- 1-0010 Download : Download high-res image (236KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Background The molecular events that drive the transformation from myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) have yet to be fully characterized. We hypothesized that detection of these mutations at the time of transformation from MDS to AML may lead to poorer outcomes. Methods We analyzed 102 MDS patients who were admitted to our institution between 2004 and 2013, had wild-type (wt) FLT3-ITD and RAS at diagnosis, progressed to AML, and had serial mutation testing at both the MDS and AML stages. Results We detected FLT3-ITD and/or RAS mutations in twenty-seven (26%) patients at the time of transformation to AML. Twenty-two patients (81%) had RAS mutations and five (19%) had FLT3-ITD mutations. The median survival after leukemia transformation in patients who had detectable RAS and/or FLT3-ITD mutations was 2.4 months compared to 7.5 months in patients who retained wt RAS and FLT3-ITD (hazard ratio [HR]: 3.08, 95% confidence interval [CI]: 1.9–5.0, p FLT3-ITD and RAS mutations had independent prognostic significance for poor outcome.

Histone deacetylase (HDAC) inhibitors are well-characterized anti-leukemia agents and HDAC gene expression deregulation has been reported in various types of cancers. This study sought to characterize HDAC gene expression patterns in several types of leukemia. To do so, a systematic study was performed of the mRNA expression of all drug-targetable HDACs for which reagents were available. This was done by real-time PCR in 24 leukemia cell lines and 39 leukemia patients, which included AML, MDS and CLL patients, some of whom received HDAC inhibitor treatment. Among the samples analyzed, there was no discernible pattern in HDAC expression. HDAC expression was generally increased in CLL patients, except for HDAC2 and HDAC4. HDAC expression was also generally increased in VPA-treated MOLT4 cells. However, this increased expression was not seen in AML patients treated with vorinostat. In summary, increased HDAC expression was noted in CLL patients in general, but the HDAC expression patterns in myeloid malignancies appear to be heterogeneous, which implies that the role of HDACs in leukemia may be related to global expression or protein function rather than specific expression patterns.

Hypomethylating agents (HMA), such as 5-azacitidine or decitabine, are currently used to treat patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) until treatment failure. However, the outcomes for patients who discontinue therapy after achieving partial response (PR) or complete remission (CR) but before treatment failure have not been reported. We present a series of 16 patients with higher-risk MDS (n=5; 31%) or AML (n=11; 69%) who achieved PR (n=1) or CR (n=15) and stopped HMA therapy while in response in the context of clinical trials. They received a median of 12 courses (range 1–24) and achieved response after a median of 1 course of therapy (1–4). Loss of response after discontinuation of therapy was rapid, with a median progression-free survival of 4 months (95% CI: 2–6). Median overall survival (OS) from the time of therapy discontinuation was 15 months (95% CI: 6–24). Patients who received 12 cycles of therapy or more had significantly better OS (median: 20 months [95% CI: 12–27]) than those who received fewer than 12 cycles (median: 4 months [95% CI: 1–8]) (p= 0.043). Poor-risk cytogenetics were also associated with lower 1-year OS (33% versus 69%; p= 0.046). According to these results and considering the poor prognosis after HMA failure, HMA interruption should be avoided once a sustained response has been achieved.

Key Clinical Message Sixty-seven-year-old patient, diagnosed with multiple myeloma who had received autologous stem cell transplantation, following bortezomib, dexamethasone and thalidomide conventional regimen, achieving complete response, developed rash, diarrhea, and severe respiratory failure, 80 days after the transplantation procedure. He was diagnosed with graft-versus-host disease and bronchiolitis obliterans syndrome.

a b s t r a c t Patients with isolated del(5q) and MDS are considered to have good prognosis as compared to other MDS subtypes. Most patients suffered of anemia and 50% of them required transfusions at diagnosis. It is known that for patients with MDS and del(5q) in transfusion dependence(TD), Lenalidomide is the first choice treatment. However, there are no data regarding natural evolution of anemia in patients diagnosed in MDS and del(5q) without TD, factors that may impact on the development of TD or disease outcome. In the present study we have performed a retrospective multicenter analysis on 83 patients with low-int 1 MDS and del(5q) without TD. During the study 61 patients became TD at a median of 1.7 years and only the Hb level 9 g/dL was associated with poorer TFS (p = 0.007) in the multivariate analysis. Among these 61 TD patients, 49 received treatment (19 Lenalidomide). Median follow up was 48 months, estimated OS at 2 and 5 year was 92% and 50% respectively. In the multivariate analysis for OS, platelets

We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250 mg (days-21 and -14), Y-90 ibritumomab IV (.4 m Ci/kg, day -14), fludarabine 30 mg/m(2) i.v. (days-3 and -2) plus melphalan 70 mg/m2 i.v. (days-3 and -2) or 1 dose of melphalan and thiotepa 5 mg/kg (day-8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P =.046) and OS (71% versus 27%, P=.047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT. (C) 2017 American Society for Blood and Marrow Transplantation.

INTRODUCTION Transplant-associated thrombotic microangiopathy (TMA) is a severe complication after allogeneic stem cell transplantation (ASCT) due to endothelial injury caused by many factors such Calcineurin-inhibitors. In most severe cases, TMA could affect different organs. Intestinal TMA could be fatal and missdiagnosed in many patients. Clinical and pathological criteria to differentiate from intestinal GVHD are needed in order to distinguish both entities with different therapeutical approach. The aim of this study was to review pathological TMA features in patients diagnosed of systemic TMA . PATIENTS AND METHODS We analyzed the incidence of TMA in 527 pts who underwent ASCT in our institution between jan-2010 and apr-2018. Patients were identified if they had TMA according to probable TMA criteria by Ho. We do a pathological review in 96 samples from 18 of 42 patients in whom an endoscopy have been performed after the diagnosis of the TMA; endoscopy have been performed between 30 days before and 60 days after diagnosis of TMA for initial clinical diagnosis of GVHD. Review was performed by a pathologist expert. He examined the biopsies in search of features of GVHD, TMA or viral infection. Diagnosis of GVHD was stablished according to Mcdonald and Sales criteria, intestinal TMA diagnosis was perfomed by the 8 criteria summarized by Warren et al (perivascular mucosal hemorrhage, endothelial cell swelling, endothelial cell separation, intraluminal schistocytes, fibrin or microthrombi, loss of glands and mucosal denudation). RESULTS Baseline/transplant characteristics of patients with TMA are shown in table 1, TMA data in 2 and review hystological features of biopsies in 3. 45 (8.5%) were diagnosed of TMA with a median time from transplant of 75 days. Median age was 49 (19-69). Prophylaxis of GVHD was: Calcineurin inhibitor-MTX in 16 (35.5%), Tacrolimus-Sirolimus in 21 (46.6%), Tacrólimus-MMF and Cyclophosphamide in 8 (17.6%). 42 (93%) had prior or simultaneous acute GVHD, half of them grade III-IV, and 80% with gastrointestinal GVHD. 42% had elevated levels of tacrolimus and 13.6% elevated levels of sirolimus, one week before the diagnosis of TMA. Gastrointestinal MAT have been reported only in 5 patients (28%) at diagnosis whereas when review based on Warren criteria was performed, in 16 patients (89%) the pathologist found at least 1 of the criteria of endothelial damage and 50 % of the patients met 3 or more Warren criteria. The most frequent features were endothelial cell swelling (13 patients, 73 %) and perivascular mucosal hemorrhage (12 patients, 66.7%). In 3 biopsies which we perfomed the inmunochemistry of C4d, an activation of classic way of complement biomarker, it was positive. 4 of the 18 patients (22.2%) presented refractory-hypertension and 3 of them (26.6%) more than 30 mg/d Lof proteinuria, both suggested of poor prognosis. Regarding GVHD, it was founded in 72% at diagnosis and in all patients (18) at pathological review. 13 had grade I, 1 grade II, 1 grade III and 3 histological grade IV). With a median follow-up of 5 months (2-25) 25 of the 45 (56%) are dead. 6 of the deaths (24%) were related to TMA (1 due to TMA, 3 due to TMA+GVHD, 2 due to TMA+infection). Other causes of death were progression (4), GVHD+Infection (7), GVHD (3), infection (2), sinusoidal obstruction síndrome (1) and other causes (2). CONCLUSION TMA is a frequent complication, related with GVHD and underdiagnosed frequently. Only 5 of 18 patients were diagnosed of gastrointestinal TMA. In our study, we found that most of our patients had endotelial damage in the gastrointestinal biopsy pathological reviews. Although histological criteria of GVHD were present at review, in most of them it was only grade I; it contrasts with the severe clinical features. That lack of correlation would suggest that TMA and not GVHD is the main feature. Management of TMA and GVHD are different. To stress an appropiate diagnosis in gastrointestinal TMA is needed in order to offer the patients the best approach. REFERENCES Warren et al. A Complete Histologic Approach to Gastrointestinal Biopsy From Hematopoietic Stem Cell Transplant Patients With Evidence of Transplant-Associated Gastrointestinal Thrombotic Microangiopathy. Arch Pathol Lab Med.2017 Nov;141(11):1558-1566. Jodele S et al. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191-204. Disclosures No relevant conflicts of interest to declare.

Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts. Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.

To evaluate if pretreatment FLT3-ITD allele burden is associated with an impact on the response to the combination of sorafenib and azacytidine. Methods: We retrospectively analyzed the clinical records for 56 patients with FLT3-ITD treated with azacytidine and sorafenib between 2009 and 2013. Results: Among the patient, 34 (54%) were male, 15 (24%) had secondary AML and 7 (11%) had therapy-related AML. The median age prior to treatment with azacytidine plus sorafenib was 64 years (range, 20-87), with the median age at initial diagnosis of 63 years (range, 19-86 years). Eastern Cooperative Oncology Group performance status was 2 in 19 patients (31%). The median number of prior therapies received was 2 (range, 0-9); 12 patients were elderly (aged 61 years) without prior therapy who were deemed unfit to receive standard cytotoxic chemotherapy. The median white blood count was 8.9 10 (range, 7.5-13.1 10) and the median bone marrow blast percentage was 56% (range, 0-99%). The median FLT3-ITD allelic burden was 0.73 (range, 0.34-0.93) Median time from diagnosis to treatment with sorafenib and azacytidine was 5.5 months (range, 3 days -27months); cytogenetics was unfavorable in 8 patients (13%), normal karyotype in 30 (48%), and miscellaneous in 24 (39%). Eight (14%) patients achieved a complete response (CR) with 7 patients (13%) achieving CR without platelet recovery (CRp) and 10 (18%) achieving CR without peripheral blood count recovery (CRi); 1 patient (1%) had partial response (PR). The overall response rate was 46%. The OS at 3 months and 12 months were 45% and 24%, respectively. FLT-3 ITD allele burden had no significant impact on overall survival (OS) [HR 0.93, 95% CI (0.79-1.10); p1⁄40.433]. The variables with significant and independent impact on OS were achieving CR/CRp/CRi [HR 0.183, 95% CI (0.77-0.435); p 1⁄4 0.000], and ECOG 2[HR 3.78, 95% CI (1.782-7.843)]. The only variable with a significant impact on the overall response rate was blast percentage [OR 1.025 (1.007-1.043); p 1⁄4 0.007]. FLT3-ITD allele burden had no impact on response rate [OR 0.63 (0.21-1.83) p 1⁄4 0.394]. Conclusion: The FLT3-ITD allele burden in patients with relapsed, refractory, or high-risk untreated AML does not have an impact on the response rate or survival.

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P

Introduction HLA-haploidentical hematopoietic stem cell transplant (Haplo HSCT) is a potentially curative strategy for patients lacking a HLA matched donor or a suitable unrelated donor. The use of post-transplant Cyclophosphamide (Cy) for GVHD prophylaxis and the particular characteristics of Haplo-HSCT can be linked to a higher risk of hemorrhagic cystitis (HC) and viral infections. In this context, our aim was to analyze HC in both haploidentical and conventional donor transplants in our center. Material and Methods We retrospective analyzed of 237 patients who received an HSCT in our center, between August-2012 and January-2016. We analyze the incidence of HC in the early post-HSCT period (6 months) and its characteristics in those patients receiving Haplo (n=36, 15%) and we compared it with a non-haploidentical donor transplant group from the same period (n=201, 85%). Results Patients' characteristics are summarized in table 1. Both groups are balanced, except for diagnosis due to the high proportion of Hodgkin lymphoma in Haplo group, conditioning regimen, and GVHD grade III-IV with a lower incidence in Haplo. Conditioning regimen in Haplo consisted of Fludarabine (30mg/m2x or 50mg/kg x 4days in RIC or MA regimen) and Busulfan (3.2 mg/kg x 2 in RIC or 3 days in MA). Post-HSCT Cy was used for GVHD prophylaxis in 94%. Median of days to reach more than 500x10^9 granulocytes and more than 20x10^9 platelets in Haplo group were 18 (13-30) and 23 (0-103) respectively. Hemorrhagic cystitis: Incidence of HC was 33% vs. 13% in conventional HSCT (p=0.03). Infectious etiology was documented in 84% of the Haplo recipients and 89% in conventional HSCT (p=0.87). In Haplo, HC was caused by BK/JC polyomavirus in 67% and adenovirus in 17%. Among conventional HSCT recipients, BK/JC was documented in 75% and adenovirus in 14% of HC. Viral infection was diagnosed by positive PCR in urine. HC appeared at a median of 65 days post-HSCT (5-557), without differences between Haplo and non-Haplo: 61 (5-423) vs. 67 (8-557). Treatment of HC consisted of hyper-hydration and spasmolytic drugs in 19 patients. Intravesical cidofovir was used in 7 and intravenous cidofovir was needed in 2 cases. Receiving an Haplo HSCT was associated with a higher risk of developing HC [OR 3.5 (95% CI 1.56-7.91); p=0.002]. We did not observed association between HC and conditioning regimen (p=0.18), receiving ATG (p=0.45) or presence of acute GVHD grade I-II (p=0.75) or grade III-IV (p=0.46). Haplo donor was the only variable with significant impact in multivariate analysis. Conclusions Incidence of HC is higher in Haplo HSCT, being viral infections and not Cy toxicity, the main cause (polyomavirus BK/JC as the first cause). Table 1 Table 1. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria.

Inflammation and innate immunity have an essential role in the pathogenesis of myelodysplastic syndromes (MDS). One of the key inflammatory cytokines that is upregulated in MDS and acute myeloid leukemia (AML) is IL-8. [Schinke C et al, 2015]. The expression of IL-8 and other inflammatory cytokines is controlled by phosphodiesterase 4 (PDE4), which has yet to be studied in MDS and AML. Furthermore PDE4 inhibitors may be useful therapeutic targets for MDS. Based on this, we evaluated the expression of PDE4 and examined its potential impact on clinical outcomes in MDS. Transcriptomic profiling was obtained from the Illumina Genome Analyzer IIx platform, using the NuGEN Ovation RNA sequencing (RNA-seq) system. Total RNA was extracted from CD34+ bone marrow hematopoietic cells from healthy individuals (n=10) and patients with MDS (n=24) or CMML (n=19). We interrogated the RNA-seq dataset to analyze expression levels of each isoform of the PDE4 (A, B, C and D) using Z-score to normalize the results. Median overall survival (OS) was estimated using Kaplan-Meier methods with the log-rank test. Survival rates for each isoform of the PDE4 were stratified by negative or positive Z-scores (low or high expression groups, respectively). The study cohort had a median follow-up of 21.2 months (range: 0.2-68). Median age at diagnosis was 69 years (range: 43-87) with 67.5 % of diagnosed patients being ≥65 years. Most of patients (72%) were male, and 21% had a prior chemotherapy and/or radiotherapy. The median count (x 109/L) for white blood cells and platelets was 12.2 (range: 0.7-67) and 97.2 (range: 11-331), respectively. IPSS risk was low and int-1 in 51.2% of patients, int-2 in 37.2%, high in 6.9%, and not available in 4.7%. The cytogenetic groups of risk were: very good and good in 53.5% of patients, intermediate in 30.2%, poor in 14% and not available in 2.3%. The overall response rate (ORR) to hypomethylation agents (HMA) was 51.1%, with 37.2% having complete response (CR), 6.9% having bone marrow CR, and 6.9% having hematologic improvement. Median OS for the whole cohort was 17.6 months (95% confidence interval [CI]: 9.6-25.6). Detailed PDE4 isoform-specific analyses are presented in Table1 . Importantly, there appears to be an impact on OS depending on PDE4 isoform expression levels, which should be confirmed in a larger patient cohort. PDE4 expression may be useful as both a prognostic factor and a potential therapeutic target for patients with MDS. The effects of PDE4 inhibitors should be investigated in vitro against MDS cell lines and in preclinical mouse models of MDS. One potential application for this study is to exploit the blockade of the PDE4 pathway on the IL8 expression, which may be a good therapeutic strategy against MDS and AML stem cells [Schinke C et al, 2015]. PDE4 inhibitors could also be included in our therapeutic arsenal in the context of the HMA failure in selected patients with MDS. | DISEASE STATE STRATIFICATION | | Mean expression (range) | p value | | EXPRESSION LEVEL STRATIFICATION | | Number of patients (%) | Mean expression (range) | Median OS, months [95% CI] | p value | | ---------------------------- | | ----------------------- | ------- | ---- | ------------------------------- | --------- | ---------------------- | ----------------------- | -------------------------- | ------- | | PDE4A | | | 0.26 | | PDE4A | | | | | 0.24 | | MDS | | 0.26 (0-5.2) | | | Low | | 27 (62.7) | 0.26 (0-0.08) | 15.8 [11.1-37.1] | | | Normal | | 0.108 (0-0.5) | | High | | 16 (37.3) | 0.65 (0.1-5.2) | 29.2 [7.60-36.4] | | PDE4B | | | 0.90 | | PDE4B | | | | | 0.87 | | MDS | | 4.90 (0.06-23.95) | | | Low | | 28 (65.1) | 2.25 (0.06-4.87) | 24.1 [11.7-19.8] | | | Normal | | 4.92 (0.06-23.95) | | High | | 15 (34.9) | 9.85 (5.21-23.95) | 22 [26.7-31.8] | | PDE4C | | | 0.03 | | PDE4C | | | | | 0.25 | | MDS | | 0.004 (0-0.045) | | | Low | | 29 (67.4) | 0.0003 (0-0.002) | 26.7 [18.6-34.8] | | | Normal | | 0.0009 (0-0.004) | | High | | 14 (32.6) | 0.01 (0.004-0.045) | 12.3 [3.40-21.1] | | PDE4D | | | 0.89 | | PDE4D | | | | | 0.95 | | MDS | | 1.55 (0.007-5.19) | | | Low | | 25 (58.1) | 0.92 (0.007-1.49) | 26.7 [4.60-48.80] | | | Normal | | 1.50 (0-3) | | High | | 18 (41.9) | 2.42 (1.51-5.10) | 16.8 [13.3-20.25] | Table 1. PDE4 isoform expression stratification by expression levels and by disease state Disclosures No relevant conflicts of interest to declare.

Results: We found that 47% (n=37) of our samples have reduced EZH2 mRNA expression (less than half that of controls), but these data not statistically significant (p=0.159). Further analyses revealed that EZH2 is significantly underexpressed in MDS cases with chromosome 7 or 7q deletion (mean=0.4 fold, p=0.006). These deletions were also associated with lower EZH2 expression than was seen in diploid cells and cells with other cytogenetic abnormalities (p=0.041). To understand the effects of EZH2 expression alteration specifically, we performed survival analysis. Multivariate analysis indicated that, in contrast to previous findings, EZH2 underexpression is associated with better overall survival (OS) (p=0.012). We also examined treatments in our patient cohort and found that 61% of patients (n=53) received hypomethylating agents (HMA). In the HMA treatment cohort, non-responding patients (n=27) had lower EZH2 expression than responders (n=26), but that effect was not significant (p=0.12). However, in HMA responders, EZH2 expression was significantly lower in patients who achieved longer responses (more than 12 months, n=15) than in those who progressed or relapsed within 12 months (p=0.02).

Background: AML-M6 is a subtype of acute myeloid leukemia associated with poor prognosis. Hypomethylating agents (HMA) have not been extensively studied in patients with AML-6. Objective: To compare HMA therapy to conventional chemotherapy (CT) in patients with AML-6 Method: We reviewed 160 consecutive patients with AML-M6 treated with HMA (n=25) or CT (n=135) between 1980 and 2014. Patient clinical and demographic data were analyzed for contribution to survival and response outcomes. Results: The median patient age for our patients was 62 years (ranges, 16-87 years). Median follow-up was 56 months (range, 2-269 months). Poor cytogenetics, including complex karyotypes and chromosome 7 alteration, were observed in 96 (60%) patients including 62% of patients in the CT arm and 76% of patients in the HMA arm, respectively (p=0.002). Mean blast percentage was 24% (26% for CT patients versus 15% for HMA patients; p=0.001). ECOG Performance status ≥2 was present in 26 (16%) patients (17% of CT patients versus 16% of HMA patients; p=0.59). Patients who received HMA were older (median age 67 vs 59; p Overall, 44% of patients treated with HMA achieved complete remission (CR) versus 66% for those treated with CT (p=0.03). However, there were no significant differences in overall response rate (ORR) for patients treated with CT and HMA (67% vs 56%, respectively; p=0.359). By univariate analysis, variables associated with ORR were age, treatment modality (CT vs HMA), poor cytogenetics, and bone marrow blast percentage. Only poor risk cytogenetics maintained significant impact on multivariate analysis (ORR=0.36 [95% CI: 0.13-0.95]; p=0.039). Median overall survival (OS) and disease-free survival (DFS) were 10 months (range, 8-12) for and 5 months (range, 3-6) respectively for the whole cohort. The 1-year OS and DFS rates were 39% and 27%, respectively. The 8-week mortality rate for patients treated with HMA and CT were 12% and 20%, respectively. In a Cox-regression multivariate model, variables with independent impact on OS were diagnosis prior to 2000 (HR=1.84 [95% CI: 1.12-3.02]; p = 0.016), age > 62 years (HR=2.03 [95% CI: 1.33-3.08]; p=0.001), CR (HR=0.301 [95% CI: 0.18-0.49]; p=0.000), poor cytogenetics (HR=4.85 [95% CI: 2.96-7.96]; p=0.000), and ECOG performance status ≥2 (HR=2.23 [95% CI: 1.21-4.09]; p=0.01). Considering only patients with complex cytogenetics and chromosome 7 abnormalities, there were no differences in median OS between CT and HMA (5 months vs 6 months; p=0.23) Conclusion: Our retrospective analysis found that HMA may be a good alternative to CT for patients with AML-M6. Patients treated with HMA had more favorable 1-year OS and DFS as well as lower 8-week mortality rates. These results were despite the fact that most of the patients treated in our HMA group had generally worse prognosis than those in the CT group. Disclosures Kantarjian: ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

The POT1 gene is located in chromosome 7 and encodes a key component of the shelterin complex, which is essential for the maintenance of telomere and chromosome integrity. Somatic mutations of POT1 have been identified in chronic lymphocytic leukemia, which indicates that POT1 dysfunction is involved in the pathogenesis of hematological neoplasms. At the same time, abnormal telomere shortening has been observed in MDS/AML and a spectrum of bone marrow failure syndromes. We therefore sought to study the potential role of POT1 in MDS by sequencing the gene and characterizing its expression in primary bone marrow specimens of patients with MDS. We first sequenced all POT1 coding regions that are known to have mutations in CLL. PCR-Sanger sequencing was performed in bone marrow mononuclear cells (BM-MNNC) of a cohort of 30 patients with MDS (15 with RAEB/RAEBT, 11 with RA/RARS/RCMD/MDS-U, 2 with CMML, and 2 with 5q- syndromes). No genetic mutations in the POT1 gene were detected. This result suggests that genetic alteration of POT1 is rare in MDS. We then evaluated the expression of POT1 using cDNA arrays (n=183) or RT-PCR (n=58) in a cohort of 241 patients with MDS from two centers. The median age of our patients was 71 years (32-95). Diagnoses included RAEB in 108 (45%), 5q- syndrome in 18 (8%), and other syndromes (RA, RCMD, and MDS-U) in 115 (47%) cases. In this cohort, 140 (58%) patients were diploid, 22 (9%) had chromosome 7 alterations, 21 (9%) had 5q deletion, and 58 (24%) had other cytogenetic abnormalities. Results indicate that POT1 was underexpressed (less than 50% of the POT1 level in normal controls) in the bone marrow CD34+ hematopoietic progenitor cell population in 138 patients (57%). However, no significant difference was observed between the whole MDS cohort and control BM CD34+ cells from healthy donors (n=25). Further subset analysis based on karyotypes revealed that 81% of patients with chromosome 7 alterations (7- and 7q-) had lower expression of POT1 versus 38% of diploid patients, 35% of 5q patients, and 42% of patients with other cytogenetic alterations (p=0.001). ANOVA testing indicated that expression of POT1 was significantly downregulated (less than 50% of control) only in patients with chromosome 7 alteration (p When we compared the survival of patients with POT1 downregulation to other groups, we observed a strong tendency toward shorter overall survival in patients with POT1 downregulation (median OS of 37 months [95% CI: 21-52] vs 53 months [95%CI: 30-75]; p=0.139). This tendency toward poorer OS was also observed when we excluded cases with chromosome 7 alterations (37 months [95% CI: 17-57] vs 53 months [95%CI: 25-80]; p=0.186). Next, we evaluated the potential impact of POT1 expression on responses to therapies. In the subgroup of patients with available treatment records for analysis (n=58), a total of 42 patients received hypomethylating agents (HMA), and 47% of them achieved responses. When comparing POT1 expression levels to HMA response, we observed significantly lower POT1 expression in HMA non-responders than in responders (U Mann-Whitney test p= 0.028). In a regression model for response to HMA, we also observed that downregulation of POT1 was associated with a poorer response to HMA (OR 4.96 [1.01-24.37]; p=0.049). However, when we introduced chromosome 7 alterations into the model, POT1 expression lost its effect, which suggests that the impact of POT1 on response to HMA is due to its interaction with chromosome 7 alterations. Taken together, the results of this study indicate that the downregulation of POT1 gene expression, which is related to chromosome 7 deletions, may play a role in the pathogenesis and prognosis of MDS, including response to HMA-based therapies. Disclosures No relevant conflicts of interest to declare.

EZH2 encodes a key histone methylation regulatory molecule. Genetic mutations of EZH2 occur in ~10% patients with MDS and are associated with poor prognosis. However, the expression patterns of EZH2 are less well studied in MDS. To characterize these expression patterns, we assessed EZH2 mRNA expression in primary patient bone marrow CD34+ cells (n=78) (age: 33-91; IPSS: low 24%, Int-1 31%, Int-2 27%, High 14%; Karyotype: diploid 62%, 5q-/7q- 23%, others 15%). QRTPCR assays indicated that 47% (n=37) of patients had reduced EZH2 mRNA expression (less than 50% of controls), but this finding was not statistically significant (p= 0.159). Subtype analyses based on various karyotypes revealed that EZH2 is significantly underexpressed in patients bearing chromosome 7 or 7q deletions (mean=0.4 fold, p=0.006). Seventy-five percent of patients with 7 or 7q deletions have EZH2 expression less than 50% of that of controls. Chromosome 7 deletions were also associated with lower EZH2 expression than that seen in diploidy and other cytogenetic abnormalities (p=0.041). Wepreviously found that the overexpression of a group of innate immune genes contributes to MDS pathogenesis and is related to deregulation of histone methylation. Because EZH2 is a key regulator of histone methylation, we assessed the relationship between deregulation of these genes and EZH2 under-expression. To exclude the effects of cytogenetic defects and EZH2 mutations, we studied only the subset of patients with normal karyotypes and wildtype EZH2. We surveyed capture deep sequencing results of 32 of the diploid patients from the cohort that had sequencing data available. Three patients carry EZH2 mutations, including missense (nt148511133), nonsense (nt148524257), and splicing mutations (nt148524257). In the remaining 29 patients with normal karyotypes and wildtype EZH2, 14 (48%) had EZH2 under-expression. We then compared mRNA expression of 11 innate immune genes known to overexpress in MDS between the patients with EZH2 underexpression and others. We observed that mRNA levels of all 11 immune genes tested were higher in the EZH2 underexpression group and statistically significant (p We then performed survival analysis for EZH2 expression in MDS. Surprisingly, multivariate analysis in the whole cohort indicated that EZH2 underexpression is associated with better overall survival (OS) (HR 0.23, 95% CI (0.07-0.72); p=0.013). We also performed analysis in the subset without chromosome 7 deletion and observed a similar association (HR 0.18 (0.06-0.55) p=0.012). To investigate whether this result was related to responses to therapy, we reviewed treatment records and found that 61% of patients in the cohort (n=53) received hypomethylating agents (HMA). In this HMA treatment subset, non-responders (n=27) tended to have lower EZH2 expression than responders (n=26) (mean EZH2 of 0.497 vs 0.944, p=0.12). However, we noticed that in the subset of HMA responders, EZH2 expression was significantly lower (p=0.02) in patients who achieved longer responses (more than 12 months, n=15) than in those who progressed or relapsed within 12 months following treatment. We are currently investigating whether this impact of EZH2 underexpression on HMA responses contributes to its effect on OS. Taken together, the results of this study indicate that underexpression of EZH2 in the bone marrow hematopoietic progenitor cell compartment may have unique effects on the molecular pathogenesis, prognosis, and treatment of MDS and may do so through a unique mechanism that differs from that of previously characterized EZH2 mutations. Further investigations are also required to determine the relationships between EZH2, HMA-based treatments, and patient survival. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding.

The prognosis of patients with untreated MDS or AML with poor performance, organ dysfunction, or other comorbidities is very poor. Most patients do not receive therapy, and a large majority of them are excluded from investigational clinical trials. We hypothesized that this group of patients would significantly benefit from participation in clinical trials. To test this concept, we performed an initial proof-of-principle study of 30 patients with these characteristics using a combination of azacitidine and vorinostat, a histone deacetylase inhibitor, with the stopping rules being survival at 60 days, a response rate (30%), and toxicity. This study indicated that treatment was associated with longer-than-expected survival and response rate and acceptable toxicity as well as demonstrating that this group of patients can be safely and efficiently enrolled in clinical trials (Garcia-Manero ASH 2010 abstract #604). To further verify these results, we subsequently expanded this trial as a randomized study comparing azacitidine versus azacitidine + vorinostat, the results of which are shown here. This study would allow further experience in the development of clinical trials for this at-risk population as well as explore the role of vorinostat in combination with azacitidine. The primary objective was survival at 60 days. The study was independently monitored by the Dept of Biostatistics at our institution. Patients were randomized using an adaptive procedure. The first 40 patients were randomized in a 1:1 ratio, and after that will be unbalanced in favor of the superior arm as efficacy (survival at 60 days) data accrue. Inclusion criteria included patients with newly diagnosed AML or higher-risk MDS who were not eligible for high-dose chemotherapy or clinical trials due to comorbidities, organ dysfunction, or poor performance status. Treatment consisted of azacitidine 75 mg/m2 IV daily x 5 (A arm) or azacitidine at the same dose schedule with vorinostat at 200 mg 3 times a day on days 1 to 5 (A+V arm). From September 2011 to March 2014, 79 patients were enrolled: 27 (34%) in the A arm and 52 (66%) in the A+V arm. Median age was 70 (30-90); median bone marrow blasts were 8% (1-89), median WBC 2.8 (0.2-102.0), median peripheral blasts 0% (0-78), poor cytogenetic risk in 41 (52%), diploidy in 20 (25%), and intermediate risk in 18 (22%). Reasons for inclusion were concurrence or previous history of other malignancies (36; 46%); ≥2 ECOG performance status (9; 11%); comorbidities including lung fibrosis, renal or liver dysfunction, or HIV positive status (17; 21.5%); or non-eligibility for others trials due to higher priority (17; 21.5%). The number of median cycles was 1 (1-12) for the A arm and 3 (1-12) for A+V arm. Study drugs were tolerated with no drug-related early stoppage (8 week mortality). Incidence of any grade 3-4 toxicity was less than 9%. Sixty-day survival was seen in 18 patients (67%) for the A arm and 44 patients (85%) for the A+V. The A+V arm was associated with a better outcome (OR 0.311, 95% CI [0.101-0.962]; p=0.043). The ORR (CR+CRp) was 12 (44%) for the A arm and 18 (35%) for the A+V arm (p=0.395). The median number of cycles for response was 1 in the A arm and 1.5 in the A+V arm. Survival was confounded by death unrelated to leukemia. The median overall (OS) and relapse-free survival (RFS) for the whole group were 7.1 months (5.5-8.7) and 5.9 months (3.1-8.7), respectively. Median OS for the A and A+V arms was 6.1 and 5.9 months, respectively (p=0.9), and median RFS for the A and A+V arms was 5.9 and 8.7 months (p=0.5), respectively. Patients who achieved CR/CRp had better OS: median 12 vs 6 months (HR: 0.41, [0.22-0.78] p=0.007). After a median follow-up of 9.5 months, 23 patients (29%) are alive at last follow-up. In conclusion, azacitidine+vorinostat was associated with a better 60-day survival than single-agent azacitidine in a patient population that is generally excluded from clinical trials. This study confirms the possibility of treating patients that are generally not considered eligible for clinical trials. Disclosures No relevant conflicts of interest to declare.