ALBERT

Description: Abstract 4013 Background: In recent years, azacytidine (AZA) has become the standard of treatment for high risk myelodysplasia (MDS). The approved schedule of AZA uses a 75mg/m2/d s.c. regimen for 7 days based on the CALGB-9221 (Silverman, JCO 2002) and the AZA-001 studies (Fenaux, Lancet Oncol 2009). The clinical response rates after AZA have been extensively presented but there is only limited data on the rates of cytogenetic response (CyR). Based on the review of the literature, there are no specific cytogenetic data published on prospective trials. Methods: We based our analysis on a randomized phase 2 study from the US Leukemia Intergroup (E1905 study, NCT00313586) testing 10 days of AZA (50mg/m2/d s.c.) vs 10 days of AZA+ the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). MDS, CMML, and AML with myelodysplasia-related changes were included. This analysis includes all patients with cytogenetic abnormalities (at baseline or acquired following treatment) with available cytogenetic follow-up (cycle 6). Of 150 patients, 70 demonstrated baseline cytogenetic abnormalities. To date, forty patients (27 MDS and 13 AML) were evaluable for both time points. Karyotypes were performed at local laboratories, and reviewed centrally (RPK and GH). Cytogenetic response was assessed using IWG 2000 (Cheson et al, Blood 2000) criteria. Results: The clinical response rate (CR+PR+ trilineage HI) according to IPSS cytogenetic risk stratification were of 20%, 33%, and 35% for favorable, intermediate and poor cytogenetic risk groups respectively (p=NS). Patients with Chr 7 abnormalities (i.e. -7 or -7q, n=18) had a response rate of 28% including 17% CR. Of patients with complete cytogenetic data, the rate of overall CyR was 52% (n=21): 22% (n=9) complete CyR, 30% (n=12) partial CyR. This represents a complete CyR of 13% and a partial CyR of 23% as a proportion of all treated patients with initial cytogenetic abnormalities (including those who did not receive six cycles of therapy). To date, confirmatory FISH analyses were available for 4 patients with CyR (2 CCyR and 2 PCyR). All four had complete clearance of their cytogenetic clone. Among the cytogenetic responders, 15 had MDS and 6 had AML (p=NS). CyR did not differ between the two treatment arms. CyR and clinical response were highly correlated (p

Description: This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels 〈 200 mU/mL vs ≥ 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein+ CD34+ marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Description: Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

Description: Background In a randomized study of single-agent eltrombopag (EPAG; n=64) versus placebo (PBO; n=34) in thrombocytopenic patients with advanced myelodysplastic syndromes or acute myeloid leukemia (AML), median overall survival (OS) was 27 weeks for EPAG versus 15.7 weeks for PBO (hazard ratio [HR]: 0.73). In addition to standard supportive care, disease-modifying treatments were generally permitted at any time at the investigator's discretion. To explore the role of concomitant anticancer therapy in this study population, a post hoc subgroup analysis was conducted in patients in each treatment group who received anticancer treatment. Methods Anticancer treatment was grouped post hoc into the following categories: palliative treatment (eg, hydroxyurea, low-dose cytarabine), hypomethylating agents (HMAs; eg, azacitidine and decitabine), induction chemotherapy (eg, 7 + 3; mitoxantrone, etoposide, and cytarabine, etc), and other (eg, lenalidomide). Baseline characteristics and safety/efficacy parameters were examined in this subgroup of patients. Results While on study treatment, a similar proportion of patients in both treatment arms of the trial received anticancer therapy (EPAG, n=28 [44%]; PBO, n=13 [38%]). The majority of patients receiving anticancer therapy in both the EPAG (64%) and PBO (54%) arms received palliative treatments (primarily hydroxyurea and low-dose cytarabine) followed by HMAs (Table). Induction chemotherapy was received by 11% of patients in the EPAG subgroup, compared with no patients in the PBO subgroup. For the subgroup of patients who received anticancer therapy, EPAG patients had higher baseline median platelet counts and absolute neutrophil counts, and a lower incidence of poor prognosis karyotype (Table). The percentage of patients with AML and those who were platelet transfusion dependent were similar between treatment arms at baseline (Table). All patients in both treatment groups experienced ≥1 adverse event (AE) while on study treatment. A lower proportion of EPAG patients experienced a serious AE (SAE) on therapy compared with PBO patients, and proportionately fewer infection-related SAEs were reported in EPAG versus PBO patients (Table). Pyrexia SAEs were higher in the EPAG (5 [18%]) arm versus the PBO (1 [8%]) arm. In the subgroup of patients receiving anticancer therapy, a similar proportion of EPAG and PBO patients experienced Grade ≥3 hepatobiliary events (3 [11%] vs 1 [8%]). Three (11%) EPAG patients experienced Grade ≥3 renal and 2 (7%) thromboembolic events on study drug, whereas no PBO patients experienced these events. A lower proportion of patients on EPAG (18%) experienced AEs that led to discontinuation of study treatment compared with those on PBO (46%). A lower proportion of EPAG patients (32%) died on therapy compared with PBO (69%); the primary cause of death in both arms was the underlying disease. Median platelet counts for EPAG patients receiving anticancer treatment increased above baseline, whereas median platelet counts remained stable at baseline levels for PBO patients. A higher proportion of EPAG patients than PBO patients achieved platelet (50% vs 31%) and red blood cell (RBC; 29% vs 8%) transfusion independence for ≥8 weeks (Table). Bleeding events (Grade ≥3) were reported in fewer EPAG patients (11%) versus PBO patients (38%). When censoring patients at the start of anticancer treatment, no apparent difference in OS was observed between treatment arms (HR: 0.97). Summary/conclusion In the subgroup who received anticancer therapy, EPAG patients had higher incidences of platelet and RBC transfusion independence, higher median platelet counts, and lower incidences of bleeding and infectious complications compared with PBO patients, with selected SAEs occurring at higher rates. These results support the safety profile of EPAG in combination with a variety of anticancer agents. In addition, these data suggest a possible beneficial supportive care effect in patients receiving concomitant therapy with EPAG and anticancer treatment. Further studies of EPAG in combination with anticancer therapy are warranted to confirm these hypotheses. Disclosures: Platzbecker: GlaxoSmithKline: Honoraria. Off Label Use: Eltrombopag is a TPO receptor agonist that is used for the treatment of thrombocytopenia due to various diseases. It is approved in cITP and now being evaluated for the correction of thrombocytopenia in subjects with MDS/AML. Wong:GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau. Verma:GlaxoSmithKline: Research Funding. Abboud:Alexion: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Teva: Speakers Bureau. Greenberg:Amgen: Research Funding; GlaxoSmithKline: Research Funding; KaloBios: Research Funding; Novartis: Research Funding; Onconova: Research Funding. Lyons:Novartis: Research Funding; GlaxoSmithKline: Research Funding; Amgen: Honoraria, Research Funding. Santini:Novartis: Honoraria; Janssen: Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria. Cheng:GlaxoSmithKline: Speakers Bureau. Dougherty: GlaxoSmithKline: Employment. Mannino:GlaxoSmithKline: Employment. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Chan:GlaxoSmithKline: Employment. Stone:GlaxoSmithKline: Employment. Giagounidis:GlaxoSmithKline: Honoraria.

Description: Abstract 1861 Introduction: Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method: Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age 〉=16, and bone marrow blasts

Description: Farnesyltransferase inhibitors (FTI) make up a novel class of anti-cancer agents that competitively and selectively inhibit farnesyl protein transferase. Early trials of the orally bioavailable non-peptidomimetic FTI tipifarnib (ZARNESTRATM, Johnson & Johnson PRD) demonstrated both clinical responses and excellent tolerability in patients with poor-risk or refractory acute myeloid leukemia (AML). (Karp, et al. Blood97:3361, 2001). We herein report updated results of a multicenter phase 2 trial of tipifarnib in an elderly, previously untreated poor-risk AML population who refused or were deemed unfit for conventional induction chemotherapy. Tipifarnib was administered orally in the outpatient setting at a dose of 600 mg BID for 21 days, followed by a 1–3 week recovery period. Up to 4 cycles of tipifarnib were permitted in patients with complete responses (CR). The primary endpoint was overall response rate (CR + PR). Secondary endpoints included toxicity rates, measurement of markers of farnesylation (HDJ-2) in bone marrow cells, measurement of signaling intermediates ERK and AKT, and RNA microarray expression patterns. Accrual to the trial is complete. 170 patients have been enrolled, 148 of whom are evaluable for response (AML=160; high-risk MDS=4; high-risk CMML=6). The median age was 73 years (range 34–85), and 76 patients (45%) were age = 75. M/F ratio was 2:1. An unfavorable karyotype and/or antecedent MDS was present in 47% and 79% of patients, respectively. The median number of cycles received was 1, and the median number of days of drug received was 36 days. Dose reductions were implemented in 38% of patients, more commonly in cycles subsequent to cycle #1. The overall response rate (CR + PR) was 34%. CR occurred in 18% of patients. Responses were evenly distributed across study centers. In patients ≥ 75 years, the overall response rate was 30% (CR 20 %). Median CR duration was 6.4 months (range 1.5–11+ months). Median overall survival was 5.6 months for all patients. CR patients had a median survival of 14.4 months, with 63% alive at 12 months. In non-responders, median survival was 3.1 months. The incidence of grade = 3 tipifarnib-related non-hematologic adverse events was 43%, comprised mainly of infectious and gastrointestinal complications. The hospitalization rate for tipifarnib-related toxicity was 18% (median duration: 12 days). The death rate from tipifarnib-related toxicity at 6 weeks was 5%. Microarray analysis of pre-and post-treatment bone marrow samples is being performed to identify both predictive and pharmacodynamic gene markers of response to tipifarnib. In summary, tipifarnib is a novel outpatient treatment with activity in previously untreated poor-risk AML. The low hospitalization rate may reflect the low incidence of severe non-hematological toxicity.

Description: Microarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene “poor risk” signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.

Description: Gene expression profiles (GEPs) were obtained from marrow hematopoietic precursor cells (HPC)(CD34+ cells) from 30 myelodysplastic syndrome (MDS) patients: RARS 2, RA 15, RAEB 9, RAEBT 4; IPSS Low 11, Int-1 10, Int-2 5, High 4, and 6 Normal individuals. Fluorescently labeled cDNA was prepared from CD34+ cells (〉90% purity), isolated by immunomagnetic column separation, after reverse transcription of high fidelity PCR-amplified poly(A) RNA (aRNA). The Cy-conjugated nucleotides for aRNA were hybridized to 40,000 gene chip microarrays obtained from the Stanford Functional Genomics Microarray Facility. aRNA from pooled normal CD34+ marrow cells was used as a Reference standard. High resolution scans were obtained to compile a dataset for each microarray, through files submitted to the Stanford Microarray Database. Dendrograms generated by unsupervised hierarchical gene clustering indicated major differences of GEP between Normal and MDS patients. Significance Analysis for Microarray (SAM) yielded 2327 genes significantly differentially expressed by MDS vs Normal: 2269 genes overexpressed, 58 underexpressed, with a false positive rate of ~10%. Prediction Analysis of Microarray (PAM) distinctly separated the MDS and Normal patients, requiring a minimum of 31 genes (which were also SAM significant). Class analysis by PAM correctly predicted 29 of the 30 to be MDS and 5 of the 6 to be Normal. Four disparate differential GEP regions in the dendrograms, comprising predominantly genes of differing functional categories provided signatures associated with differing MDS clinical subgroups. Nine of 10 patients with poor clinical outcomes were associated with a differing GEP signature than that which occurred in 14 of 20 patients with relatively good outcomes. Compared to the remainder of MDS patients, those with 5q- syndrome (n=5) had a differing GEP signature, with under-expression of 1018 genes, 11 of which were within the 5q31–32 CDS. Two of these genes (antioxidant protein1 and interferon regulatory factor1) have previously been proffered as candidate genes for this syndrome. Analysis of FACS-sorted highly purified marrow HPC subsets: CD34+38+ (late) and CD34+38- (early HPCs), indicated these ratios to be 4.3±2.1 (n=2) for MDS and 3.2±1.2 (n=12) for Normals. These findings suggest that the differing GEPs between the MDS and Normal CD34+ cells were not due to major differences in their proportions of CD38 cell subsets. SAM and PAM significant differential GEPs were noted between these cell subsets (also differing between MDS and Normal), indicating alteration of gene expression during differentiation. Wnt1 and β-catenin1 (genes involved in cell self-renewal) were over-expressed in both MDS CD38- and CD38+ cells compared to Normal. These data demonstrate: (1) molecular differences between MDS and Normal HPCs and within HPC subsets; (2) GEP signatures characterizing MDS patients with differing cytogenetic abnormalities (eg, 5q-) and clinical outcomes; (3) molecular criteria refining the prognostic categorization of MDS; and (4) gene expression data aiding characterization of the heterogeneous nature of this spectrum of diseases.