Transfusion-dependent Myelodysplastic Syndromes Research Articles

Elevated Basal Autophagy in SF3B1 Mutated Myelodysplastic Syndromes: Relationship with Survival Outcomes and Therapeutic Implications

About 60-80% of patients with myelodysplastic syndromes (MDS) manifest with anemia. Red blood cell (RBC) transfusions are the most commonly used therapy to alleviate anemia in patients that are ineligible for other curative approaches. Transfusion-dependent patients frequently develop iron overload, which correlates with infections, mortality, leukemia, and organopathy. At the subcellular level, long-term iron exposure produces iron-catalyzed hydroxyl radicals that induce oxidative damage to mitochondria and disrupt bioenergetic homeostasis. The use of iron-chelating drugs to counter transfusion-related iron overload remains controversial due to the significant side effects that these agents cause. New therapies that effectively address iron overload in transfusion-dependent MDS patients are clearly needed. Mitochondrial dysfunction frequently occurs during MDS cell maturation and leads to abnormal iron distribution. However, the mechanistic basis of this biological phenomenon has not been rigorously studied. We previously linked the presence of Splicing factor 3b subunit 1 (SF3B1) mutations, which are frequent in patients with refractory anemia with ring sideroblasts (RARS), with abnormalities in mitochondrial iron. Transmission electron microscopy and flow cytometry showed that mitochondria of SF3B1 mutant RARS patients have higher iron content than those of wild type (WT) RARS patients and expressed an increased mRNA level of the iron transporter, Mitoferrin 1. Despite these prevalent mitochondrial abnormalities and transfusional dependence, SF3B1 mutant lower-risk MDS patients experienced significantly longer median survival compared to SF3B1 WT lower-risk MDS patients (34 mos vs. 13 mos; P = .002; N=16 vs. 101). Autophagy is an evolutionarily conserved lysosomal mechanism of protein degradation that plays a critical role in the elimination of damaged mitochondria and other organelles. We hypothesized that autophagic clearance of defective mitochondria may contribute to the superior survival of SF3B1 mutant patients suffering from transfusion-mediated iron overload. We conducted RNA sequencing analyses on a group of fresh bone marrow (BM) cells of SF3B1 mutant and WT RARS patients and healthy donors (n = 11) to investigate the basal autophagy status in this distinct patient population. In addition to confirming increased levels of mitochondrial transporters such as Mitoferrin 1 and 2 (FC = 2.0), we detected a striking increase in multiple genes involved in the proximal and distal regulation of autophagy in cells of SF3B1 mutant RARS compared to WT RARS patients. Genes controlling the early stages of autophagy including the protein kinases ULK1 (FC = 2.0) and ULK3 (FC = 3.9; P=.05), ATG complexes ATG2A/B (FC = 1.9), ATG9A (FC = 5.5; P=.05), ATG18 (FC = 4.8; P=.02) and the cysteine proteases ATG4A/C (FC = 2.0) were all elevated in SF3B1 mutant RARS vs. SF3B1 WT RARS patients. Key components of the late stages of the autophagic degradation cascade, including multiple members of the cathepsin family of lysosomal proteases [CTSL1: FC = 20.9; CTSD: FC = 5.8 (P=.06); CTSB: FC = 2.1; CTSE: FC = 5.9 (P=.01); CTSD: FC = 1.8], were also significantly increased. qRT-PCR confirmed higher expression levels in the BM cells of RARS patients carrying sole SF3B1 mutations compared to cells of SF3B1 WT RARS patients. The link between SF3B1, mitochondrial iron, and elevated autophagy was specific as evidenced by the unmutated status and lack of significant mRNA changes in any other splicing factor genes including PRPF8. Our data demonstrate that autophagy may play an important, previously unreported role in SF3B1 mutant RARS. Based on our findings, we hypothesize that SF3B1 mutant RARS cells stimulate autophagy to eliminate damaged mitochondria and alleviate iron overload and that further stimulation of autophagy will diminish the pathogenic effects of chronic transfusions. We are currently investigating the therapeutic benefit and pharmacodynamics of autophagy-modulating drugs (temsirolimus, metformin, arsenic trioxide) in in vitro (primary cells) and in vivo (SF3B1 haploinsufficient mice) models of MDS to facilitate the design of an investigator-initiated clinical trial that will test autophagy modulation as a new precision strategy for the treatment of transfusion-dependent patients with low-risk MDS carrying SF3B1 mutations. DisclosuresSekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Carew:Boehringer Ingelheim: Research Funding.

Quality of End-of-Life Care for the Myelodysplastic Syndromes: Findings from a Large National Database

Background: End-of-life (EOL) care has been shown to be more intensive for blood cancers compared to solid tumors (e.g. Hui, Cancer, 2014); however, data are sparse regarding predictors of intensive care unit (ICU) use in the last 30 days of life and hospice enrollment among patients with specific hematologic malignancies. Moreover, little is known about EOL care specifically for the myelodysplastic syndromes (MDS), which are distinguished among the blood cancers by their relative indolence in many patients and high rate of transfusion dependence.Methods: We conducted a retrospective analysis using the Surveillance Epidemiology and End Results (SEER)-Medicare database. Patients ≥ 65 years of age who had a primary diagnosis of MDS between 2006 and 2011, lived for at least 30 days after their diagnosis, and died prior to December 31, 2012 were eligible for inclusion. Outcomes were two well-established quality measures for EOL care in oncology (Earle, JCO, 2003; Keating, Cancer, 2010): ICU admission within the last 30 days of life (an indicator of poor quality), and enrollment in hospice for any length of time (an indicator of good quality). After determining their overall prevalence, we fit multivariable logistic regression models to investigate sociodemographic and clinical associations (see table) with each outcome.Results: A total of 6,955 MDS patients were eligible. Overall, 28% were admitted to the ICU in the last month of life, and 49% had enrolled in hospice. In multivariable analyses, transfusion-dependent patients were more likely to be admitted to the ICU and less likely to enroll in hospice (both p<0.001). There was no significant association with marital status or time from diagnosis to death for either outcome. Patients who died in later years had a higher prevalence of ICU admissions (p=0.05) and were more likely to enroll in hospice (p<0.001). Additional multivariable associations are shown below.*Adjusted for all variables listed as well as marital status and time from diagnosis to deathConclusions: Only about half of the MDS patients in our cohort were enrolled in hospice; however, the odds of enrollment increased over time. Interestingly, the odds of ICU admission within the last 30 days of life also increased over time, a trend that has been seen in solid tumors (e.g. Wright, JCO, 2014). As bone marrow failure in MDS can lead to reversible sepsis and the need for temporary blood pressure support, it is difficult to determine if this trend truly represents a worsening in quality of EOL care. Finally, our finding that transfusion-dependent MDS patients were less likely to receive hospice suggests that one reason for suboptimal enrollment is that the current hospice model-which largely disallows transfusions-is not meeting the specific palliative needs of this population. [Display omitted] DisclosuresGore:Celgene: Consultancy, Honoraria, Research Funding. Davidoff:Celgene: Consultancy, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy.

Second international round robin for the quantification of serum non-transferrin-bound iron and labile plasma iron in patients with iron-overload disorders.

Non-transferrin-bound iron and its labile (redox active) plasma iron component are thought to be potentially toxic forms of iron originally identified in the serum of patients with iron overload. We compared ten worldwide leading assays (6 for non-transferrin-bound iron and 4 for labile plasma iron) as part of an international inter-laboratory study. Serum samples from 60 patients with four different iron-overload disorders in various treatment phases were coded and sent in duplicate for analysis to five different laboratories worldwide. Some laboratories provided multiple assays. Overall, highest assay levels were observed for patients with untreated hereditary hemochromatosis and β-thalassemia intermedia, patients with transfusion-dependent myelodysplastic syndromes and patients with transfusion-dependent and chelated β-thalassemia major. Absolute levels differed considerably between assays and were lower for labile plasma iron than for non-transferrin-bound iron. Four assays also reported negative values. Assays were reproducible with high between-sample and low within-sample variation. Assays correlated and correlations were highest within the group of non-transferrin-bound iron assays and within that of labile plasma iron assays. Increased transferrin saturation, but not ferritin, was a good indicator of the presence of forms of circulating non-transferrin-bound iron. The possibility of using non-transferrin-bound iron and labile plasma iron measures as clinical indicators of overt iron overload and/or of treatment efficacy would largely depend on the rigorous validation and standardization of assays.

Variations in erythropoiesis-stimulating agent administration in transfusion-dependent myelodysplastic syndromes impact response

IntroductionErythropoiesis-stimulating agents (ESAs) reduce red blood cell (RBC) transfusions in approximately 40% of patients with myelodysplastic syndrome (MDS) in clinical trials. We studied the association of timing of ESA initiation, agent (epoetin alfa, darbepoetin) and number of weeks of ESA use with response in MDS patients in routine practice. MethodsPatients diagnosed with MDS from 2001 to 2005 were identified in the Surveillance Epidemiology and End Results-Medicare linked database. The study cohort consisted of patients with new-onset transfusion dependence (TD). All patients received an ESA at least once during the study period, which began the week that criteria for TD were met and continued until transfusion independence (TI). Kaplan–Meier statistics and Cox Proportional Hazard models were used to assess relationships between time to ESA initiation, agent and number of weeks of ESA use and TI attainment. ResultsOf 610 TD patients treated with ESAs, 210 (34.4%) achieved TI. Median time from ESA initiation to TI was 13 weeks. Shorter time from TD to ESA initiation and use of darbepoetin were associated with higher probability of achieving TI. The probability of achieving TI decreased beyond 8 weeks of treatment, and was very low beyond 16 weeks (8–15 weeks: HR=0.64, 16–31 weeks: HR=0.25, 32+ weeks HR=0.10). ConclusionsIn this observational, population-based study, variations in ESA administration impacted response in transfusion-dependent MDS patients, with higher response rates with early administration and use of darbepoetin, and low response likelihood in non-responders beyond 16 weeks of therapy.

Deferasirox chelation therapy in patients with transfusion-dependent MDS: a 'real-world' report from two regional Italian registries: Gruppo Romano Mielodisplasie and Registro Basilicata.

Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion-dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large 'real-world' MDS population. One hundred and eighteen patients with transfusion-dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion-dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients.

The Fas Ligand Inhibitor APG101 in Transfusion Dependent Patients with Low Risk MDS: Interim Results from a Phase I Study

Introduction: Myelodysplastic syndromes (MDS) are heterogeneous diseases characterized by clonal, ineffective hematopoiesis resulting in peripheral cytopenia and an increased risk of progression to acute myeloid leukemia. Particularly in low risk MDS a pro-apoptotic milieu has been found with increased levels of apoptosis-promoting factors such as tumor necrosis factor and fas ligand (CD95 ligand). This is thought to be a major pathomechanism in low risk MDS resulting in increased apoptosis of medullary erythroid progenitors leading to peripheral cytopenia. APG101 is a fusion protein consisting of the extracellular domain of human CD95 and the Fc domain of human IgG1. APG101 binds to CD95 ligand expressed on effector cells as well as to functionally active ligand in solution, thus blocking the interaction between CD95 and its ligand. Here, we report on interim results of a phase I study in transfusion dependent low risk MDS patients treated with APG101.Methods: A total of 15 patients have been enrolled by July 30th 2014. All patients gave their written informed consent. Patients were treated for 12 weeks with weekly intravenous infusions of 100 mg or 400 mg APG101, respectively. Thereafter the treatment was discontinued and the patients were followed for another 6 months. Bone marrow biopsies were taken prior to the first APG101 dosing (baseline), at the end of treatment (EOT, week 12), at week 25 (follow up) and at week 37 (follow up). Methylcellulose assays on isolated CD34+ cells from the bone marrow aspirates at the different time points were performed. In addition, bone marrow samples at each time point were subjected to amplicon deep sequencing to detect gene mutations prior to APG101 dosing and to follow the mutational allele burden during and after treatment. This was done by sequencing of genomic DNA from ficollized mononuclear bone marrow cells on a Roche 454 GS Junior system.Results: At data cut-off, 5 patients (3 male) had completed the study. Median age was 77 (range 65-78). WPSS categories were low in 2 patients and intermediate in 3 patients, respectively. According to the exclusion criteria none of the patients showed a medullary blast count ≥ 5%. Two patients received 400 mg weekly while 3 patients received 100 mg APG101 weekly, respectively. All patients stayed on treatment as scheduled and no adverse events were reported so far. Careful evaluation of bone marrow smears as well as immune phenotypic analysis of bone marrow aspirates showed no increase in bone marrow blasts at any time point. Moreover, quantification of the allele burden of pre-existing mutations (mutations of ASXL1 and SF3B1 in one patient and DNMT3A in the other patient) showed no significant expansion of the mutated clones. Ex vivo differentiation analyses revealed an increase in granulocytic colony forming as well as CFU-E/BFU-E forming capacity. With regard to efficacy, 4 of 5 patients showed a decrease in transfusion frequencies, which so far did not fulfill the IWG 2006 criteria for hematologic improvement (HI).Conclusions: APG101 is a well tolerable compound in transfusion-dependent low risk MDS patients, particularly in elderly patients. None of the patients discontinued treatment due to toxicity. Monitoring did not reveal any signs of progress i.e. increase in medullary blasts in any of the patients. Deep amplicon sequencing did not show any signs of expansion of preexisting clones during therapy, i.e. APG101 did not provide malignant clones with a survival benefit. Although no major or minor HI (IWG 2006) was seen in 5 analyzed patients, the majority of patients showed a slight reduction in transfusion need which makes APG101 an interesting target for further investigation. DisclosuresKunz:Apogenix GmbH: Employment. Fricke:Apogenix GmbH: Employment. Nolte:Apogenix GmbH: Consultancy, Research Funding.

International Comparison Study of Toxic Iron Assays in Patients with Iron Overload Disorders

Background:Imbalances in iron homeostasis result in a variety of disorders. Excess iron accumulates in the circulation and tissues of patients with hereditary hemochromatosis (HH), iron-loading anemia (β-thalassemia major and intermedia (Thal), myelodysplastic syndromes (MDS) and sickle cell disease after transfusion (SCD). To prevent iron-induced tissue damage, detection of impending iron toxicity is needed before complications develop and become irreversible. Plasma non-transferrin bound iron (NTBI) and its labile (redox active) component (LPI) are thought to be potentially toxic forms of iron identified in the serum of patients with iron overload.Objective:To increase our insights into NTBI and LPI concentrations measured by the current worldwide leading analytical assays in four different categories of iron overloaded patients (HH, Thal, MDS, transfused SCD) undergoing various treatments (phlebotomies, iron chelation, red blood cell transfusions).Methods:We compared 10 different assays (5 NTBI, 1 NTBI isoform specific and 4 LPI) as part of an international inter-laboratory study. Serum samples were from 60 patients with 4 iron overload disorders. Serum samples were split into two aliquots, coded (blinded), stored at -80°C and shipped for analysis to 5 different laboratories worldwide. Laboratories performed duplicate measurements on each aliquot of a serum sample on 2 different days, resulting in a total of 4 measurements for each sample. Some laboratories provided multiple assays.Results:NTBI and LPI measurements in the serum of iron-overloaded patients showed good reproducibility with a high between-sample (range 67.1-97.2%) and a low within-sample variance (0-2.2%) relative to the total variance of each assay. Absolute NTBI and LPI levels differed considerably between assays. Four assays (2 LPI and 2 NTBI) also reported negative values. LPI levels were ± 10% of the NTBI levels. Highest levels were observed in patients with naive HH and naive Thal intermedia, transfusion-dependent MDS and transfusion-dependent Thal major. These 4 patients groups also had the highest transferrin saturation (TSAT) levels, but only 3 of them were among the groups with the highest ferritin levels. Eight (4 LPI and 4 NTBI) of the 10 assays could discriminate well between iron overload diseases.In general correlations were highest within the same group of NTBI or LPI assays. Interestingly, one of the LPI assays showed better correlations with NTBI assays (range rs=0.85-0.90) than with the other LPI assays (range rs=0.61-0.77). In contrast, one of the NTBI assays showed better correlations with LPI assays (range rs=0.67-0.75) than with the other NTBI assays (range rs=0.50-0.59). The assays show a hyperbolic relation with TSAT; NTBI and LPI concentrations only substantially increase above a certain TSAT level of ~70% and ~ 90%, respectively. This is illustrated for both a representative NTBI (Figure 1A) and LPI assay (Figure 1B). This relation does not exist between any of the assays and ferritin (Figure 1C,D).Conclusions:While NTBI and LPI values of various assays are well correlated and discriminate between iron overload disorders, absolute values differed considerably between assays. Both standardization of assays and clinical outcome studies to determine clinically relevant toxic thresholds are needed. At present TSAT may provide a useful alternative in the clinical management of patients with iron overload. [Display omitted] DisclosuresDe Swart:Novartis Europe: Research Funding. Swinkels:Novartis Europe: Research Funding.

Prophylactic Rh and Kell Antigen Matching Significantly Decreases Rates of Alloimmunization in Transfusion Dependent MDS Patients

Background: 40-80 % of patients with myelodysplastic syndrome (MDS) become transfusion dependent during their disease course and are at risk for the development of alloimmunization. Red blood cell (RBC) alloantibodies can make finding compatible blood for transfusion more difficult, expensive and time consuming. Allommunization rates of approximately 30-47% have been reported in patients with sickle cell disease and the transfusion of RBCs prophylactically matched for Rh antigens E and C, and K antigens reduced the rate of alloimmunization from 3% to 0.5% per unit (Vichinsky et al, 2001). In 2007, our hospital instituted a policy of transfusing prophylactic Rh and K matched blood to MDS patients. The objectives of this study were to compare the rates of alloimmunization in MDS patients who received prophylactic Rh and K matched blood compared to those that did not and identify potential risk factors for alloimmunization. Methods: 193 Transfusion dependent MDS patients were identified out of 387 patients registered and prospectively followed in a local MDS registry. Transfusion dependence was defined as the receipt of at least 1 unit of PRBC every 8 weeks for a minimum of 16 weeks. Records of transfusions received up to May 1, 2014 were collected from blood bank databases of the hospitals at which patients were transfused. Patients were classified according to whether phenotyping had been performed, the location of transfusions (transfused only at our institution, transfused only at an outside institution or transfused at both sites) and whether prophylactic Rh (E, C antigens) and K matched blood was transfused. Data were descriptively analyzed and we conducted univariate and multivariate logistic regression using p< 0.05 as statistically significant to identify risk factors for alloimmunization.Results: 176 MDS patients with complete transfusion records are included, 73 transfused at Sunnybrook, 92 transfused in community hospitals and 11 at both. The median age was 72 yrs (range 22-89), 60% were male, and 8%, 43% and 27% had very low, low and intermediate risk R-IPSS scores respectively. Median follow up was 2.9 years (IQR 1.6-5) 3.49 SD). Blood groups O, A, B, AB and O were 45%, 38%, 15% and 2% respectively, while 85% were RhD+. The median time from diagnosis until first transfusion was 4 months (IQR: 0.2-14), with 51 patients having received at least 1 transfusion prior to diagnosis at a median time of 0.9 months. 4.5% had a pre-existing allo-antibody at time of MDS diagnosis. With a median follow up from diagnosis of 3 years (IQR:1.6-5)), the median number of RBC units transfused was 38 (IQR: 15-98)) and 36 (20%) patients developed new alloantibodies (median 2 (IQR (1-2.5) alloantibodies). The median number of RBC units until first allo antibody was 13.5 units (range 0-121) and 1.25 years from diagnosis (95% CI:0.4-2.1). The majority of the alloantibodies were in the Rh (n=28) and K (n=14) groups (80%) and co-existed 27% of the time. More patients transfused at our hospital received prophylactic Rh K matched blood sometimes or always (60% versus 26%) and rates of allo-immunization were decreased by 65% (absolute rate of alloimmunization 10% versus 29%). By multivariate analysis analysis, number of rbc transfused (p<.0001), receiving prophylactic phenotype matched blood (p=.0008) and location of transfusions (Sunnybrook versus elsewhere (p=.03)) were independent risk factors for alloimmunization.Conclusions: 20-30% of RBC transfusion dependent MDS patients will become allo-immunized to clinically significant blood group antigens, the majority being Rh and K antigens. The practice of phenotyping at baseline and prophylactically transfusing Rh and Kell matched blood decreases rates of alloimmunization up to 65% and should be strongly considered for routine transfusion practice in centres that treat MDS.Table 1All Patients (n=176)Sunnybrook (n=73)Community(n=92)Ever phenotyped45%64%28%Phenotyped before 1st transfusion20%38%8%Developed allo-antibodies20%10%29%Received prophylactic Rh K matched blood(developed alloantibodies)NeverSometimesAlways58% (16%)24% (42%)18% (6%)40% (3%)23% (23%)37% (7%)74% (22%)22% (60%)4% (0%) [Display omitted] DisclosuresWells:Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Buckstein:Celgene: Research Funding.

A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML.Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards.Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone.Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination.TablePatient IDDiagnosisPrior HMA% Blasts in BM at Baseline% Blasts in BM after TreatmentIWG Response1MDSNo21CRi2AMLNo400CRi3AMLNo22N/ANE4MDSAzacitidine00NE5AMLNo59N/ANE6MDSNo21<5CRi7MDSNo21CR8MDSNo2.52SD9AMLDecitabine25N/ANE10MDSDecitabine123CRi11CMMLAzacitidine23SD12MDSAzacitidine41HI-E13AMLAzacitidine4740TE14AMLDecitabine77TE15MDSNo95TE16AMLNo256TE17AMLNo1519TE18AMLAzacitidine6445TEIWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early DisclosuresWilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

Use of Deferasirox in Transfusion-Dependent Myelodysplastic Syndromes with Iron Overload

SUMMARY In myelodysplastic syndromes (MDS), transfusion-dependent anemia has been established as an independent risk factor for decreased survival. Although evidence from prospective studies is still lacking, several guidelines recommend iron-chelating therapy in MDS patients with a longer life expectancy. With the recent introduction of deferasirox, an oral active iron-chelating drug, which has shown dose-dependent efficacy and acceptable tolerability, this therapeutic option has become feasible even in the elderly. Several retrospective and prospective studies showed that in MDS patients deferasirox is effective in reducing iron burden and in maintaining the circulating toxic iron fraction within the normal range. Moreover, in a substantial fraction of patients treated with deferasirox a significant improvement of peripheral cytopenias may occur.

Clinical Reasoning: A 68-year-old man with a first presentation of status epilepticus

A 64-year-old man with transfusion-dependent myelodysplastic syndrome (MDS), hypertension, chronic obstructive pulmonary disease, hypothyroidism, blindness from treated syphilitic chorioretinitis, and no prior seizure history presented in generalized status epilepticus. His daily home medication regimen included prednisone 20 mg (chronic therapy for MDS), diltiazem 120 mg, digoxin 250 μg, tiotropium 80 μg, and levothyroxine 112 μg. On admission he was febrile to 39.9 °C and in atrial fibrillation with rapid ventricular rate. Initial hematologic profile showed 11,910 leukocytes/mm(3) (12% immature forms, 46% neutrophils, 32% lymphocytes), hematocrit of 30.8%, and platelet count of 215,000/mm(3), with an otherwise normal serum chemistry.

Adequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients with lower risk myelodysplastic syndromes

Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of iron overload and associated organ damage, and death. Emerging evidence indicates that iron chelation therapy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especially those classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1). Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centers in Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 μg/L. Of the 80 chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox following deferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patients chelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiac mortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1 years for non-chelated patients (p<0.001). For patients chelated ≥6 m or patients classified as adequately chelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusion intensity (HR=1.08, p=0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m (HR=0.24, p<0.001). Six or more months of adequate ICT is associated with markedly better overall survival. This suggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS.

Long-term hematological response in a patient with 5q- syndrome after suspension of lenalidomide therapy and further improvement with deferasirox therapy.

Long-term hematological response in a patient with 5q- syndrome after suspension of lenalidomide therapy and further improvement with deferasirox therapy.

Review Of Published Survival Evidence For Iron Chelation Therapy (ICT) In Patients With Myelodysplastic Syndromes (MDS)

Iron overload due to frequent blood transfusions in patients with myelodysplastic syndrome (MDS) is associated with complications, including a risk of cardiac disease and transformation to acute myeloid leukaemia (AML). Iron chelation therapy (ICT) with deferasirox and desferrioxamine is an essential part of the management of iron overload in low and intermediate prognostic risk MDS patients [NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes; Bennett 2008]. However, despite the risks of cardiac complications and AML, prior to 2009 there was little published evidence that ICT could improve survival outcomes in patients with MDS. A PubMed and ASH abstract search (conducted July 2013) has revealed a growing body of evidence indicating increased survival of a median of 2 – 6 years in transfusion-dependent MDS patients treated with ICT, relative to patients without ICT (see Table).All the published evidence for survival benefit is in lower IPSS risk MDS patients, with a significant survival benefit seen in the sub-group of patients with non-RARS (Leitch 2012). The main limitation of the studies is that they are all based on retrospective or prospective observational study designs; hence have a risk of selection bias, although many utilize multivariate techniques to control for confounding factors. Furthermore, none of the studies assess survival associated with type of ICT although there is an ongoing RCT (TELESTO) addressing the impact of deferasirox on OS in low risk MDS patients. In addition, it would be useful to explore whether the observational data from each study could be pooled to assess OS outcomes in transfusion-dependent lower risk MDS, by MDS sub-group and by type of ICT. In conclusion, there is now extensive evidence of an association between ICT and survival improvement in transfusion-dependent lower prognostic risk MDS patients. Disclosures:Tolley:Tolley Health Economics: Consultancy. Off Label Use: ICT for patients with iron overload due to blood transfusion in patients with MDS. Vieira:Novartis: Employment. Strickson:Tolley Health Economics: Consultancy. Kundishora:Novartis: Employment.

Lenalidomide Treatment For Lower Risk Non-Deletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Prior To Azanucleosides

▪ IntroductionLenalidomide (LEN) is the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndromes (MDS) with chromosome 5q deletion (del 5q). In the MDS-002 study, 26% of lower risk transfusion dependent MDS patients became red blood cell transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment alternative for transfusion dependent anemia in lower risk non-del 5q MDS after azanucleosides failure. The response rate to LEN after azanucleosides failure, however, is not known given that the MDS-002 study preceded FDA approval of azanucleosides. To address the best sequence of LEN to optimize response potential in lower risk MDS, we examined the response rates to LEN in non-del 5q lower risk MDS when offered as first line after (erythroid stimulating agents) ESA's or after azacitidine failure. MethodsThis was a retrospective study conducted using the Moffitt Cancer Center (MCC) MDS database. We identified patients with lower risk MDS who received both LEN and azacitidine as first or second line therapy after erythroid stimulating agents. Lower risk MDS was defined according to the international prognostic scoring system (IPSS) Low or intermediate-1 (int-1) risk groups. The primary endpoint was to compare rates of erythroid hematological improvement (HI-E) between the group of patients who received LEN as first line therapy followed by azacitidine as second line (LEN 1st line group) and those who received LEN as second line therapy after azacitidine (LEN 2nd line group). HI was defined according to international working group criteria (IWG 2006). Chi- square test was used for categorical variables, T-test was used for continuous variables, and Kaplan Meier estimates for overall survival. All analyses were conducted using SPSS statistical software (IBM version 21) ResultsWe identified 63 patients who received both azacitidine and LEN as first and second line where 37 patients were in group 1 (LEN 1st line) and 26 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table-1. There were no statistically significant differences between the 2 groups in terms of mean age at diagnosis, gender, WHO subtype, revised IPSS, or mean blood counts. The majority of patients had refractory cytopenia with multilineage dysplasia (RCMD) and had low risk revised IPSS .Table-1Baseline characteristicsLen 1st line(n=37)Len 2nd line(n=26)P-valueAGEMean66.365.70.85GenderMale26 (70%)18 (69%)0.6Female11 (30%)8 (31%)WHO subtypeRARARSRCMDRAEB-1CMMLMDS/MPN4 (11%)9 (24%)14 (38%)5 (14%)2 (5%)3 (8%)4 (15%)7 (27%)13 (50%)1 (4%)1 (4%)00.3Revised IPSSVery lowLowIntermediateHighVery High4 (11%)20 (57%)8 (23%)3 (9%)05 (19%)17 (65%)3 (12)01 (4%)0.25CBCHgb (g/dl)PlateletsANC9.12362.89.12332.30.90.90.47The rate of HI-E was 38% (n=14) among LEN 1st line group compared to 12% (n=3) in LEN 2nd line group. (p=0.04). There was no difference in overall survival (OS) among the two groups with a median OS of 104 months and 87 months, respectively, p=0.55. There was no difference in AML transformation rate, 5.4% (n=2) and 11% (n=3) among the two groups, respectively, p=0.33. There were no differences in response rates to azacitidine among the two groups. Among the Len 1st line group response to 2nd line azacitidine was 38% (n=14) compared to 35% (n=9) among those who received azacitidine as first line followed by LEN as 2nd line. (p=0.69). ConclusionLEN yields a higher rate of HI-E in non-del 5q lower risk MDS when used as first line therapy. If validated in a larger cohort, LEN should be considered for 1st line therapy after ESAs rather than after azacitidine failure. Responses to azacitidine were similar among the two groups, indicating no adverse effect of LEN on azacitidine response. Disclosures:Komrokji:Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Oral Rigosertib (ON 01910.Na) Treatment Produces An Encouraging Rate Of Transfusion Independence In Lower Risk Myelodysplastic Syndromes (MDS) Patients; A Genomic Methylation Profile Is Associated With Responses

▪Rigosertib, a novel orally bioavailable small molecule inhibitor of PI3-Kinase and PLK1 pathways, was tested in a phase II study in lower risk (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. This randomized, two-arm study administered rigosertib (560 mg bid) either intermittently (2 out of 3 weeks) or continuously to transfusion-dependent patients (4 units RBC transfusions over 8 weeks). Erythrocyte stimulating agents (ESAs) were allowed on study. Forty eight patients have been enrolled as of August 2nd, 2013 and another 12 patients will be enrolled. Continuous dosing was stopped after 9 patients due to a higher urinary toxicity resulting in 39 patients receiving intermittent dosing. Overall the drug was well tolerated, except for reversible grade 3 urinary toxicity (dysuria, hematuria, cystitis, and urinary urgency) in 6/48 (12%) patients while 17/48 (35%) experienced grade 2 urinary toxicity. Notably, no significant treatment emergent myelosuppression was evident in these patients. Dosing has been modified to a total daily dose of 840 mg (560 mg am/280 mg afternoon) to improve urinary tolerability. Other measures to manage urinary symptoms include hydration, sodium bicarbonate and dose reduction or interruption. Of 33 patients (3 with del5q) on intermittent dosing treated for at least 8 consecutive weeks, 15 (45%) achieved transfusion independence (TI or no RBC transfusion for at least 8 consecutive weeks) lasting 8 to 53+ weeks (median=17 weeks). Intent-to-treat analysis showed 17/48 (35%) patients achieved TI. Twelve of 15 responding patients were refractory to prior treatment with ESAs. Fourteen of 15 responding patients (11 out of 12 ESA refractory) received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance or potential synergy with ESA. These effects are being explored in additional trials now in planning.There was no obvious correlation of response to karyotype or other classifications. We hypothesized that DNA methylation profiles could help explain the differences between responders and non-responders. Pre-therapy bone marrow mononuclear cells from 32 patients (including 4 from the prior Phase I study previously reported in ASH 2011) were analyzed using the Illumina 450K methylation array platform. Seven had complete response or CR (TI + increase in Hb >2Gm/dL), 10 had partial response or PR (TI without Hb increase) and 15 had no response or NR. Supervised hierarchical clustering by methylation intensity demonstrated a distinct profile associated with complete responders. Bisulfite sequencing (which allows quantification of multiple consecutive CpGs in an amplicon) of several differentially methylated loci confirmed the Illumina 450K data. In general, hypermethylation of a group of genes was associated with responders. Functional annotation of the hypo and hypermethylated genes which best distinguished CRs from NRs showed that the genes most affected by methylation were related to regulation of transcription followed by genes involved in cell-cell adhesion, inflammatory response, apoptosis and proliferation. Additional patient samples are being analyzed to confirm these results. In this interim analysis the observed correlation of hematological response to genomic methylation status suggests the possibility of preselecting patients likely to benefit from treatment with rigosertib. ConclusionsIntermittent dosing of oral rigosertib is well tolerated and active in producing transfusion independence in lower risk MDS patients. A genomic methylation signature, once confirmed in prospective studies, may allow pre-selection of responders. Disclosures:Raza:Onconova Therapeutics: Research Funding. Al-Kali:Onconova Therapeutics: Research Funding. Tibes:Onconova Therapeutics: Research Funding. Spitzer:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Mukherjee:Onconova Therapeutics: Research Funding.

Health-Related Quality Of Life In Transfusion-Dependent Patients With Myelodysplastic Syndromes Treated With Deferasirox. A Multicenter Prospective Study

BackgroundAnemia is a common symptom in patients with Myelodysplastic Syndromes (MDS) and although erythropoietic agents are often active, it is frequently treated with red blood cell (RBC) transfusions. A substantial proportion of patients might also eventually become transfusion-dependent and, Iron-chelating therapies might be important to minimize complications of iron overload. ObjectivesTo investigate the impact of deferasirox therapy on health-related quality of life (HRQOL) of lower risk transfusion-dependent MDS patients over a one year period. Secondary objectives were to investigate relationships between HRQOL and ferritin levels and to explore the prognostic value of baseline HRQOL on the probability of achieving transfusion independence. Patients and MethodsThis was a prospective study whose clinical findings (i.e., primary endpoint was safety and tolerability) were previously reported. HRQOL was a secondary endpoint of the study and we herein report, for the first time, HRQOL prospective findings. Eligible patients included: MDS patients 18 years or older, International Prognostic Scoring System (IPSS) low or intermediate-1 risk and diagnosed with transfusional siderosis following a minimum of 20 blood transfusions. Patients received daily oral deferasirox at a dose between 10 and 30 mg/kg of body weight for a period of 1 year. HRQOL was assessed with the EORTC QLQ-C30. HRQOL at baseline and at 3, 6, 9 and 12 months after treatment start. The EORTC QLQ-C30 consists of 30 items and includes five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The mean trend of HRQOL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Such covariance structure provided the best model fit among those investigated. ResultsOverall, 159 patients were screened at 37 centers. The median duration of disease at enrollment was 32 months and median number of units of packed RBC received was 37. Seven patients did not start treatment at all and thus there were 152 expected HRQOL forms at baseline assessment. Out of these, 146 patients returned the questionnaire yielding a baseline compliance of 96%. No statistically significant differences over time were found for any scale of the EORTC QLQ-C30. Figure 1 depicts mean scores over time for selected scales of: fatigue, physical functioning, pain and global HRQOL. No HRQOL differences were found between patients with serum ferritin levels lower or higher than 2000 μg/L (pretreatment median value) at baseline. Also, the possible impact of ferritin level on HRQoL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Coefficients and p values are reported in table 1. The prognostic impact of baseline HRQOL on the probability of achieving transfusion independence (i.e., defined as freedom from transfusion for 3 consecutive months) was investigated. Higher severity of pain (P=0.007) was associated with a greater likelihood of achieving transfusion independence. Multivariate analysis, controlling for age, IPSS risk score, time from diagnosis, number of previous blood transfusions and baseline ferritin level confirmed the independent value of pain (P=0.003). [Display omitted] Table 1Impact of ferritin level (μg/L) on HRQoL over time.EORTC QLQC30 scalesβPPhysical functioning-0.000970.1444Role functioning-0.001640.0687Emotional functioning-0.000840.1957Cognitive functioning-0.001660.0071Social functioning-0.001230.1385Global health status/QoL-0.000570.4463Fatigue0.0009980.1887Nausea/Vomiting0.0001160.7724Pain0.0003830.6626Dyspnea0.0011830.1891Insomnia-0.000560.5171Appetite loss0.0001890.8143Constipation0.0008580.3019Diarrhea0.0003140.6131 ConclusionCurrent findings suggest that Deferasirox therapy does not decrease HRQOL in lower risk transfusion-dependent MDS patients. Patients with higher baseline pain severity seems more likely to achieve transfusion independence and further analysis is needed to understand underlying reasons. Disclosures:No relevant conflicts of interest to declare.

Infiltrative acute myeloid leukaemia as a cause of acute kidney injury.

A 75-year-old male was admitted for investigation of acute kidney injury. His medical history was significant for hypothyroidism and transfusion-dependent myelodysplastic syndrome. A bone marrow biopsy 1 month prior to admission had categorized him as having refractory anaemia with excess blasts (RAEB) Stage-II. His medications included thyroxine, cholecalciferol and the cytotoxic agent azacitadine. Over the preceding 6 months, he had noticed progressive lethargy, loss of weight and functional decline. Examination was unremarkable. Biochemistry demonstrated a serum creatinine level of 350 µmol/L, which had markedly worsened over 2 months. This was associated with 1.06 g/day proteinuria but no haematuria. Haematology showed normocytic anaemia (Hb 70 g/L), thrombocytopaenia (Plt 48 × 109/L) and marked leucocytosis (WCC 38.8 × 109/L). Dysplastic changes and occasional blasts were noted on the blood film (Figure 1). Serum protein electrophoresis, uric acid, autoimmune studies, hepatitis and HIV serology were unremarkable. Ultrasound demonstrated normal-sized kidneys of normal echogenicity and no evidence of obstruction. Fig. 1. May–Grunwald–Giemsa staining of the peripheral blood film shows pleomorphic population of blasts with an open chromatin and high nuclear:cytoplasmic ratio (thick arrows). Dysplastic neutrophils are also noted with abnormal segmentation ... A renal biopsy was performed, which showed renal cortex with heavy infiltration of atypical cells within the interstitium and lumina of small vessels. These cells had irregular nuclear membranes, prominent nucleoli and granular cytoplasm, and showed positive immunoperoxidase staining with myeloperoxidase, confirming the diagnosis of acute myeloid leukaemia (AML) with renal infiltration (Figures 2 and ​and33). Fig. 2. Highly cellular infiltration in the renal interstitium, atypical myeloid blasts with irregular nuclear membranes, prominent nucleoli and granular basophilic cytoplasm (H&E ×200). Fig. 3. Positive immunohistochemical staining for myeloperoxidase (MPO IHC ×100). A repeat bone marrow biopsy was subsequently performed which showed transformation into AML. The cause of the progressive kidney dysfunction was thus attributed to renal infiltration from AML. In view of the patient's poor prognosis and functional state, community-based palliative care was instituted. He passed away several weeks later. Malignant infiltration of the kidneys as a cause of renal failure has been well described [1–3]. The commonest causes are low-grade non-Hodgkin's lymphoma and acute lymphocytic leukaemia [4]. AKI due to diffuse kidney infiltration from AML has been reported in the setting of other precipitants [5]. Our case is unique, in that it demonstrates acute kidney injury resulting directly from malignant infiltration of renal parenchyma from AML. Conflict of interest statement. None declared.

Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.

7031 Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.

Utilization Patterns of Iron Chelation Therapy in Transfusion-Dependent Myelodysplastic Syndrome Patients Enrolled in Medicare Part D.

AbstractAbstract 3178 Background:Anemia is present in up to 90% of patients (pts) with myelodysplastic syndromes (MDS), with as many as 40% developing red blood cell (RBC) transfusion-dependency. Though studies have reported clinical utility of iron chelation therapy (ICT) in MDS pts, its impact on overall survival from prospective studies is yet to be demonstrated. Reflective of this therapeutic equipoise and lack of uniform recommendations in the published guidelines, clinical utilization practices vary significantly. To better understand the utilization patterns of ICT, we conducted a retrospective analysis of a large transfusion-dependent MDS cohort enrolled in Medicare Part D from 2005 to 2008. Methods:MDS pts were identified using ICD-9 CM codes (1 inpatient or 2 outpatient) from a 100% Medicare sample. Pts meeting a minimum transfusion threshold of cumulative 20 packed RBC were considered “ICT eligible”. The study cohort consisted of ICT-eligible pts enrolled in Medicare Part D, allowing characterization of oral drug use. The observation period began the week (wk) after pts met the transfusion threshold and lasted until death or end of study. Transfusion use was captured based on specific Health Care Common Procedure Coding System (HCPCS) or revenue codes. Use of drugs, including ICT, was captured using specific HCPCS and National Drug Code (NDC) codes in Medicare Part B and D claims. Age at MDS diagnosis, race, and sex were determined from Medicare enrollment files. Logistic regression models were used to identify correlates of ICT use. Results:Among 125,290 MDS pts, 12,691 met the minimum transfusion threshold and were considered ICT eligible. Of those, 5,079 (40%) were enrolled in Medicare Part D and constituted the study cohort. In the study cohort, 65.6% of pts were ≥75 years old, 90% white, 47.8% males, and 13.9% had a poor predicted performance status (PS). MDS was classified as low-risk in 13.1%, 5q deletion-associated in 2.1%, high-risk in 6.9%, and not otherwise specified (NOS) in 77.9%. Common comorbidities included coronary artery disease (47.9%), congestive heart failure [CHF] (43.6%), cardiac conduction disorders or arrhythmias (44%), and renal disease (35.5%). The median follow-up was 95 wks (range 2–208). Pts were transfused a median of 13 (range 0–369) additional RBC units during the observation period. Among the entire study cohort, 793 patients (15.6%) received ICT; 513 (10.3%) received only deferasirox (DFX), 187 (3.8%) received only deferoxamine (DFO), and 93 (1.9%) received both. Median time from cohort entry to ICT initiation was 18 wks. The average dose for DFO was 2,932 mg/wk and for DFX, 1300 mg daily, relative to recommended levels of 10,000–14,000 mg/wk for DFO and 1,000–2,000 mg/daily for DFX. Median ICT therapy duration was 11 wks (1–168) for DFO, and 19 wks (1–139) for DFX. ICT was received for <26 wks in 60% of DFO and 57% of DFX users. Among ICT users, 71%, 37%, and 21%, received erythropoiesis-stimulating agents, hypomethylating agents (HMAs) and lenalidomide, respectively, during the observation period. No significant differences in ICT use were seen between low-risk, 5q deletion, and high-risk MDS pts (13.9% vs. 11.5% vs. 15.8%, P=0.52). In multivariate analysis using Cox proportional hazard models, the following were negatively associated with probability of receiving of ICT: age ≥ 90 years (Hazard ratio [HR] 0.557, 95%CI 0.347–0.894), female gender (HR 0.781, 95%CI 0.672–0.906), poor predicted PS (HR 0.725, 95%CI 0.541–0.972), history of CHF (HR 0.817, 95%CI 0.679–0.982), cardiac conduction disorders and arrhythmias (HR 0.824, 95%CI 0.694–0.979), and renal disease (HR 0.758, 95%CI 0.632–0.910). The likelihood of receiving ICT was higher among African American pts relative to whites (HR 1.579, 95%CI 1.157–2.156), residents of the South 2000 Census region (HR 1.27, 95%CI 1.005–1.604), and those pts receiving HMAs (HR 1.026, 95%CI 1.018–1.033) or lenalidomide (HR 1.007, 95%CI 1.003–1.012). Conclusions:Overall, ICT utilization rates among elderly transfusion-dependent MDS pts and among those with significant comorbidities were low. Also, ICT therapy was more likely to be of short duration among the elderly. Utilization rates were higher for DFX than DFO, and doses closer to recommended levels for DFX than DFO, likely reflecting greater ease of administration. Disclosures:Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Sasane:Novartis Pharmaceuticals: Employment. Paley:Novartis: Employment. Davidoff:Celgene: Equity Ownership, Research Funding; National Institutes of Health: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.