ALBERT

Description: Abstract 4155 Beyond the conventional criteria of lymphoma classification (integrated clinical, morphological, immunophenotypic, and molecular features) additional markers are still required for a more precise differential diagnosis and a better understanding of lymphoma pathogenesis. MicroRNAs (miRNA) are non-coding small RNAs that play an important role in gene expression regulation, contributing to cell differentiation and tumorigenesis. Specifically, miRNAs have been already described to play a relevant role in B cell differentiation, and in some cases proposed to constitute lymphoma-type specific markers and possible therapeutic targets. We explore the potential diagnostic application of miRNA expression in a large series of 147 cases including all B-cell non-Hodgkin lymphomas (NHL) major types and appropriate controls. As an example of a practical application, data were also used to identify miRNAs differentially expressed when comparing Burkitt Lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) in paraffin-embedded samples. Each lymphoma type (BL, CLL, DLBCL, FL, MCL, MZL/MALT, NMZL and SMZL) was compared to the whole series of NHL by Significant Analysis of Microarray (SAM) method. The analysis identified a set of 128 characteristic miRNAs (FDR1.5 log2). All lymphoma types were characterized by specific miRNA signatures, reflecting cell of origin and/or discrete oncogene alterations. Of interest is also the comparison with reactive lymphoid tissues, since it revealed a specific B-cell lymphoma miRNA profile, which includes a cluster of downregulated miRNAs, such as let7 family, miR-1 and miR-200 family. Burkitt Lymphoma was also directly compared to DLBCL, and 43 miRNA selected by SAM analysis were studied in a new series of 28 BL and 43 DLBCL samples using quantitative RT-PCRIn this second step, the differential expression of a set of 19 miRNAs was confirmed between BL and DLBCL. (FDR 〈 0.05 after t-test (limma)). These findings expand the potential diagnostic markers in lymphoma diagnosis and provide useful information on lymphoma pathogenesis. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1339 There is conflicting data on the capacity of single-unit UD-UCBT to achieve stable engraftment. Moreover, criteria for UCB unit selection in adults with hematologic malignancies undergoing sUCBT are mainly based on registry studies that in most cases lack homogeneity in patient selection and management, analyse pooled data from adults and children with benign conditions and malignant disorders, and lack of specific information on potentially relevant characteristics of the UCB unit. The aim of the present study was to identify by multivariate analysis relevant prognostic factors of myeloid engraftment in a large series of adults with high-risk hematologic malignancies undergoing sUCBT after myeloablative conditioning at a single institution. One hundred and seventy-eight consecutive patients (112 males, 66 females) with median age 32 yr (range, 15–52) who underwent single-unit UD-UCBT after myeloablative conditioning at Hospital Universitario La Fe from 1997 until 2010 were included in the analysis. One hundred and twenty-four patients (70%) had acute leukemia (62 AML, 62 ALL) while the remaining 54 patients (30%) had a variety of high-risk hematological malignancies. Disease stage at transplantation by CIBMTR criteria was early in 75 (42%), intermediate in 44 (25%) and advanced in 59 (33%). Conditioning regimen consisted of thiotepa, busulfan (oral, 43; IV, 135), cyclophosphamide (72) or fludarabine (106), and anti-thymocyte globulin. Cyclosporine and prednisone (128) or cyclosporine and mycophenolate mofetil (50) were used for graft-versus-host disease (GVHD) prophylaxis. Most patients (94%) received an HLA-mismatched single UCB unit with 1 (29%), 2 (64%) or 3 (1%) mismatches with the recipient. The median number of total nucleated cells (TNC) was 2.9 × 107/kg (range, 1–7.5) at cryopreservation and 2.4 × 107/kg (range, 1–5.9) at infusion. Median number of CD34+ cells was 1.6 × 105/kg (range, 0.2–6.6) at cryopreservation and 1.2 × 107/kg (range, 1–5.9) at infusion. Eight patients died early without engraftment and five had primary graft failure. The remaining 165 patients experienced myeloid engraftment with full donor chimerism at a median time of 22 days (range, 11 – 57) and the cumulative incidence (CI) of myeloid engraftment at 57 days was 93%. Disease stage at time of transplantation was the only transplant or patient-related characteristic affecting engraftment. The CI of myeloid engraftment for patients transplanted in advanced and non- advanced stage was 86% and 96%, respectively (P = 0.002). All other variables with an influence on neutrophil recovery were related to UCB unit cell content. Cell dose information at time of freezing offered by UCB banks and that obtained at time of infusion were analyzed separately. For variables considered at time of UCB unit selection (data provided by UCB banks), only CD34+ cell dose with a best cut-off at 1.5 × 105/kg had a statistically significant and independent impact on multivariate analysis. CI rates of myeloid engraftment for patients receiving UCB units with CD34+ cells above and below 1.5 × 105/kg, were 96% and 90% respectively (P = 0.003). At time of infusion, cell dose measurements showing a significant and independent influence on myeloid engraftment in multivariate analysis were CD34+ cell dose with a best cut-off at 1 × 105/kg (P 〈 0,01), CFU-GM with a best cut-off at 2 × 104/kg (P 〈 0,01) and lymphocyte dose with a best cut-off at 1 × 107/kg (P 〈 0,01). Neither TNC dose at cryopreservation or at infusion nor degree of HLA disparity between the UCB unit and the recipient had any impact on myeloid engraftment.These results confirm that sUCBT after busulfan-based myeloablative conditioning offers high rates of myeloid engraftment in adults with hematological malignancies. UCB cell dose, especially CD34+ cell dose, is the most important predictor of engraftment in adults with hematologic malignancies undergoing sUCBT. CD34+ cell dose at cryopreservation provided by UCB banks, although not fully standardized, offers more valuable information than TNC dose and should be used for UCB unit selection. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4134 Gene expression profile (GEP) allows to distinguish two groups with different origin in patients with diffuse large B-cell lymphoma (DLBCL): germinal-center (GC) and activated (ABC), with the latter having a significantly poorer outcome. However, GEP is a technique not available in current clinical practice. For this reason, attempts to reproduce GEP data by immunophenotyping algorithms have been made. The aim of this study was to apply the most popular algorithms in a series of patients with DLBCL homogeneously treated with immunochemotherapy, in order to assess the correlation with GEP data and their usefulness to predict response and outcome of the patients. One hundred fifty seven patients (80M/77F; median age 65 years) diagnosed with DLBCL in 5 institutions of the Grup per l'Estudi dels Limfomes de Catalunya I Balears (GELCAB) during a 5-year period, treated with Rituximab-containing regimens (in most cases, R-CHOP), in whom histological material to construct a tissue microarrays (TMA) was available, constituted the subjects of the present study. Four algorithms were applied: Colomo (Blood 2003, 101:78) using CD10, bcl-6 and MUM1/IRF4; Hans (Blood 2004, 103:275) using CD10, bcl-6 and MUM1/IRF4; Muris (J Pathol 2006, 208:714) using CD10 and MUM1/IRF4, and Choi (Clin Cancer Res 2009, 15:5494), using CD10, bcl-6, GCET1, FOXP1 and MUM1/IRF4. The thresholds used were those previously described. GEP studies were performed in 62 patients in whom fresh frozen material was available. Main clinical and evolutive data were recorded and analyzed. The proportion of positive cases for the different single antigens was as follows: CD10 26%, bcl-6 64%, GCET1 46%, FOXP1 78% and MUM1/IRF4 28%. The distribution of cases (GC vs. non-GC) according to the algorithms is detailed in the table. In 88 of 110 patients (80%) with all the antigens available, the patients were allocated in the same group (either GC or non-GC). When the immunochemistry was compared with GEP data, the sensitivity in the GC group was 59%, 52%, 70% and 40% for Colomo, Hans, Muris and Choi algorithms, respectively. The sensitivity in the non-GC group was 81%, 85%, 62% and 84%, respectively. On the other hand, the positive predictive value (PPV) in the GC group was 81%, 83%, 72% and 77%, respectively. In non-GC subset the PPV for the different algorithms was 59%, 55%, 72% and 52%, respectively. We observed a higher percentage of misclassified cases in the GC-phenotype subset than in the non-GC subgroup. None of the immunohistochemical algorithms showed a significant superiority as surrogate of GEP information among the others. The ability of GEP groups as well as of groups defined by the algorithms to predict complete response (CR) rate, progression-free survival (PFS) and overall survival (OS) of the patients is showed in the table. Thus, whereas the GEP groups showed significant prognostic value for CR rate, PFS and OS, none of the immunohistochemical algorithms were able to predict the outcome. In conclusion, in a homogeneous series of DLBCL patients treated with immunochemotherapy, the different immunohistochemical algorithms were not able to mimic the GEP information. The prognostic impact of the groups defined by immunohistochemistry (GC vs. non-GC) was particularly low. N (%) CR rate N (%) 5-year PFS (%) 5-year OS (%) Colomo algorithm GC 53 (44) 39 (74) 48 54 Non-GC 68 (56) 53 (78) 55 62 Hans algorithm GC 61 (41) 47 (77) 54 60 Non-GC 88 (59) 67 (76) 52 59 Muris algorithm GC 87 (57) 63 (72) 48 57 Non-GC 65 (43) 51 (78) 56 63 Choi algorithm GC 45 (33) 32 (71) 48 54 Non-GC 90 (67) 70 (78) 52 61 Gene expression profile 30 (58) 25 (83) 76* 80** GC Activated 22 (42) 17 (77) 31* 45** * p=0.005, ** p=0.03. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4086 Definition of resistance/intolerance to hydroxyurea (HU) in essential thrombocythemia (ET) has been proposed by the European LeukemiaNet (ELN) however its clinical utilility has not been validated yet. We have retrospectively evaluated such criteria in 166 ET patients treated with HU for a median of 4.5 years. Response to HU treatment was categorized using the ELN criteria. The ELN definitions of resistance/intolerance to HU required the fulfillment of at least one of the following criteria: platelet count greater than 600 × 109/L after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400 × 109/L and leukocytes less than 2.5 × 109/L or hemoglobin (Hb) less than 100 g/L at any dose of HU; presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU; HU-related fever. Survival and time-to-event curves were estimated using the Kaplan-Meier method.Variab les attaining a significant level at the univariate analysis were included in a Cox proportional hazards model. Overall, 134 patients achieved a complete clinicohematologic response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n=15) or intolerance (n=21) to HU. Fifteen cases developed anemia with thrombocytosis. Other definitions of resistance were less useful. When compared with the others, resistant patients were more likely to display hyperproliferative features at ET diagnosis, such as higher levels of leukocytes (p= 0.05), platelets (p=0.004) and serum LDH (p=0.02). Eleven patients developed leg ulcers leading to a permanent discontinuation of the drug in 8 cases. No distinctive clinical profile could be ascribed to patients exhibiting leg ulcers, with the exception of a high prevalence of cardiovascular risk factors. Other unacceptable mucocutaneous manifestations occurred in 9 patients. Hematologic and mucocutaneous complications were unrelated, with only two patients presenting both types of toxicities. With a median follow-up from ET diagnosis of 7 years (range: 0.5–23), 38 patients (23%) had died, resulting in a survival probability of 65% at 10 years from HU start. The risk of death from any cause was increased by 6.2-fold (95%CI: 2.3–16.7, P0.001). In conclusion, the best discriminating ELN criterion of resistance to HU is based on the detection of anemia. Moreover, such criterion is particularly useful since it also identifies a subset of ET patients with a poor prognosis. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 769 Despite the many and diverse therapeutic approaches used to treat patients with mantle cell lymphoma (MCL), it remains an incurable disease. Recently, attention has turned into novel therapies targeting MCL-specific oncogenic pathways important for the growth and maintenance of the transformed phenotype. The chromosomal translocation t(11;14)(q13;q32) leading to cyclin-D1 over-expression is the hallmark of MCL. Constitute cyclin-D1 activation in B-lymphocytes maintains retinoblastoma protein in a phosphorylated state and promotes cell cycling, thus initiating the tumorigenesis process. Cyclin-D1 has been postulated as a putative target for therapeutic intervention, however its evaluation has been hampered by the incomplete understanding of the mechanism underlying this cyclin oncogenic function and by the lack of valid MCL models. To investigate these issues, we developed a combined cellular-genomics screening whereby responses to known cytotoxic compounds targeting cancer-related molecular pathways were correlated with genomic, gene expression and proteomic profiles of human MCL cells. Results showed that cyclin-D1 silencing had minimal antitumoral effects but significantly increased the therapeutic efficacy of several compounds, especially the BH3 mimetics that inhibited anti-apoptotic protein BCL-2. To further evaluate this finding we generated a MCL mouse model by transducing a tetracycline-regulatable cyclin-D1-expressing vector in murine pro-B cells, which allowed modulating cyclin-D1 expression levels. These mice generated lymphomas recapitulating most of the cellular, histopathological and molecular features of human MCL. Similar to the previous in vitro findings, cyclin-D1 inhibition in this model did not induce lymphoma regression, but sensitized cells to apoptosis. Analysis of the mechanisms underlying this therapeutic synergy identified a novel role for cyclin-D1 as a pro-survival molecule. Specifically, cyclin-D1 sequestrated the pro-apoptotic effector protein BAX in MCL cells, thereby favoring BCL2 anti-apoptotic function. Accordingly, therapeutic cyclin-D1 inactivation released BAX, thus sensitizing cells to apoptosis and inducing lymphoma regression. Interestingly, pharmacological blockade in vivo of cyclin-D1 with Roscovitine synergistically cooperated with the BH3 mimetic ABT-737 to effectively inhibit MCL tumor growth. In summary, our study reveals a novel role for cyclin-D1 in deregulating apoptosis in MCL cells and highlights the potential benefit of cyclin-D1 targeting, thus providing the rationale for the clinical evaluation of drugs targeting cell proliferation and survival pathways in MCL. Disclosures: Siebert: Abbott: Honoraria.

Description: Abstract 3783 Introduction: Dengue fever is the most prevalent mosquito-borne viral disease, and its clinical signs and symptoms can vary widely. Since hemorrhagic manifestations are common, hematologists are often included in the care of these patients, and face a difficult challenge trying to discriminate dengue fever from other more common viral infections. Laboratory tests used in this context are less than optimal. The expected findings of leukopenia and thrombocytopenia are absent in many cases, thus delaying the suspicion for dengue and the ordering of confirmatory serological tests. Leukocyte morphology changes in numerous medical conditions, including infections. The VCS technology available in the LH and DxH hematology analyzers is capable of automatically quantifying leukocyte morphologic characteristics: cell volume by voltage impedance (V); cytoplasmic and nuclear density by radio frequency conductivity (C); and cytoplasmic granularity and nuclear complexity by laser light scatter (S). The mean and standard deviation of each parameter is calculated. This data is collected for neutrophils, lymphocytes, monocytes and eosinophils separately. Previous studies have demonstrated the significant value of these VCS parameters in improving the laboratory diagnosis of malaria and septicemia, both in adults and neonates. The objective of this study was to compare the performance of the VCS parameters with that of traditional hematological tests used in the diagnosis of dengue fever. Methods: We included in this study 174 patients who were clinically suspected to have dengue fever, as indicated by the clinicians ordering serological testing. Of these, 92 patients were positive and 82 negative by serology. Using the Mann-Whitney U test, we compared the mean VCS values, as well as total leukocyte counts, leukocyte differential counts and platelet counts, between both groups. For those tests that showed a statistically significant difference between dengue positive and dengue negative patients, their diagnostic performance was compared by ROC curve. Finally, we separated patients with normal platelet and WBC counts, likely to be misdiagnosed based on these traditional laboratory tests, and evaluated the diagnostic performance of the VCS parameters in this subgroup. Results: Tests that showed a statistically significant difference (p

Description: In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2−/−γc−/− mice and of murine B220+IgM+ B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM+/− transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.

Description: Abstract 3045 Background: Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and established clinical efficacy and safety in patients with multiple myeloma (MM). Lenalidomide plus dexamethasone (Len + Dex) was well tolerated and demonstrated significant improvements in response and favorable overall survival (OS) compared with Placebo + Dex in 2 pivotal phase 3 registration trials in patients with relapsed/refractory MM (RRMM; Weber et al, NEJM 2007; Dimopoulos et al, NEJM 2007). Previously, in a phase 3, multicenter, single-arm, open-label, expanded-access study (MM-018), Len + Dex demonstrated a predictable safety profile that can preserve patient quality of life (QoL) (Yong et al Haematologica 2010 [abstract #0944]). Here we report efficacy, safety, and QoL data for patients enrolled in the Spanish cohort of MM-018. Methods: Patients with progressive disease after 〉 2 cycles of antimyeloma treatment, or after relapse from treatment, with ECOG performance status ≤ 2 received 28-day cycles of Len (25 mg/day, D 1–21) plus Dex (40 mg/day, D 1–4, 9–12, and 17–20 for cycles 1–4; D 1–4 in subsequent cycles). Endpoints included overall response (≥ partial response [PR] by European Group for Blood and Marrow Transplantation criteria) and QoL assessments measured by EORTC QLQ C-30 and EORTC QLQ MY-20 questionnaires at baseline and week 24. All prophylaxis was administered at the investigator's discretion. Results: Sixty-three patients receiving ≥ 1 dose of Len + Dex were evaluated for efficacy, safety, and QoL. Median age was 62 years (21 [33.3%] were 〉 65 years). Prior therapies included thalidomide (n = 15, 24%) and bortezomib (n = 37, 59%). Additionally, 5 (8%) patients had a history of deep vein thrombosis (DVT), and 23 (37%) had a history of peripheral neuropathy. A PR or better was observed in 49 (78%) patients, including complete response (CR) in 13 (21%), very good partial response (VGPR) in 13 (21%), and PR in 23 (37%) patients. Median time to first response and best response was 2.7 and 4.5 months, respectively. Median duration of response was 18.4 months. Response depth improved after long-term treatment with Len + Dex, and 32/63 (51%) patients received 〉12 cycles of therapy. Beyond 12 cycles of therapy, 8 patients achieved VGPR and 12 patients achieved CR; compared with 5 patients and 1 patient, respectively, prior to 12 cycles. Median time to progression and progression-free survival were both 13.3 months; median OS has not yet been reached. Forty-two (67%) patients remained on study at 6 months. Compliance to QoL assessment questionnaires was ≥ 80%. Patient-reported improvements in QoL and disease symptoms measured by both questionnaires were observed in nearly all scales. EORTC QLQ C-30 scores revealed clinically meaningful improvement (〉 5 points) for global QoL (n = 15, 40%), fatigue (n = 16, 42%), emotional function (n = 15, 40%), physical function (n = 12, 32%), role function (n = 11, 29%), social function (n = 11, 29%), cognitive function (n = 10, 26%), and pain (n = 9, 24%) at 6 cycles compared with baseline. Preservation of QoL in role function, emotional function, social function, and pain scores was observed at 6 cycles when compared with baseline in responders (≥ PR). EORTC QLQ MY-20 results revealed no relevant median change (〉 5 points) from baseline in all scales for all patients completing questionnaires at baseline and 6 cycles, except for a meaningful improvement in future perspective scores (median 11.1-point change). Adverse events observed in this study were consistent with those previously reported with Len + Dex. Grade 3/4 hematologic events were experienced by 40 (64%) patients, and included neutropenia (n = 32, 51%), thrombocytopenia (n = 11, 17%), anemia (n = 10, 18%), and febrile neutropenia (n = 4, 6%). DVT (all grades) was experienced by 5 (8%) patients, and only one grade 3/4 new-onset peripheral neuropathy was observed after 6 cycles of treatment. Conclusions: Len + Dex treatment in this expanded-access study demonstrated efficacy and predictable safety, consistent with that of previously published trials for patients with RRMM. More patients achieved VGPR and CR after long-term therapy compared with those receiving 〈 12 cycles of therapy. Furthermore, QoL assessments at baseline and 6 months revealed that patients treated with Len + Dex showed meaningful improvements in certain QoL and symptom scores. Disclosures: Oriol-Rocafiguera: Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy. García-Laraña:Celgene: Consultancy; Janssen-Cilag: Consultancy. Mateos:Celgene: Honoraria. Cibeira:Celgene: Honoraria for Lectures; Janssen-Cilag: Honoraria for Lectures; Pharmion: Honoraria for Lectures. Knight:Celgene: Employment. Rosettani:Celgene Corporation: Employment.

Description: Extracellular factors control the angiogenic switch in endothelial cells (ECs) via competing survival and apoptotic pathways. Previously, we showed that proangiogenic and antiangiogenic factors target the same signaling molecules, which thereby become pivots of angiogenic balance. Here we show that in remodeling endothelium (ECs and EC precursors) natural angiogenic inhibitors enhance nuclear factor-κB (NF-κB) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-κB pathway abolishes multiple antiangiogenic events in vitro and in vivo. NF-κB induction by antiangiogenic molecules has a dual effect on transcription. NF-κB acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-κB increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-κB increases histone deacetylase 1 (HDAC1), decreases p300 and histone acetylation, and reduces the recruitment of NFAT, a transcription factor critical for cFLIP expression. Finally, we found a biphasic effect, when HDAC inhibitors (HDACi) were used to test the dependence of pigment epithelial-derived factor activity on histone acetylation. The cooperative effect seen at low doses switches to antagonistic as the concentrations increase. Our study defines an interactive transcriptional network underlying angiogenic balance and points to HDACi as tools to manipulate the angiogenic switch.

Description: Abstract 612 Background: Chromosome 5q deletion (del5q) is the most common cytogenetic abnormality in myelodysplastic syndrome (MDS). Although haplodeficiency of several genes may contribute to the disease phenotype, allelic deletion of the ribosomal protein S14 (RPS14) gene is a key effector of the hypoplastic anemia. Disruption of ribosome assembly arising from RPS14 deletion leads to nucleolar stress that triggers p53 activation. In a murine model of the human 5q- syndrome, TP53 inactivation was alone sufficient to rescue the hematologic phenotype, indicating that the molecular pathogenesis of del(5q) MDS is p53-dependent. The tumor suppressor TP53 gene is a key regulator of stem cell homeostasis and senescence. A well described single nucleotide polymorphism (SNP) located at codon 72 in the proline-rich, pro-apoptotic domain of TP53 has been linked to cancer and mutagen susceptibility, and treatment outcome. Substitution of a cytosine (‘C’ allele) for the more common guanine (‘G’ allele) results in translation of a proline rather than arginine residue at position 72, with diminished apoptotic potential. Given the pathogenetic role of p53 in del(5q) MDS, we hypothesized that homozygosity for the ‘C’ allele may be associated with disease predisposition. Methods: Bone marrow and blood samples were investigated from 118 del(5q) MDS patients, 102 non-del(5q) MDS patients, and 98 healthy controls. Genomic DNA was extracted and codon 72 of the TP53 gene was amplified by PCR. Forward and reverse Sanger sequencing was performed to determine genotype. Relationship to disease specific features at diagnosis including cytogenetic risk category, IPSS score, blast percentage, and age were investigated as well as the relationship to response to lenalidomide and AML transformation using SAS software (Version 9.2, SAS Institute Inc., Cary, NC, USA). Results: Genotype distribution significantly differed between del(5q) MDS patients (18% CC, 47% CG, and 35% GG), non-del(5q) MDS patients (9% CC, 58% CG, and 33% GG),and healthy controls (7% CC, 43% CG, and 50% GG) (p=0.01). The frequency of the homozygous CC genotype was 〉2x greater in del(5q) MDS (18%) compared to both non-del(5q) MDS (9%) and healthy controls (7%) (p=0.05). There was no significant frequency difference between non-del(5q) and healthy controls. Del(5q) MDS patients were 〉6 times more likely to carry the CC genotype vs. GG when compared to healthy controls [odds ratio (OR)=6.71, 95% CI: 1.56 to 28.86], whereas non-del(5q) patients were 〉3 times more likely to carry the CC genotype vs. GG when compared to healthy controls (OR=3.87, 95% CI: 0.66 to 22.71). The corresponding ‘C’ allele frequency was significantly greater among del(5q) MDS patients (41.7%) compared to healthy controls (28.6%) (p=0.006), and approached significance in non-del(5q) patients (37.8%) versus controls (p=0.06). There was no association between TP53 R72P genotype and cytogenetic risk group in either del(5q) (p=0.67) or non-del(5q) MDS patients (p= 0.60), IPSS (del5q, p=0.29; non-del5q, p=0.89), or response to lenalidomide (del5q, p=0.57; non-del5q p=0.89). Mean age at diagnosis was significantly (p=0.04) lower in del(5q) MDS (67.4 years; SD=11.1 years) compared to non-del(5q) MDS patients (70.8 years; SD=9.1years), although significant differences in age according to TP53 R72P genotype were not apparent in either MDS cytogenetic group (del5q, p=0.99; non-del5q, p=0.89). Conclusion: Our findings indicate that the TP53 R72P homozygous CC genotype occurs with significantly greater frequency in del(5q) MDS compared to both non-del(5q) MDS patients and healthy controls, suggesting that this polymorphism may play a key role in the pathogenesis of and predisposition to del(5q) MDS. Disclosures: Kurtin: Celgene: Honoraria. Maciejewski:Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Nevill:Celgene: Honoraria. Karsan:Celgene: Research Funding. List:Celgene: Research Funding.