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Abstract Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

Objectives:With the introduction of novel immune therapeutics for the treatment of disseminated malignancies, we sought to evaluate whether deliberate sequencing of immunotherapy before/after conventional cytotoxic chemotherapy would have an impact on clinical outcomes in patients with previously treated metastatic melanoma. We sought to evaluate whether or not ipilimumab immunotherapy administered before or after cytotoxic chemotherapy (nab-paclitaxel+bevacizumab, AB) would impact clinical outcomes.Methods:We conducted a randomized phase 2 clinical trial of patients with BRAF wild-type metastatic melanoma (up to 2 prior therapies) who received either: (A) AB followed by ipilimumab therapy at progression; or (B) ipilimumab followed by AB treatment at progression. The primary goal of the study was a comparison of AB versus ipilimumab progression-free survival, with secondary clinical and laboratory endpoints.Results:This study did not reach full accrual due to concurrent Food and Drug Administration approval of anti-programmed cell death 1 agents. Nevertheless, the available data suggests a cumulative therapeutic advantage to the sequential use of ipilimumab followed by AB. Correlative laboratory data revealed a favorable effect on systemic immune homeostasis in patients receiving AB therapy, of potential interest in further investigations, especially in the context of chemotherapy/immunotherapy combinations.Conclusion:Albeit limited in scope, our data suggest that cytotoxic therapy with nab-paclitaxel and bevacizumab appear to favorably alter systemic parameters of immune function of potential benefit in combination T-cell directed immune checkpoint inhibitor therapy.

Prior to the advent of the monoclonal antibody trastuzumab, human epidermal growth-factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) was associated with an aggressive clinical course and poor survival outcomes. In the era of effective HER2-directed therapies, median survival rates for patients with metastatic HER2+ BC now approach 5 years. Despite these improvements, the majority of affected patients unfortunately die from disease. Therapies to overcome treatment resistance are being actively pursued. One strategy has been to target the cyclin-dependent kinases 4/6 (CDK4/6), as they are downstream of HER2 and many of the cellular pathways driving resistance to HER2-targeted therapies, and play a key role in proliferation by controlling transition through the G1 restriction point to the S phase of the cell cycle. In this article, we review the published literature with regard to the rationale for CDK4/6-directed therapies in HER2+ BC and discuss ongoing clinical research and new challenges in the field.

Background: MM is associated with significant morbidity even at the time of presentation and there is ample data to support that MM treatment improves overall survival (OS) as well as quality of life (QoL) due to effective symptom control. Patient refusal to recommended cancer treatment is not common in clinical practice but has been reported in certain cancers. There is no data on characteristics of MM patients who refuse treatment despite physician recommendation and outcomes of such patients. Methods: We used the National Cancer Database (NCDB) from 2004-2015 to extract data on adult MM patients who refused any systemic therapy as part of their initial care despite physician recommendation. Information on patient age, gender, race/ethnicity, education, year of diagnosis, income, geographical location, comorbidities, systemic treatment, survival time and vital status was obtained. Average annual percent change (AAPC) and average percent change (APC) were calculated to analyze the trends, and periods with similar APC were compared for statistically significant changes by applying join point regression. Multivariate models were employed to identify factors predicting refusal to therapy and to assess its impact on OS. Results: Of 75,734 eligible patients who were recommended treatment for MM (chemotherapy and or immunotherapy), 2138 (2.8%) patients did not receive any treatment due to refusal. Significantly higher number of females, patients in older age groups (age groups 60-79 and ³ 80 years), Medicare recipients and with ≥2 comorbidities refused treatment recommendation. On multivariate analysis, advanced age groups 60-79 years (OR = 1.47; 95% CI 1.27-1.31 p<0.001) and ³80 years (OR = 5.02; 95% CI 4.23-5.96, p<0.001), female gender (OR =1.16 ; 95% CI 1.05-1.27, p<0.001), patients with certain primary payor types including Medicaid (OR = 1.59; 95% CI 1.28-1.98, p<0.001), Medicare (OR = 1.63; 95% CI 1.43-1.87, p<0.001) and uninsured (OR = 1.81; 95% CI 1.38-2.38, p<0.001), and presence of ³2 comorbidities (OR = 1.39; 95% CI 1.2-1.61, p<0.001) were the independent factors associated with higher likelihood of refusing treatment. Whereas being seen at academic research programs (OR = 0.7; 95% CI 0.6-0.8, p<0.001), higher education (OR =0.81 ; 95% CI 0.67-0.98, p=0.03), geographical location (Midwest OR =0.87 ; 95% CI 0.76-0.99, p=0.04), longer distance to facility being at 3rd quartile (10.1-26.2 miles: OR =0.78 ; 95% CI 0.68-0.89, p<0.001) or 4th quartile (>26.2 miles: OR = 0.59; 95% CI 0.51-0.68, p<0.001) were associated with lower likelihood of refusing treatment. The overall rate of refusing treatment by MM patients was quite stable during 2004-2015 with an AAPC of 1.1 (95% CI -1.1-3.3 p=0.3). However, on fitting scatter plot into Joinpoint regression model, a concerning trend in the more recent years was noted. While the rate of refusing recommended treatment decreased during 2004-2008, a rising trend was observed during the period 2008-2015 with an APC of 3.8 (95% CI 1.3-6.4, p≤0.001) (Fig 1a). Patients who were recommended treatment but refused had significantly worse survival than those who received treatment (median survival 17.7 vs 52.9 months, Cox hazard ratio 1.21; CI 1.17-1.24, p<0.001) (Fig 1b). Conclusions: The percentage of MM patients refusing any systemic treatment as a part of their initial care despite physician recommendation appears to be increasing in recent years and this needs to be systematically addressed. Disparities in refusal to recommended treatment are independently associated with several variables including age, gender, comorbidities, geographical location, facility and insurance type. These need to be addressed urgently since there are several effective and well-tolerated anti-MM treatments which can potentially benefit patients in case the initial socioeconomic, clinical and psychosocial barriers are overcome. Disclosures Chanan-Khan: Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding. Ailawadhi:Pharmacyclics: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy.

Background: Median age at diagnosis for MM is 69 years with approximately 33% of the newly diagnosed MM (NDMM) patients aged ≥80 years (elderly). Yet, outcomes data and clinical trial participation in elderly MM patients are limited due to frailty and frequent comorbidities. Moreover, elderly patients are not candidates for stem cell transplant (SCT) and age is an independent poor prognostic marker, leading to disparate outcomes. The present study evaluated trends in outcomes and predictors of survival among elderly NDMM patients in the United States (U.S.). Methods: Using Surveillance Epidemiology and End Results (SEER) database, we extracted data on age, gender, geographical regions, year of diagnosis, and vital status for elderly patients (age ≥ 80 years) with MM from 1975 to 2016. Relative survival (RS) was estimated as the ratio of observed survival to the survival expected in the general population in the absence of malignancy. This adjusted for the competing causes of mortality prevalent in elderly patients. Mortality rates were age-adjusted. To estimate trends in mortality, we estimated annual percentage change (APC) and average annual percentage change (AAPC) by fitting the data in the join point regression model using the NCI's Join point Regression Program, Version 4.5.0.1. A multivariate analysis was conducted to analyze the predictors of overall and myeloma-specific mortality among elderly patients fitting into Cox proportion hazard regression model. Results: A total of 17,265 elderly MM patients were eligible for the study. Majority were females (n=9,487, 55%), were non-Hispanic whites (NHW) (n=12,895, 74.7%) and were diagnosed in the Western region of the U.S. (n=8,541, 49.5%). The median age was 84 years (IQR 81-87). The median RS for the whole period (1975-2016) was 19.8 months with 1- and 5- year RS of 60.1% (95%CI: 58.8-61.3) and 20.9% (95%CI: 19.5-22.3) respectively. The median RS increased from 8.45 months in 1975 to 29.86 months in 2013. One and 5- year RS also increased from 42.7% (95%CI: 32.4-52.5) and 12.9% (95%CI: 5.8-22.7) in 1975 to a 1- and 5-year RS of 72.3% (95%CI: 65.4-78.1) and 31.1% (95%CI: 23.4-39.1) in 2013, respectively (Fig.1). However, the age standardized mortality rate for the whole period showed an increasing trend with an AAPC of 2.3 (0.5-4, P<0.001). On fitting joinpoint regression, 2 distinct joinpoints were identified, calendar years 1977 and 1989 (Fig 2). Most of the increase in mortality rate was noted in the period 1975-1989. Since 1989, the mortality rates have shown a decreasing trend which is marginal but statistically significant, with an APC of -0.41 (95%CI: -0.7- -0.1, p<0.001). On multivariate analysis, increasing age (p<0.001) and non-northeast location (p<0.01) were associated with higher overall and MM-specific mortality. Female gender was associated with lower overall mortality (p<0.001) but not myeloma-specific mortality. While "other" race/ethnicity (not NHW, non-Hispanic black; NHB or Hispanic) was associated with lower risk of overall and myeloma-specific mortality, NHB were associated with a lower MM-specific (p<0.001) but not overall mortality. Conclusions: Our results suggest that although RS has improved significantly in the elderly patients, the mortality rates have not changed drastically over the years. Besides, factors like advancement in diagnosis and treatment which have improved RS, early diagnosis (leading to lead time bias) may also be contributing. Furthermore, there are several gender-specific, geographic and racial/ethnic disparities in outcomes of elderly MM patients, which need to be assessed prospectively. Although, a small decline in mortality rates in the more recent time is promising, further studies are warranted on interventions including aggressive supportive care directed at elderly patients with MM, so that MM survivorship can be improved. There should be strong consideration to increaseenrollment of the elderly in prospective clinical trials so that evidence-based guidelines can be developed. Disclosures Manochakian: Takeda: Membership on an entity's Board of Directors or advisory committees; Guardant Health: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Novocure: Membership on an entity's Board of Directors or advisory committees. Chanan-Khan:Merck: Research Funding; Ascentage: Research Funding; Millennium: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Pharmacyclics: Research Funding; AbbVie: Research Funding; Xencor: Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding. Off Label Use: Do not remove- this information is relevant to Abstract ID 125629: TAK-169 is a dimeric fusion protein of an anti-CD38 antibody single chain variable fragment fused to a modified Shiga-like toxin-A subunit..

Abstract Background: The phase 3 double-blind, CALGB/Alliance 100104 study assessed the efficacy and safety of lenalidomide (LEN) or placebo maintenance therapy until relapse in post-autologous stem cell transplantation (ASCT) patients with newly-diagnosed multiple myeloma (NDMM). Interim analyses demonstrated superiority for LEN versus placebo for time to progression (TTP), thus meeting the primary TTP endpoint of the trial. The study was unblinded in December 2009 and, based on the TTP and overall survival (OS) benefit observed with LEN, patients in the placebo arm (who had not yet progressed) at the time of unblinding were given the option of crossing over to receive LEN. Data have been reported for a follow-up of 91 months based on the planned intention to treat (ITT) analysis, yielding a TTP hazard ratio (HR) 0.57 and an OS difference of HR 0.61 (Holstein SA, et al. Lancet Haematol. 2017;4:e431-42). Crossover to active treatment enabled patients to benefit from LEN maintenance and collection of additional efficacy and safety data; however, crossover can confound the estimates of OS for longer follow-up. We report the results of an analysis adjusted for crossover, thus aiming to provide a more accurate estimate of the survival benefit achieved with LEN maintenance therapy. Methods: Results are reported for an analysis based on an updated data cutoff, post-October 2016. The rank-preserving structural failure time model (RPSFTM) was considered the most appropriate method to adjust for crossover (Robins JM, Tsiatis AA. Commun Stat Theory Methods. 1991;20:2609-31). This method requires that the assumption that the treatment effect is the same for patients who receive LEN at randomization as those who receive LEN as crossover treatment is not violated; a landmark analysis was performed to explore this. The iterative parameter estimation (IPE; Branson M, Whitehead J. Stat Med. 2002;21:2449-63) algorithm was used as validation. Both the RPSFTM and IPE analyses assume a residual LEN effect after discontinuation (base case). Results: A total of 76 NDMM patients who had not progressed, as determined by central adjudication, crossed over from placebo to LEN and were included in the analysis. The landmark analysis of OS from the date of unblinding indicated that the treatment effect for the crossover versus the non-crossover placebo group was HR 0.57 (95% confidence interval [CI] 0.29-1.15) (Figure). This also provided a measure of the benefit of LEN maintenance in patients who started maintenance therapy after the trial-specified 90-100 day window post-ASCT (median 11.5 months post-randomization; range 3.2-51.0 months). Adjustment for crossover using the RPSFTM or IPE resulted in an increase in the relative treatment effect of LEN maintenance (vs placebo) on OS from 30.8 months for the ITT analysis (HR 0.61; 95% CI 0.47-0.81) to 40.1 months (HR 0.52; 95% CI 0.36-0.73) for the RPSFTM analysis and 38.8 months (HR 0.52; 95% CI 0.37-0.74) for the IPE analysis (Table). Results were consistent across the two methods. Discussion: This analysis was performed on an updated version of the data set reported in the Holstein article. Once we adjusted for crossover, depending on the methodology used, there was an additional gain of ~40 months of OS. Previously, a pre-planned, pooled meta-analysis of 3 studies that included CALGB/Alliance (McCarthy PL, et al J Clin Oncol. 2017;35:3279-89) indicated that the OS gain was 2.5 years; however, our analysis from the CALGB study alone shows that LEN maintenance may provide a survival benefit of > 3 years. In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of LEN maintenance therapy post-ASCT and support guideline recommendations to offer LEN maintenance therapy to all patients post-ASCT. Support: U10CA180821, U10CA180882, U10CA180820; ClinicalTrials.gov Identifier: NCT00114101. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cooper:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Saunders:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Dhanasiri:Celgene: Employment, Equity Ownership. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Chronic idiopathic myelofibrosis (MF) is a clonal hematopoietic disorder that leads to progressive marrow fibrosis and peripheral cytopenias. Very little is known about the role of aberrant DNA methylation in the pathobiology of this disease. Whole genome methylation was analyzed by a recently described novel method, the HELP assay (HpaII tiny fragment Enrichment by Ligation-mediated PCR; Khulan et al, Genome Res. 2006 Aug;16(8)) that uses differential methylation specific restriction digestion by HpaII and MspI followed by amplification, two color labeling and cohybridization to quantitatively determine individual promoter methylation. A whole genome human promoter array (Nimblegen) was used to determine the level of methylation of 25626 gene promoters by calculating HpaII/MspI cut fragment intensity ratio. Peripheral blood leucocytes from 9 patients with IMF were compared to 9 age-matched normal and anemic controls. Gene expression analysis was performed using 37K oligo maskless arrays using cDNA from the same samples. Methylation analysis showed that myelofibrosis samples clustered separately from normal and anemic controls when grouped by unsupervised clustering based on Pearson’s correlation coefficient. On the other hand, global gene expression demonstrated no clear cut differences between myelofibrosis and control samples suggesting that methylation profiling has greater discriminatory power when compared to conventional gene expression profiling. A high correlation (r=0.88–0.96) was observed between whole genome methylation profiles of matched sets of bone marrow and peripheral blood leucocyte samples from selected patients demonstrating that peripheral blood leucocytes can act as a valid surrogates for epigenomic analysis. Further analysis showed that genes aberrantly methylated in all myelofibrosis samples included v-myc, histone 2A, TNF, TNF Receptor1, FGF14 and others. Functional pathway analysis by Ingenuity showed that pathways involved in Inflammation and Cell signaling were the most affected by epigenetic silencing. Most interestingly, a large proportion of gene promoters were also aberrantly hypomethylated. These included genes for chemokine CXCL13, APC, IL-3, STAT2 and others. The pathways most activated by hypomethylation were involved in hematopoiesis and cell growth and proliferation demonstrating the biological validity of our analysis. Thus, our data demonstrates that myelofibrosis is characterized by distinct epigenetic aberrations that are preserved in peripheral blood leucocytes. These can be the basis of future studies on pathogenesis and diagnosis for this disease and lead to translational studies with agents targeting DNA methylation.

Abstract Introduction Cancer associated thrombosis is the second most common cause of mortality among patients with malignancy. While preventive low molecular weight heparin is effective in preventing venous thromboembolism (VTE), lack of agreement on risk stratification methods have precluded its widespread use. The most studied VTE prediction tool is the Khorana score, but it does not capitalize on the use of novel biomarkers. We aimed to evaluate the value of biomarkers in prediction of VTE among patients with active cancer receiving outpatient chemotherapy. Methods We prospectively collected pre-chemotherapy blood samples on adult patients with solid organ tumors. We excluded patients on anticoagulation and those unable or unwilling to consent. Along with demographics and cancer specific variables, potential novel predictors of VTE were selected a priori and included: coated platelets (CP), D dimer (DD), protein C (PC), fibrin monomers (FM), mean platelet volume (MPV), platelet microparticles (PMP). Type of cancer was grouped according to the Khorana score (Very high risk: Stomach, Pancreas; High risk: Lung, Gynecologic, Bladder, Testicular; Low/Moderate risk: all other sites). VTE events were adjudicated at 6 months of follow up. For all statistical analyses we used SAS 9.2 (SAS Institute Inc., Cary, NC, USA). A p value of <0.05 was considered as statistically significant. We only performed univariate analysis at this point of our study due to the stage of recruitment and period of follow-up. Results We have recruited a total of 101 patients (mean + standard deviation age 59.7+11 years, 68% female), 20% of the 75 patients with complete follow up have developed a VTE. We found no significant association between the incidence of VTE and age, gender, or baseline Khorana score. The variables associated with incident VTE were: BMI (odds ratio [OR] 8.5 for BMI<25 kg/m2, p<0.001), type of cancer (OR 14.5 for very high risk compared to high risk, p<0.01) and protein C (OR 3.3 for protein C<110ug/mL the lowest tertile, p=0.05). The rest of the tested potential biomarkers did not have a strong association with incident VTE in the current analysis (Table). Twenty percent of the patients were on aspirin and none of them developed VTE compared to 23% of those not taking aspirin who developed VTE, (p=0.2). Conclusion Pre Chemotherapy level of Protein C is a potential biomarker for the incidence of VTE. We confirm that cancer type and BMI are predictors of cancer associated VTE. In addition, lower BMI is not usually recognized as a potential predictor of VTE in other prediction scores. We were underpowered to detect differences in the VTE incidence according to Khorana score. Finally, aspirin may have a role in outpatient cancer associated VTE prevention and deserves further investigation. Disclosures: Tafur: Stago Diagnostica: Research Funding. Rathbun:Stago Diagnostica: Research Funding.

Abstract Background: Patients (pts) withHR-MDS have a median OS of 4 to 6 months (mo) after HMA failure (Prebet et al, J Clin Oncol 2011) and no approved salvage therapy. Development of new therapeutics for this population will benefit from the availability of surrogate endpoints and markers that can predict survival. Gore et al established response to azacitidine (Vidaza®) in first-line therapy for HR-MDS as a reasonable surrogate to predict survival (Gore et al, Haematologica 2013). Rigosertib, a novel dual PI3K/PLK pathway inhibitor, has been shown to reduce bone marrow blasts (BMBL) in these pts (Seetharam et al, Leuk Res 2012). Silverman et al described complete or partial bone marrow (BM) response, or stabilization after 4-8 weeks (wks) of treatment with rigosertib as a potential surrogate for predicting survival in pts with HR-MDS after failure of primary HMA therapy (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized Phase III trial. Methods:Pts with HR-MDS were randomly assigned 2:1 to rigosertib or best supportive care (BSC) after progressing on, failing to respond to, or relapsing after HMA treatment. BM aspirates were assessed pretreatment, at 4 weeks and at 8-week intervals thereafter. Central slide review was undertaken in a representative population of samples. The BMBL response at each time point was assessed using the following definitions: bone marrow complete response (mCR) = BMBL ≤ 5% and decrease of ≥ 50% from baseline; bone marrow partial response (mPR) = BMBL decrease from baseline of ≥ 50%, but BMBL still > 5%; stable disease (SD) = BMBL decrease or increase from baseline of < 50%; progressive disease (PD) = BMBL increase from baseline of ≥ 50% by an absolute minimum of 5%; Not evaluable (NE). Results:Bone marrow assessment was carried out in 156 patients (pts) on the rigosertib arm and 24 pts on the BSC arm at 4 wks after enrollment, and in 86 and 20 pts, respectively, at 12 wks. The invasive BM procedure was optional on the BSC arm, which accounts for the low number of assessments in this group. BM responses at the 2 time points are presented in Table 1. Since no difference in overall survival was noted between pts who had objective BM response and those who did not progress (ie, stable disease), a landmark analysis was conducted that separated pts who were alive at the 4-wk landmark time into two 4-wk response categories: BM response + SD vs. PD. Results of this analysis in rigosertib-treated patients were statistically significant at p = 0.011, with a hazard ratio (HR) of 0.62 and a median OS (from 4 wks onward) of 9.8 months in the mCR + mPR + SD group vs. 4.6 months in the PD group (Figure 1). Another landmark analysis was conducted at 12-wks. Results of this analysis were also significant (p < 0.001) in rigosertib-treated patients, with an HR of 0.39 and a median OS (from 12 wks onward) of 10.4 months in the mCR + mPR + SD group vs.7.5 months in the PD group (Figure 2). A time-dependent Cox regression of OS by 4-wk BMBL response reinforced the validity of the 4-wk and 12-wk BM assessments as surrogate biomarkers for survival (Table 2). Conclusions: These data suggest that BMBL response at 4 or 12 weeks was correlated with OS in this population of pts with HR-MDS treated with rigosertib after HMA failure and are consistent with previous observations in Phase II studies. Table 1 4- and 12-week Bone Marrow Blast Response (Intention-to-Treat Population) Number (%) of Patients 4-wk BMBL Response 12-wk BMBL Response Rigosertib N = 199 BSC N = 100 Rigosertib N = 199 BSC N = 100 Pts with BMBL assessment 156 (78) 24 (24)* 86 (43) 20 (20)* BM complete response (mCR) 22 4 11 5 BM partial response (mPR) 8 2 9 2 Stable disease (SD) 77 9 32 8 Progressive disease (PD) 49 9 34 5 * Bone marrow assessment was not required on the BSC arm. Figure 1 Figure 1. Figure 2 Figure 2. Table 2 Time-dependent Cox Regression of Overall Survival by Bone Marrow Blast Response Analysis Rigosertib BSC Wald P-value Hazard Ratio (95% Confidence Interval) Wald P-value Hazard Ratio (95% Confidence Interval) By 4-wk BMBL response 0.051 0.72 (0.51 - 1.00) 0.56 0.83 (0.45 - 1.54) By 12-wk BMBL response 0.0005 0.55 (0.39 - 0.77) 0.16 0.68 (0.39 - 1.17) *Stratified by pretreatment BMBL: 5%-19% vs. 20%-30% 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. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Azarnia:Onconova Therapeutics, Inc: Employment.