ALBERT

Description: Introduction The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival (OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These criteria were originally proposed by an international group of experts based on available data and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG criteria, pts who achieved hematological improvement (HI), complete response (CR), marrow CR (mCR), or partial response (PR) demonstrated improved OS. The aim of this study is to validate the IWG 2006 response criteria among a large cohort of higher-risk MDS pts. Methods Pts with higher-risk MDS (intermediate-2 (Int-2) or High Risk by International Prognostic Scoring System (IPSS)) who had received treatment and for whom details of response and outcome were available were included from the MDS CRC database. Pts were also classified per IPSS-R. The best response to treatment was categorized per the published IWG 2006 response criteria as CR, PR, mCR, HI, stable disease (SD) or progressive disease (PD). The primary endpoint was OS. Results We identified 646 treated higher-risk MDS pts. Table-1 summarizes baseline characteristics. The first line treatment was hypomethylating agent-based therapy (HMA) in 470 pts (74%). The median duration of follow up was 23.2 months (mo) (95% CI: (19.9, 26.5). Median OS from diagnosis was significantly longer for pts with int-2 IPSS risk disease IPSS (26.2 mo (21.5, 29.7)) compared to those who were High Risk (18.8 mo (15.9, 23.6); (p = 0.026). Median OS from diagnosis also differed by IPSS-R category (p 〈 0.001): for pts with Low risk (n = 6) it was not reached; Intermediate risk it was 41.7 mo (31.8, NR); High Risk it was 28.4 mo (24.1, 33.2); and for pts with Very High it was 16.5 mo (15.3, 19.1). The best IWG 2006 response rate for first line therapy among evaluable pts (n=597) was CR in 93 pts (16%), mCR in 10 (2%), PR in 57(10%), HI in 60 (10%), SD in 233 (39%), and PD in 144 (24%). The median OS based on IWG 2006 best response for first line therapy was 41 mo for CR, 12 mo for mCR, 26 mo for PR, 13 mo for HI, 14 mo for SD and 7 mo for PD. (p

Description: Background: Several validated prognostic models exist for patients (pts) with myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), the Revised IPSS (IPSS-R), the World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS), and the MD Anderson Prognostic Scoring System (MDAPSS). All were developed in pts with newly diagnosed MDS, and their prognostic value in subsequent stages of disease, such as at the time of hypomethylating agents failure (HMAs, azacitidine (AZA) and decitabine (DAC), has not been established. Despite this, the IPSS and IPSS-R is often used to determine clinical trial eligibility for pts who fail HMA and has been used by the FDA for drug labeling in this setting. Here in we developed a new prognostic model that predicts outcome post HMAs failure (HMAF). Methods Included patients were diagnosed with higher-risk MDS (per 2008 WHO criteria, higher-risk defined as IPSS Intermediate-2/High) with clinical and pathologic data entered into the MDS Clinical Research Consortium database. The IPSS, IPSS-R, WPSS and MDAPSS were calculated at the time of diagnosis and HMAF. HMAF was defined as no response to AZA or DAC following 〉4 cycles, loss of response, or progression to acute myeloid leukemia (AML) at any time after starting therapy. Responses were defined per International Working Group criteria (IWG 2006). Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow up when the models were applied at diagnosis and from HMAF date to time of death or last follows up when the models were applied at the time of HMAF. Cox proportional hazard analysis within the multivariable model-building with fractional polynomials (MFP) approach, which automatically select from all factors at the time of HMAF, was used to build the new model. Akaike information criterion (AIC) was used to compare fits from Cox proportional hazards models. Results Of 450 higher-risk MDS pts who failed HMAs, 311 (69.1%) were treated with AZA and 139 (30.9%) with DAC. The median age at diagnosis was 70 years (range: 35-91). Best responses (BR) to HMA were: 96 (21.3%) with complete remission, 40 (8.9%) partial remission, 46 (10.2%) hematologic improvement, 180 (40.0%) stable disease, and 88 (19.6%) with progressive disease. The median number of cycles received during treatment was 6 (range, 2-51). With a median follow up of 17.4 months (IQ range, 16.1, 18.7), the median OS from diagnosis for the entire group was 18.5 months (IQ range, 17.2, 19.8). Median OS from diagnosis was similar for patients treated with AZA compared to DAC (18.0 months vs. 20.3 months, p = .36). The median OS after HMAF was 7.3 months (IQ range, 6.3, 8.4). Survival plots for each prognostic scoring system at diagnosis and HMAF are shown in Figure 1. Comparing the predictive power of these scoring systems at the time of HMAF, the AICc for each model was: MDASS (3541.1); IPSS-R (3562.0), IPSS (3570.0), and WPSS with AICc of (3572.2) (lower AICc indicates better fit of the model). Given the lower predictive power of the current prognostic models at the time of HMAF, we developed a new prognostic model specific for this patient population. Our MFP modeling approach selected 6 factors that have significant association with OS at the time of HMAF in the final Cox multivariate model (Table 1). The new model identified two risk groups: Low: score 〈 2.25, median OS 11.0 months (95% CI 8.8-13.6) and a high risk group with score of 〉 2.25 and median OS 4.5 months (95% CI 3.9-5.3). Using the internal model validation assessment, the estimated AICc for the new model was 3520.4 (lowest AICc). When the new model was applied at time of diagnosis, the AICc decreased to 3515.1, a much smaller decrease compared to the existing prognostic systems built at diagnosis: MDASS (3515.7), IPSS-R (3528.2), WPSS (3537.5) and IPSS (3537.7). Conclusion Currently available MDS prognostic scoring systems should be used cautiously in pts at the time of HMAF and, given their inconsistent reliability, should be avoided for clinical trial eligibility or drug labeling. A new prognostic model was developed specific for this patient population. Table 1. The Post-HMA model Table 1. The Post-HMA model Figure 1. Overall survival by scoring systems at diagnosis and at the time of HMA failure Figure 1. Overall survival by scoring systems at diagnosis and at the time of HMA failure Disclosures Komrokji: Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Sekeres: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.

Description: Background The standard first-line therapy for higher-risk myelodysplastic syndromes (MDS) are the hypomethylating agents (HMA). While clinical characteristics, molecular markers, and karyotype can contribute to predicting prognosis in MDS, these parameters have not identified differential response rates between the HMAs decitabine (DAC) and azacitidine (AZA). Gender differences have been associated with varied outcomes in multiple cancers, and are thought to be related to differences in disease biology, treatment response, or adherence to therapy. Relevant to MDS, gender can effect expression of cytidine deaminase, which inactivates the HMAs. Male have increased levels compared to females. The impact of gender on response to HMAs is not established. Methods A dataset from the MDS CRC database was analyzed. Patients (pts) were diagnosed with higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High) and per 2008 WHO criteria and were treated with AZA or DAC as first-line therapy. Response was assessed per International Working Group (IWG) criteria (2006). The IPSS and its revision (IPSS-R) were calculated at presentation. Missing data were multiply imputed 100 times using the mice approach. Differences among variables were evaluated by the chi-square test and Mann-Whitney U test for categorical and continuous variables, respectively, with continuous variables summarized by median and range. Overall survival (OS) was calculated from presentation date to date of death or last follow up. Propensity scores were calculated for DAC vs AZA using all variables available pre-treatment. Propensity weighted Cox proportional analysis and log-rank tests were used to model and test OS. Results Of 625 higher-risk MDS pts, 33.7% were women (Table 1). The median OS for the cohort was 16.9 months (95% CI 15.6-18.2); 17.8 months for men (95% CI 16.4-19.2) and 15.0 months for women (95% CI 12.1-18.6). Approximately one third of pts received DAC as front line HMA in both gender groups. While most variables had similar distributions between DAC and AZA within genders, two variables showed differences between HMA treatments in both genders: bone marrow blast percentage at diagnosis and IPSS-R cytogenetic category, with blast percentage consistently higher in the DAC treated set. In addition, DAC-treated females were on treatment longer than AZA-treated females There was no difference in median OS across gender (p=0.33). DAC-treated pts had marginally better OS than AZA pts (p=0.043), (median OS of 18.7 months vs 16.3 months), but the difference varied strongly by gender (Figure 1). Female DAC pts had much better OS than female AZA pts (p=0.0014), with a median OS of 21.2 months (95% CI 16.1-27.9) versus 13.1 months (95% CI 10.7-15.9). Males showed no significant difference (p=0.59), with a median OS of 18.3 months (95% CI 14.9-22.2) compared to 17.6 years (95% CI 16.0-19.5). Female DAC survival improvement remained significant in a Cox PH analysis after adjusting for cytogenetic category and bone marrow blast % at diagnosis. (Figure 1) Conclusion Women with higher-risk MDS may live longer when treated with DAC than with AZA. While factoring in gender as a variable in therapeutic choice between the HMAs remains premature, future prospective investigations of both drugs in men and women are warranted. Table 1. Patient characteristics by Sex FemaleN=210, 33.7% MaleN=415, 66.3% Parameter DAC AZA P-value DAC AZA P-value N=7234.3% N=138 65.7% N=130 31.3% N=285 68.7% Age, years 67.4 35-84 68.9 36-91 0.222 70.0 38-89 70.8 31-99 0.641 ANC X 109 L 1.06 0.04-27.7 0.83 0.10-20.4 0.085 1.04 0.02-44.9 1.01 0.01-42.6 0.900 Platelets X 109 L 57.8 2.0-412.4 59.4 4.9-655.2 0.820 55.6 3.0-654 66.2 2.5-451.3 0.095 Hemoglobin g/dL 9.53 4.38-12.90 9.27 4.91-14.04 0.271 9.40 4.10-13.93 9.13 3.00-15.91 0.086 Bone marrow blasts % 13.0 0.27-29 10.0 0-84

Description: Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Although HMA (azacitidine [aza] or decitabine [dac]) are standard of care therapies for HR-MDS pts, responses may not be seen for 4-6 months and occur in

Description: Background: Aberrant epigenetic modifications, fundamental to the pathogenesis of MDS, provide rationale for the use of the so-called hypomethylating agents, decitabine (DAC) and azacitidine (AZA). As depletion of DNA methyltransferase 1 (DNMT1) by these agents is S-phase dependent, episodic dosing used in common practice (SD-DAC; 20 mg/m2 x 5 days, every 28 days, SD-AZA; 75 mg/m2 x 5-7 days, every 28 days) affects only a fraction of the malignant clones. Alternative dosing schedules of decitabine with lower doses given more frequently (LD-DAC; .1-.2 mg/kg SC once/twice weekly) may decrease toxicity and increase response rates by improved hematopoietic differentiation and DNMT1 depletion while avoiding cytotoxicity. Data comparing use of very low and standard-dose DAC or AZA are lacking. Methods: We compared response, survival, and toxicities of 242 MDS patients (pts) treated at our institution from 9/06-10/13 with LD-DAC (n=39), SD-DAC (n=17), or SD-AZA (n=186). Response was assessed per International Working Group 2006 (IWG) criteria, progression-free (PFS) from date of response, and overall survival (OS) from diagnosis. Results: There were no significant differences in baseline characteristics, including median age (70 vs. 74 years, P=.93), proportion of patients with ≥5% bone marrow blasts (27% vs. 35%, P=.54), high/very high cytogenetic risk by the Revised International Prognostic Scoring System (IPSS-R, 25% vs. 40%, P=.31), number of pts with comorbidities (44% vs. 29%, P=.38), median time from diagnosis to treatment (14.6 vs. 6.4 months, P=.25) or prior MDS treatment (AZA and/or lenalidomide, 46% vs. 53%, P=.17), between the LD-DAC and SD-DAC groups, respectively. Likewise, the LA-DAC and SD-AZA groups were similar with respect to median age (70 vs. 68 years, P=.15), proportion of patients with ≥5% bone marrow blasts (27% vs. 39%, P=.19), and high/very high cytogenetic risk by the IPSS-R (25% vs. 27%, P=.83). However, pts in the SD-AZA group had a shorter median time from diagnosis to treatment (2.9 vs. 14.6 months, P=.009) compared to LD-DAC. Median treatment duration was longer in LD-DAC pts compared to SD-DAC (9.1 vs. 3.1 months, P=.0008) with a median cumulative dose of 8.4 mg/kg (range 1.2-41.2) and 350 mg/m2 (range 175-975) for LD-DAC and SD-DAC, respectively. Compared to SD-DAC, the LD-DAC group required more frequent dose reductions/delays (67% vs. 20%, P=.004) and experienced more hematologic toxicity (85% vs. 29%, P〈 .0001), respectively. While median time to best response was similar for LD-DAC and SD-DAC (3 vs. 4.1 months, P=.52) there was a trend for higher IWG response rates (30% vs. 18%, P=.06) and lower disease progression rates (18% vs. 41%, P=.06) for LD-DAC compared to SD-DAC. However, this did not translate into a difference in median PFS (11 vs. 7.6 months, P= .34) or OS (23.9 vs. 18.2 months, P=.64, Figure 1). Comparing these results to SD-AZA, while LD-DAC had a longer median treatment duration (9.1 vs. 5.1 months, P=.052) and shorter median time to best response (3 vs. 5.3 months, P=.005) than SD-AZA, response rates were similar (30% vs. 31%, P=.5) and there were no significant differences with respect to median PFS (11 vs. 7.1 months, P=.059) or OS (23.9 vs. 21.1 months, P=.5, Figure 1). Conclusion: Pts treated with the LD-DAC strategy have a response rate at least equivalent to SD-DAC and SD-AZA, though they required more dose adjustments and receive treatment for a longer time period. Survival was similar for all dosing strategies. Very low-dose DAC is an active treatment approach and will be compared to standard-dose DAC and AZA in an upcoming randomized, prospective trial conducted through the MDS Clinical Research Consortium. Figure 1 Figure 1. Disclosures Off Label Use: Subcutaneous administration of very low-dose decitabine in treatment of MDS .

Description: Background The primary treatment goal in higher-risk MDS patients (pts) is to prolong survival by altering the natural history of the disease and delaying progression to acute myeloid leukemia (AML). Treatment with HMA such as azacitidine (AZA) improves overall survival (OS) in pts who achieve a response of stable disease (SD) or better (complete remission [CR], partial remission [PR], or hematologic improvement [HI]) (Gore et al, Haematologica, 2013). However, it is not well established if pts who achieve SD by 6 months (mo) of therapy should be offered different therapies to optimize their response or continue with the same HMA regimen. Methods Clinical data were obtained from the MDS Clinical Research Consortium database. Pts treated with either AZA or decitabine (DAC) were included and categorized per the Revised International Prognostic Scoring System. Responses were evaluated per International Working Group (IWG 2006) criteria. SD was defined as no evidence of progression and without achievement of HI. Early response was defined as achievement of CR, PR, HI, or SD between 3-6 months (mo) of therapy. Best response was assessed after 6 mo of treatment. OS was calculated from the start of therapy to date of death or last follow up. Differences were evaluated using the Fisher-exact test and Mann-Whitney U tests for categorical and continuous variables, respectively. Results Of 291 pts with higher-risk MDS and available response data, 248 (85%) received treatment with AZA and 43 (15%) with DAC. Median age was 70 years (range, 35-99), median absolute neutrophil count (ANC) was 1.05 X109/L (range, .58-68), hemoglobin 9.3 g/dL (range, 3.7-14.3), platelets 73 X109/L (range, 4-659), and bone marrow blasts 10% (range, 0-19). Per IPSS-R, 20% of pts were intermediate risk, 37% high, and 43% very high. A total of 142 pts (49%) progressed to AML. Median time from diagnosis to start of HMA was 28 days. Early responses (3-6 mo) were: CR 10%, PR 5%, HI 10%, and SD 49%. Among the 144 pts who achieved SD at 3-6 mo, 29 (20%) achieved a better response (CR, PR, or HI) later during their treatment, with a median time to better response of 3.7 mo (range,1.2-14.5); 113 (89%) remained with stable disease, and 2 (1%) progressed to AML. With a median follow up of 16.5 mo (range, 2.5-120.2), the median OS by best response at any time point during therapy: CR 19.7 mo, PR 12.6 mo, HI 15.4 mo, and SD 13.8 mo. Pts who achieved CR had superior OS compared to SD (p=.03) but similar survival compared to pts who achieved PR (p=.45) or HI (p=.24). Of 29 pts with SD who achieved a better response 〉 6 mo, 16 (55%) achieved a CR and 13 (45%) achieved a PR or HI. Pts with SD who subsequently achieved CR had superior OS compared to pts who remained in SD (28.1 vs 14.4 mo, respectively, p=.04), while pts who subsequently achieved PR or HI had a similar survival compared to pts who remained in SD (12.1 vs 14.4 mo, respectively, p=.81). Conclusion Among MDS pts treated with HMAs, 20% who have SD at initial assessment go on to have a better response later in their treatment course, However, only 11% of SD pts achieved a CR thereafter, which predicted better OS. Thus, pts who achieve SD by 6 mo should be offered a clinical trial with novel agents to improve their chances of achieving CR. If a clinical trial is not available, pts should remain on HMA therapy until disease progression. Disclosures No relevant conflicts of interest to declare.

Description: Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P 〈 0.00001). The specific cytogenetic abnormality was predictive for survival (P 〈 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P 〈 0.00001). Complex karyotype (〉/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P 〈 0.00001). Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P 〈 0.00001). Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; 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. Steensma:Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet:Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.

Description: Introduction Somatic mutations in SF3B1 ,a gene encoding a core component of RNA splicing machinery, have been identified in patients (pts) with myelodysplastic syndrome (MDS). The SF3B1 mutation (MT) is more commonly detected in pts with ring sideroblasts (RS) morphology and is associated with favorable outcome. The pattern of response among SF3B1 mutated MDS pts to available treatment options, including erythropoiesis stimulating agents (ESA), hypomethylating agents (HMA) and lenalidomide is not known. The distinct underlying disease biology among such pts may alter response to treatment. Methods Pts treated at MDS CRC institutions with MT vs wild-type SF3B1 (WT) controls were matched 1:2. Matching criteria were age at diagnosis, year of diagnosis and International Prognostic Scoring System (IPSS) category at diagnosis. IPSS category was split into two groups (Low or Int-1 vs. Int-2 or High). Matching was performed using the R package by calculating a propensity score, which was then used to determine the two most similar WT SF3B1 patients for each SF3B1-mutated pt, without replacement. Additionally, to be included in the population, pts also had to have been treated with one of the following: ESAs, HMA, or lenalidomide. Response to treatment was evaluated by international Working Group criteria (IWG 2006) and classified as response if hematological improvement or better was achieved (HI+). Survival was calculated from date of treatment until date of death or last known follow-up, unless otherwise noted. Results: We identified 48 Pts with MT and 96 matched controls. Table 1 summarizes baseline characteristics comparing MT vs WT SF3B1 cohorts. SF3B1 MT was detected more often in association with RS, as expected. The majority of pts had lower-risk disease by IPSS and revised IPSS (IPSS-R). Pts with MT had higher platelets than controls. The most common concomitant somatic mutations observed were TET2 (30%), DNMT3A (21%), and ASXL1 (7%). Median follow-up time from diagnosis was 35 months (mo). Median overall survival (OS) from diagnosis was significantly longer for patients with SF3B1 MT (108.5 mo (68.8, NA)) than wild-type controls (28.3 mo (22.3, 36.4); p 〈 0.001). Patients with an SF3B1 MT had a decreased hazard of death (hazard ratio [HR]: 0.49 (95% confidence limits [95% CL]: 0.29, 0.84); p = 0.009) ESA was the first line therapy for 43 pts (88%) with MT and 55 WT Pts (56%). For ESA treated pts, 14 out 40 MT Pts responded (35%) compared to 9/56 among WT Pts (16%), p 0.032. Among those treated with HMA therapy, 5 out 21 (24%) MT pts responded compared to 11/46 (24%) WT Pts (p 0.99). Finally, for Pts treated with lenalidomide 4/16 (25%) and 4/21 (19%) responded among SF3B1 MT and WT Pts respectively, p 0.7. Conclusions SF3B1 somatic mutation in MDS is commonly associated with RS, lower risk disease, and better OS. Pts with SF3B1 mutation had higher response to ESA compared WT SF3B1. No difference in response to HMA or lenalidomide was observed compared to WT patients. Response rates to lenalidomide and HMA were low in both MT patients and controls. Biologically rational therapies are needed that target this molecular disease subset. Table 1. Baseline characteristics SF3B1 MT (n=48) SF3B1 WT (n=96) P value Age median 65 67 0.6 Gender male 29 (60%) 64(67%) 0.5 Race White 44/45 (98%) 83/90 (92%) 0.34 WHO classification RA RARS RCMD RARS-T Del5 q RAEB-I RAEB-II MDS-U MDS/MPN CMML 3 24 8 4 1 3 3 2 0 0 6 9 17 2 6 10 9 3 11 9 IPSS Low Int-1 Int-2 High 29 (60%) 16 (33%) 3 (6%) 0 21 (22%) 69 (72%) 4 (4%) 2 (2%) 〈 0.001 IPSS-R Very low Low Intermediate High Very High 15 (31%) 26 (54%) 5 (10%) 2 (4%) 0 11 (11%) 37 (39%) 26 (27%) 18 (19%) 4 (4%)

Description: Background: The majority of MDS patients (pts) have anemia and are treated initially with ESAs. Particularly for lower-risk MDS pts (International Prognostic Scoring System (IPSS) Low and Int-1), once ESAs are no longer effective, treatment options are limited to drugs commonly used for higher-risk MDS, such as hypomethylating agents, or off-label use of immunomodulatory drugs. As a result, most pts receive only transfusion support post-ESA, representing a pt group with an unmet medical need frequently targeted for drug development, for whom long-term outcome is unknown. Methods: We studied pts diagnosed with lower-risk MDS from 1997-2014 at MDS CRC institutions and treated with ESAs (epoetin alpha (epo) or darbepoetin (darb)). The best response to treatment was categorized per International Working Group 2006 response criteria (hematological improvement (HI), complete response (CR), or partial response (PR)). The primary endpoint was overall survival (OS) at the time of ESA failure, defined as cessation of treatment due to relapse or refractoriness; a secondary endpoint was time to AML transformation or death, from time of response (for responders) or failure (for nonresponders) determination. Descriptive statistics were used for baseline characteristics. The Kaplan Meier method was used to estimate OS and a log rank analysis was used to compare response categories. Cox regression analysis was performed for multivariable analysis. Results: Of 206 patients included in analyses, median age was 71.6 years (range: 25.3-88.1), 36% were female, 5% were African-American, and 11% had t-MDS. WHO categories included RA (14%), RARS (16%), RCMD (42%), MDS-u (6%), del (5q) (4%), RAEB-1 (9%), RAEB-2 (2%), RARS-T (2%), MDS/MPN-u (3%), and CMML-1 (2%), with pts classified as IPSS Low (39%), Int-1 (61%), or IPSS-R Very Low (16%), Low (55%), Intermediate (26%), and High (4%). IPSS cytogenetic risk groups were Good (72%), Intermediate (22%), and Poor (6%). Baseline median hemoglobin was 9.4 g/dl (range: 5.5-14.2), serum epo level was 97.2 (range: 14.2-3899.0), and 11% were transfusion-dependent. Treatment included darb (59%) and epo (41%) at median doses of 300 mcg (range: 100-500) and 40,000 units (range: 5,000-80,000), respectively. Pts remained on therapy for a median of 30.4 weeks (range: 0.0-447.7) and had a median follow-up of 28.4 months (95% confidence interval (CI): 24.5, 45.4). First treatments following ESA failure included azacitidine (41.7%), decitabine (10.2%), lenalidomide (16.6%), experimental drugs (3.1%), other growth factors (13.6%), ATG and/or other immunosuppressants (8%), chemotherapy (0.1%) , transplant (0.1%) and others (6.6%). The overall response rate (ORR) to ESAs was 18.8%, with 0% achieving CR; 0.1% PR; and 18.7% HI. Responses for epo were 17.3% and for darb were 19.8% (p=.67 for difference). For both ESAs, 81.2% of patients had disease refractory to treatment: 69.4% with stable disease and 12% with progressive disease with no significant differences between epo and darb by responder status. Median response duration for epo and darb were 21.9 weeks (range: 3.0 - 447.7) and 39.1 weeks (range: 0.0 - 350.7) respectively (p=0.045). Median survival from the date of diagnosis was 28.4 months (95% CI: 24.5, 45.4), and from ESA failure was 23.9 months (95% CI: 19.9, 33.0): 21.6 months (95% CI: 15.6, 39.2) for epo and 28.8 months (95% CI: 21.2, 39.7) for darb (p=0.99) (Figure). Median time to AML transformation or death was 17.4 Months (95% CI: 14.1, 22.9): 25.4 months for responders and 16.8 months for non-responders (p=.069). For patients who received ESAs for a minimum of 4 months (39% of pts for epo and 61% for darb), ORR was 16.5%, and median survival from ESA failure was 23.0 months (95% CI: 14.7, 33.0): 22.3 months (95% CI: 13.1, NA) for epo and 24.7 months (95% CI: 14.3, 39.7) for darb (p=0.87). Conclusion: In this large, but uncontrolled cohort, response rates were similar for lower-risk MDS patients treated with epo and darb, though duration was longer for darb. There was a trend for improved outcomes in patients who responded to ESAs. Lower-risk MDS patients treated with ESAs have an OS of less than 2 years from the time of failure, and can thus be considered a high-risk MDS group for whom subsequent therapies are not standardized, representing an unmet medical need. Figure 1. Figure 1. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Komrokji:Incyte: Consultancy, Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Speakers Bureau.