Patnaik, Mrinal M.

Abstract Background: Myelodysplastic syndromes (MDS) are rare hematological neoplasms that are more typically seen in elderly patients. Young patients (< 50 years old) have been reported to comprise between 3-6% in the Surveillance, Epidemiology and End Results (SEER) (Ma X et al, Cancer 2007; Rollison R et al, Blood 2008) with a better overall survival (OS). We hereby report the characteristics of young MDS patients with long survival follow-up. Methods: A total of 1012 MDS patients' data from Oct 1993 to Dec 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients youngers than 50 years old (yMDS) were included as cohort 1, while the rest was included as control group (cohort 2). Prognostic factors were analyzed by univariate and multivariate analyses. Survival estimates were calculated using Kaplan-Meier curves and univariate and multivariate analyses was based on log-rank testing using JMP software version 10. Results: Characteristics: We identified 68 (7%) yMDS patients with a median age of 42 years (range, 18-49). Female gender was more common in yMDS (43% vs 31%, p= 0.05). Upon comparison between cohort 1 and 2, only platelets were significantly lower in yMDS (61 vs 102, p <0.0001), but not white blood cells, hemoglobin or degree of marrow fibrosis. MDS subtyping according to World Health Organization 2016 showed single lineage dysplasia in 15% vs 2%, multilineage dysplasia 24% vs 36% , ring sideroblasts 9% vs 15%, isolated del (5q) 1% vs 3%, excess blasts 44% vs 31%, and unclassifiable in 6% vs 5%. As expected, therapy related MDS (t-MDS) was more frequent in yMDS (33% vs 17%, p= 0.005). Transformation to acute myeloid leukemia (AML) was also more frequent in yMDS (28 % vs 11%, p= 0.0004). Compared to cohort 2, yMDS IPSS-R scores were very high, high, intermediate, low, and very low in 24% vs 13%, 29% vs 16%, 21% vs 20%, 19% vs 35%, and 7% vs 17%, respectively. Allogenic hematopoietic cell transplantation (HCT) was more frequent in yMDS (42% vs 4%, p< 0.0001). Survival outcome: Median OS was longer for cohort 1 vs cohort 2 but did not reach statistical significance (43 vs 21 months, p= 0.1). Median progression free survival (PFS) was shorter for cohort 1 vs cohort 2 but did not reach statistical significance (8 vs 12 months, p= 0.3). Median OS for cohort 1 based on R-IPSS was 44, 105, 40, 18, and 12 months for very low, low, intermediate, high and high risk groups, respectively (p= 0.09). Median OS was shorter in t-MDS vs de novo MDS in cohort 1 (13 vs 47 months, p = 0.04). Young patients who had transformed to AML had a worse median OS (18 vs 93 months, p=0.001). On multivariate analysis neither t-MDS nor R-IPSS had a statistically significant impact on OS. Conclusions: MDS is rarely diagnosed under the age of 50. IPSS-R was less powerful in detecting differences between its risk groups for this patient population, although more than half of the patients with yMDS had either high or very high risk. Among this cohort of yMDS patients, there was a significantly higher proportion with therapy-related myeloid neoplasms compared to older patients (one third of patients), with subsequent higher rates of transformation to AML and higher allogeneic HCT. In our study, we did not find an improved OS for yMDS patients compared to older patients. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Background: Approximately 1,000 acute promyelocytic leukemia (APL) patients are diagnosed in the US annually. APL has the highest cure and early mortality rates of all acute leukemias. The availability of all trans-retinoic acid (ATRA) in 1995 and arsenic trioxide in 2000 has further improved the overall survival (OS). However, whether there is uniform improvement in OS across demographic subgroups and if sooner time-to-treatment (TTT) reduces early mortality are unknown. We used the National Cancer Data Base (NCDB), a nationwide oncology registry covering 70% of the US cancer population to answer these questions. Methods: We identified patients with APL diagnosed from 1998-2011 using ICD-O-3 code 9866. Survival functions were estimated using the Kaplan-Meier method and 30-day mortality was estimated as 1-survival at 30 days. We compared OS according to demographic subgroups (gender, age [18-40, 41-64, and >65 years], race [White, Black, Native American, Asian/Pacific Islander, and other], and ethnicity) across years of diagnosis (Period [P] 1: 1998-2001, P2: 2002-2006, and P3: 2007-2011). For 30-day mortality, we compared the rates according to demographic subgroups and time periods and determined the effect of TTT (days from APL diagnosis to ATRA and/or chemotherapy). For this analysis we included only patients treated within 30 days of diagnosis and those diagnosed from 2003 to 2011. TTT was grouped as 0, 1, 2, or >3 days. We used mixed-effects logistic regression model to obtain odds ratio comparing treatment delays. Our model accounted for multiple subjects per facility with a random intercept and was adjusted for gender, Charlson-Deyo score, and year of diagnosis. Results: Characteristics: There were 8,084 APL patients in our study. The median age at diagnosis was 51 (24% were older than 65) years and 50% were females. White race (85%) was the most common, followed by black (11%) and Asian (3%). Twelve percent were Hispanic in origin. Slightly more patients (54.8%) were treated in academic centers. Thirty seven percent had either Medicaid or Medicare insurance. OS: Race had no impact on OS, although Asians had a trend towards improved OS (P=0.06). Both females and young age affected OS favorably (P <0.0001). In general, OS improved over the three time periods (P=0.002). Across Periods 1-3, we observed significant improvement in OS among the males (P=0.03), 18-40 (P=0.035) and 41-64 (P=0.005) age groups, Whites (P=0.012), and non-Spanish/Hispanics (P=0.002), but not among their counterparts. 30-day mortality rate: Age above 65 years was associated with highest 30-day mortality (33%). Similarly male gender had statistically significant higher 30-day mortality (shown in the Figure). There was no statistically significant difference among Periods 1-3. As expected, untreated patients had an increased risk of death versus treated (HR=1.9, confidence interval 1.7-2.1). TTT: A third (33.5%) of the patients was treated within two days of APL diagnosis. TTT was not independently associated with lower 30-day mortality rate (shown in the Table). Presence of disseminated intravascular coagulopathy (DIC) data was not available to analyze. Conclusions: From 1998-2011, the OS of APL continued to improve but not uniformly across demographic subgroups. In contrast, the 30-day mortality did not improve in the same time period. Both Age above 65 and male gender predicted worse 30-day mortality and OS. Our study did not find a favorable association between shorter TTT and lower 30-day mortality rate. Our study was not able to study these findings among different risk groups. Disclosures Al-Kali: Celgene: Research Funding. Tibes:TetraLogic Pharmaceuticals: Research Funding.

Abstract Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS). Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R. Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems. Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Molecular profiling has revolutionized the field of hematology, and in particular myeloid neoplasms. NPM1+/FLT3- mutational status has been shown to have a favorable prognostic impact in patients with acute myeloid leukemia (AML). However, little is known about its interaction with age. Methods: We retrospectively analyzed the overall survival (OS) in newly diagnosed AML patients, whose FLT3 and NPM1 data were available, and were treated with cytotoxic chemotherapy at our institution between 2003 and 2013. Patients 18 to 60 years of age were categorized as adult, and those above 60 years were classified as elderly. Each of the elderly or adult groups were further divided according to the presence or absence of combined NPM1+/FLT3- mutational status. Estimated probabilities of overall survival were calculated using the Kaplan-Meier method, with the log-rank test to compare groups. Demographics and continuous variables were compared using the Wilcoxon rank sum test. Appropriate IRB approval was obtained. Results: Out of 835 patients with AML, 86 patients with both known FLT3/NPM1 mutation status and receiving induction chemotherapy were found. NPM1+/FLT3- mutational status was present in 11 elderly (median age 68 yr, hemoglobin (Hb) 8.7 g/dL, white blood cells (WBC) 9.6 x109/L, platelets (PLT) 100 x109/L, peripheral blood blasts percentage (PB%) 31), and in 11 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21). Twenty-eight elderly patients (median age 66 yr, Hb 9.4 g/dl, WBC 15.7 x109/L, PLT 66 x109/L, and PB% 33), and 36 adult patients (median age 49 years, Hb 9.1 g/dL, WBC 14 x109/L, PLT 67 x109/L, and PB% 21) were carrying genotypes other than NPM1+/FlT3-. There was no statistical significant difference in the median age, Hb, WBC, PLT, and PB% at the time of diagnosis. Out of 86 patients, 79 had intermediate, 6 had adverse, and 1 had favorable cytogenetic risk. All elderly and adult patients with NPM1+/FLT3- genotype had intermediate risk cytogenetics. When treated with cytotoxic chemotherapy, elderly patients with NPM1+/FLT3- genotype demonstrated a significantly better overall survival compared to elderly patients without this genotypes (p=0.015), and interestingly also to adult AML carrying other genotypes (p=0.028). Surprisingly, there was not an improved survival in adults with NPM1+/FLT3- genotype compared to adults carrying other genotypes (p=0.14), but this may have been related to the small numbers in each group. No significant difference in the overall survival was observed between elderly and adult patients who were carrying NPM1+/FLT3- mutational status (p=0.4). The estimated 5-year survival rates for elderly with and without NPM1+/FLT3- status were 71% vs. 14%, and for adults with and without this genotype were 49% vs. 19%, respectively. Conclusion: Age does not have an impact on the OS in AML patients with NPM1+/FLT3- mutational status, arguing strongly for intense chemotherapy in this group. Elderly AML patients with NPM1+/FLT3- genotype have a superior OS compared to both adult and elderly patients carrying other genotypes, when treated with cytotoxic chemotherapy. Further validation in large prospective studies is warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Myelodysplastic syndrome (MDS) is a heterogeneous disease characterized by cytopenias and a propensity to progress into acute myeloid leukemia in a subset of patients. Clinical trials which led to FDA approval of hypomethylating agents (HMAs) stratified patient's risk status per the IPSS. In 2008, WHO further categorized patients into different groups and the IPSS was revised into the IPSS-R. Therefore, there is a paucity of data regarding the response rates and clinical outcomes of HMA therapy when stratified per WHO subtype and IPSS-R. Goal: We carried this review to assess whether WHO subtypes or IPSS-R had a differential response with corresponding impact on survival. Methods: After IRB approval, all MDS pts who received hypomethylating agents (HMA) (azacitidine or decitabine) with available response data (2000-2014) were included. Clinical characteristics were obtained retrospectively. IPSS-R (Greenberg 2012) was used for risk stratification. Response assessment was based on IWGR 2006 criteria. Statistical comparisons were performed with the χ2 test for categorical variables and the Wilcoxon test for continuous variables. Survival analysis was based on the Kaplan-Meier method and log rank test. For all analyses, P ≤ 0.05 was considered statistically significant. Results: We identified 823 pt in our MDS database; among those that received HMA therapy 70 patients (pts) had evaluable response data. The median age at diagnosis was 67 years (31-85) and 49 (70%) were males. MDS subtypes per WHO 2008 classification were 31(44%) RAEB1/2, 26(37%) RCMD, 10(14%) MDS-U, 2(3%) RARS, and 1(1%) MDS 5q. Fifteen (33%) patients had secondary MDS. 23(32%) developed AML, and median time to leukemic transformation was 14 months (7.8-21). Median time to start HMA was 2.7 months (0-77). Median follow up from initial diagnosis was 20 months (3-118) at which time 22(31%) deaths were documented. A. Patient characteristics: Prior to HMA therapy median laboratory values included; Hemoglobin 9.6 g/dL (6.6-14.8), ANC 1.1 x1010 (0.01-16), Platelet 66 x1010 (4-937), peripheral blast % 0 (0-18), and bone marrow blast % 5 (0-17). IPSS-R for our cohort was as the following, 15(27%) Very high, 14(25%) high, 10(18%) intermediate 12(21%) low, and 5(9%) very low risk. B. HMA Response rates based on WHO subtype: We observed no significant difference in response (p = 0.6) when comparing response rate among different groups. Response rates per WHO subtype were as follows: i. RAEB: 7 (22%) pts achieved CR/Marrow CR, 1(3%) had HI/PR, 17(55%), and 6(20%) had stable disease (SD) and progressive disease (PD), respectively. ii. RCMD: 2 (8%) pts achieved CR/Marrow CR, 4(16%) had HI/PR, 12(46%), and 8(30%) had SD and PD, respectively. iii. MDS-U: 1 (10%) pt achieved CR/Marrow CR, 1(10%) had HI/PR, 6(60%), and 2(20%) had SD and PD, respectively. iv. MDS 5q/RARS: 1(33%) had SD, and the remaining three pts had PD. C. HMA Response rates based on IPSS-R: i. Very low: 1(20%) had HI/PR, 3(60%), and 1(20%) had SD. ii. Low: 2(17%) pts achieved CR/Marrow CR, 3(25%) had HI/PR, 4(33%), and 3(25%) had SD and PD, respectively. iii. Intermediate: 2 (20%) pts achieved CR/Marrow CR, 5(50%), and 3(30%) had SD and PD, respectively. iv. High: 2(14%) pts achieved CR/Marrow CR, 2(14%) had HI/PR, 7(50%), and 3(21%) had SD and PD, respectively. v. Very high: 1(7%) pts achieved CR/Marrow CR, 9(60%), and 5(33%) had SD and PD, respectively. Comparing responses among IPSS-R risk stratification groups, was not statistically significant (p = 0.49). We did not observe a difference in response rate when we further classified pts into low risk (very low, low & intermediate), and high risk (high, very high) (p = 0.27). D. Response effect on Survival: Overall survival was not statistically different among responders (CR/Marrow CR/HI &PR) and non-responder (SD & PD); 22.3 vs 14.7 months respectively (p = 0.21) (Figure1). Conclusion: Using contemporary MDS risk stratification and WHO classification was not predictive of response to hypomethylating agents. Responders did not seem to benefit from prolongation of survival. Given the small sample size in this cohort, this should be further explored in larger groups to identify if there are any potential subgroups that would benefit more from such therapy. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background: Acute erythroleukemia (AML-M6) is an aggressive myeloid leukemia, with poor outcomes (median survival < 12months). In 2008, the WHO further sub-classified this disease into two subgroups- erythroid leukemia and pure erythroid leukemia, based on the number of erythroblasts and myeloblasts. We carried out this study to evaluate differences in presenting features and outcomes between erythroid leukemia and pure erythroid leukemia. Methods: After due IRB approval, out of 923 AML, 43(4.6%) pts who met the 2008 WHO criteria for acute erythroleukemia (2000-2014) were identified, and clinical characteristics retrospectively reviewed. A diagnosis of erythroid leukemia (M6a) was considered if > 50% of the total nucleate BM cells were of erythroid lineage and > 20% of non-erythroid cells were myeloblasts. Pure erythroid leukemia (M6b) was diagnosed in pts who presented with > 80% of BM nucleate cells consisting of immature erythroid precursors. Cytogenetic risk stratification was based on NCCN AML guidelines. Statistical comparisons were performed with the χ2 test for categorical variables and the Wilcoxon test for continuous variables. Univariate and multivariate analyses were performed with the Cox logistical regression. Survival analysis was based on the Kaplan-Meier method and log rank test. For all analyses, P ≤ 0.05 was considered statistically significant. Results: The median age at diagnosis was 65 years (27-90) and 34(79%) were male. 30 (69%) had M6a and 13 (30%) had M6b. 27 (62%) had de novo AML M6, whereas 16 (37%) had secondary AML (9 underlying MDS and 7 therapy related).The median time to leukemic transformation for pts with underlying MDS was 8 months (2-83). Median follow up in our cohort was 7.2 months (2-157) at which time 13 (30%) deaths were documented. A. Patient characteristics: At time of diagnosis median laboratory values included; Hemoglobin 8.5 g/dL (4.6-11), WBC 2x109 (0.7-11.1), ANC 0.47x109 (0.01-4.07), Platelet 33x 109 (7-177), peripheral blast % 2 (0-35), and bone marrow blast % 11 (0-84). Cytogenetic information was available in 38 pts; of which 6(16%) were diploid, 21(55%) were complex/monosmal and 1(3%) was complex/non monosomal. Intermediate risk cytogenetic was observed in 15 pts (39%), and poor risk cytogenetic was identified in 23(61%). Comparing M6a and M6b, we observed that pts with M6a tend to have more leukopenia and neutropenia and higher marrow blast percentage compared to M6b (Table 1). None of the patients experienced extramedullary disease or CNS involvement. B. Outcome and prognostics: We did observe a trend towards worse survival in pts with M6b, 7 months vs 12.9 months with M6a (p= 0.08) (Figure 1). There was no difference in survival in acute erythroleukemia compared to other acute myeloid leukemias, 10.1 vs 14 months (p= 0.28), respectively (Figure 2). In univariate analysis, WBC, ANC, and cytogenetic risk impacted survival (Table 2), however only cytogenetic risks retained significance in the multivariate model; Intermediate risk HR 0.18 (0.05-0.51; p = 0.0009) and poor risk HR 5.4 (1.9-17.6; p = 0.0009). Conclusion: Acute Erythroid Leukemia is a rare leukemia with ~5% incidence in our cohort. We observed that regardless of the percentage of bone marrow erythroblasts and myeloblasts, survival in patients with Acute Erythroleukemia are predominantly impacted by cytogenetic risk stratification. This raises a question on the clinical relevance of the sub-categorization of acute erythroleukemia into erythroid leukemia and pure erythroid leukemia. Larger studies are needed to validate our results. Figure 1. Figure 1. Disclosures Al-Kali: Celgene: Research Funding.

Abstract Background: Combination studies with histone deacetylase (HDAC) inhibitors plus hypomethylating agents (HMA) have suggested beneficial clinical activity in higher risk MDS and AML, though exceptions have also been reported. Pracinostat is a potent oral HDAC inhibitor selective for class I, II and IV isoforms. A pilot phase Ib study of pracinostat in combination with azacitidine (AZA) in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). Preliminary data on 33 patients from a multi-center, open-label, single-arm Phase II study of Pracinostat in combination with AZA in elderly AML also reported a high CR/CRi rate (ASH 2014). Herein we report the latest survival and response results for this study. Methods: Eligibility includes previously untreated AML (≥20% bone marrow blasts), age ≥65 years, unsuitable for intensive therapy due to co-morbidities and/or AML related features, and intermediate or high-risk cytogenetics. Study therapy includes pracinostat, 60 mg p.o. 3 alternate days/week for 3 weeks plus AZA, 75 mg/m2) days 1-7 or days 1-5 and 8-9 either s.c. or i.v. with cycles repeated every 28 days until progressive disease, lack of response or intolerance. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) per IWG criteria. Response assessments occur at the end of cycle 1 or 2 then every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, a=0.10, power=0.90. Stage 1 n=27 and total stage 2 n=40. Secondary endpoints include overall response rate (ORR; CR+CRi+MLFS+partial response [PR]+PRi), duration of response and overall survival. Results: Between Dec 2013 and Dec 2014, 50 patients from 15 study sites were enrolled. At this time, 50 are evaluable for efficacy. Baseline disease characteristics for all patients include: median age 75 (range 66-84); 32 de novo AML, 13 evolved from AHD, 5 were treatment-related; 28 intermediate-risk and 20 high-risk cytogenetics and 2 unknown; baseline bone marrow blast counts ranged from 20% to 89% with a median of 40%. Thirty-one patients (62%) continue to be followed for survival (range: 8.5 to 18.5 months). Median overall survival has not been reached in the overall study population and neither in patients with high-risk cytogenics or those with AML secondary to MDS or prior anti-cancer therapy. The 1-year overall survival estimate is 60%. The primary endpoint of CR +CRi +MLFS has been observed in 27/50 evaluable patients (54%) to date, including 21/50 (42%) CR. The 60-day all-cause mortality rate is 10% (5/50). Treatment emergent adverse events (TEAEs) Grade ≥3 seen in >5% of patients: febrile neutropenia 30%; thrombocytopenia 22%; neutropenia 10%; cellulitis 10%; anemia 8%; fatigue 8%; sepsis 6%, and pancytopenia 6%. TEAE's leading to study therapy discontinuation: peripheral motor neuropathy (1), parainfluenza (1), atrial fibrillation/prolonged QTc (1), subdural hematoma after a fall (1), and sepsis (3). Conclusions: Pracinostat plus AZA produces a high rate of durable responses in this AML population. Median overall survival has not been reached; 1-year overall survival is estimated at 60%. Final response data and overall survival estimates will be presented at the meeting. Disclosures Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Khaled:Sequenom: Research Funding. Arellano:Cephalon Oncology: Research Funding. Butler:MEI Pharma, Inc.: Employment. Ashby:MEI Pharma, Inc.: Employment. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria.

Abstract Background: Ring sideroblasts (RS) are erythroid precursors with perinuclear mitochondrial iron accumulation seen in clonal disorders, such as myelodysplastic syndromes (MDS), and non-clonal conditions, including copper deficiency, lead poisoning, and congenital sideroblastic anemias (CSAs). CSAs involve a broad clinical and pathological spectrum related to mutations in ALAS2, ABCB7, etc. or mitochondrial aberrations (Pearson Syndrome; Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA); etc.). MDS-RS is often associated with SF3B1 mutations, which have not been reported in other SAs. This study sought to further describe the characteristics and outcomes of patients with CSAs. Methods: After due IRB approval, we retrospectively identified all patients with a CSA diagnosis seen at our institution from 1990-2014. All bone marrow (BM) slides were re-reviewed to confirm the presence of RS. Secondary causes of SA were excluded. Genetic testing on the BM specimen was carried out when possible through research collaborations with the Boston Children's Hospital. Data was retrospectively extracted and is reported in Table 1. Data was analyzed based on the presence or absence of mitochondrial inheritance. Results: Seventeen patients with CSA were identified, 3 (17.6%) with mitochondrial inheritance. In the non-mitochondrial inheritance group, the median age at diagnosis was 29 years (range, 1-61 years). Six (42.9%) were males. At a median follow-up of 119 months (range, 1-401 months), 1 (7.1%) death was documented. The median overall survival (OS) has not been reached. Six of 14 (42.9%) underwent genetic testing, and a mutation was identified in 4 (ALAS -2, FECH -1, and a novel mutation, currently being validated). Six of 6 (100%) samples analyzed for SF3B1 mutations were negative. Median laboratory values at diagnosis included hemoglobin 9.5 g/dL, MCV 85.8, WBC 6.4, and platelets 297,000. Three (21.4%) patients had splenomegaly. Nine (64.3%) had iron overload; 3 (33%) were treated with iron chelation therapy, with only 1 documented response (≥ 500 µg/L reduction in serum ferritin). Twelve (85.7%) were treated with pyridoxine. Outcomes of pyridoxine treatment are described in Table 1. Three of 14 (21.4%) received red blood cell transfusions, and 3 (21.4%) received erythropoiesis stimulating agents (ESA). One (7.1%) patient underwent allogeneic stem cell transplant. Three patients had SAs of mitochondrial inheritance; aberrations were identified in 2 (YARS2 and a 4 kilobase mitochondrial deletion). In this group, the median age at diagnosis was 2 years (range, 1-13 years), and all were males. At a median follow-up of 173 months (range, 119-329 months), 2 (66.7%) deaths were documented. Median laboratory values at diagnosis included hemoglobin 9.0 g/dL, MCV 97.0, WBC 5.2, and platelets 175,000. Conclusions: Congenital SAs are rare, and the majority are of non-mitochondrial inheritance. The molecular basis for disease can be ascertained in less than 50% of patients. Unlike MDS with RS, CSAs are not characterized by the SF3B1 mutation, which may be used to establish clonality. With appropriate supportive care measures, survival for non-mitochondrially inherited CSA remains favorable. Table 1. Demographics and Outcomes for 17 Patients with CSA Age at Diagnosis (Years) Gender Molecular Mutation Additional Features Pyridoxine Response Iron Overload Survival (Months) Outcomes Non-Mitochondrial Inheritance 5 M R452H in ALAS2 N Y2 Y 173 Alive3 3 M Mutation being validated Splenomegaly Y2 Y 254 Alive3 6 M Unknown, PTPN11, ALAS 2, ABCB7 negative Splenomegaly N Y 137 Alive, status-post transplant 29 F Unknown1 N N/A N 131 Alive3 41 F Unknown1 N Y2 N 83 Alive4 40 M Promoter mutation in ALAS2 Splenomegaly N N 106 Alive4 31 F Unknown1 N N Y 401 Deceased 54 M Unknown1 N Lost to follow-up Y 1 Alive3 3 M FECH N N/A N 189 Alive3 1 F SCAD -VUS N Lost to follow-up Y 13 Alive3 29 F Unknown1 N N Y 205 Alive3 58 F Unknown1 N N Y 47 Alive, unknown transfusion status 61 F Unknown1 N Y2 Y 58 Alive3 23 F Unknown1 Alpha-thalassemia-2-trait Y2 N 37 Alive3 Mitochondrial Inheritance 13 M YARS2 MLASA N Y 329 Alive4 2 M Unknown, mitochondrial deletions and ABCB7 negative Myopathy, Ataxia N/A N 173 Deceased 1 M 4 kilobase mitochondrial deletion Pearson Syndrome, B cell lymphoma Y2 N 119 Deceased 1No molecular testing performed 2Sustained hemoglobin response of ≥ 1 g/dL over baseline for ≥ 12 weeks 3Transfusion-independent 4Transfusion-dependent Disclosures Steensma: Incyte: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

Abstract Background : Prognosis in chronic myelomonocytic leukemia (CMML) is dire and blast transformation (BT) is a main cause of death. Current risk factors and prognostic models are mostly designed to predict overall (OS) and not leukemia-free (LFS) survival. Established risk factors for OS in CMML include anemia, thrombocytopenia, leukocytosis, monocytosis, presence of circulating immature myeloid cells (IMC), peripheral blood (PB) and bone marrow (BM) blasts, lymphocytosis, ASXL1 mutations, high risk abnormal karyotype and advanced age. In the current study, we examined risk factors for BT in CMML and survival outcome after BT. Methods : All CMML patients seen at our institution and with complete presentation data were considered. Clinical and laboratory variables, including cytogenetic information, at time of CMML diagnosis and also at time of BT were collected. DNA analysis for SRSF2, SF3B1, U2AF1, ASXL1 and SETBP1 mutations was carried out on specimens obtained at time of CMML diagnosis. We used both conventional and revised (see accompanying ASH 2014 abstract) cytogenetic risk models to query their influence in the current study population. Results: Clinical and laboratory features at time of CMML diagnosis: 277 consecutive patients (median age 71 years, range 18-91; 67% males) with WHO-defined CMML were considered. 236 (85%) patients had CMML-1 and the remainder CMML-2. According to the molecular Mayo risk model, 86 (33%) were high, 77 (29%) were intermediate-2, 77 (29%) were intermediate-1 and 24 (9%) were low risk. Mutational frequencies were 40% for ASXL1 (n evaluable =264), 44% for SRSF2 (n evaluable =263), 5% for SETBP1 (n evaluable =263). According to the revised Mayo-French consortium cytogenetic risk model, karyotype was high risk in 5%, intermediate in 21% and low risk in 74%. Risk factors for blast transformation (BT) : At a median follow-up of 16.2 months for all 277 patients from time of CMML diagnosis, 204 (74%) deaths and 38 (14%) BTs were documented. Median time from CMML diagnosis to BT was 13.3 months. In univariate analysis, female sex, younger age, lower hemoglobin, higher leukocyte count, higher absolute monocyte count, higher lymphocyte count, presence of circulating immature myeloid cells (IMC), increased peripheral blood (PB) blast %, increased bone marrow (BM) blast %, BM blasts ≥10%, CMML-2, abnormal karyotype, high risk karyotype per the Spanish or Mayo-French consortium, and higher risk disease per Mayo, MDACC or Dusseldorf models were all associated with higher risk of BT. In contrast, ASXL1 (p=0.84), SRSF2 (p=0.28) or SETBP1 (p=0.97) mutations were not found to be significant. In multivariable analysis, only PB blast % (p<0.0001), presence of PB IMC (p=0.004) and younger age (p=0.03) remained significant. Outcome of blast transformation : At time of BT, karyotype was abnormal in 58% and clonal evolution from time of CMML diagnosis was documented in 13 (36%) of 36 evaluable patients. Among the 38 patients with BT, induction chemotherapy was documented in 12 patients and allogeneic stem cell transplant (ASCT) in 6. At a median follow-up of 4.2 months from time of BT, 34 (89%) of the 38 patients with BT had died. Among the four patients who were alive at the time of this writing, 3 had received induction chemotherapy and two ASCT. Median survival of patients with BT, from time of disease transformation, was 4.5 months with 1, 2 and 3 year survival rates of approximately 30%, 16% and 3%, respectively. In univariate analysis, higher leukocyte count (p=0.01) and not receiving induction chemotherapy (p=0.03) were associated with shortened survival. Neither ASXL1 nor SRSF2 mutations affected survival after BT. Conclusions : Blast transformation in CMML occurs in approximately 14% of patients followed for a median of less than 1.5 years. Presence of circulating immature cells and percentage of peripheral blood blasts are the major determinants of BT in CMML. Genetic risk factors for overall survival did not appear to influence leukemia-free survival. Prognosis of post-CMML BT is dismal with median survival of less than 6 months and a 3-year survival of less than 5%. Outcome was better in patients receiving induction chemotherapy followed by ASCT. Disclosures No relevant conflicts of interest to declare.

Abstract Background:Morphologic complete remission (CR) is the gold standard for assessing response in acute myelogenous leukemia (AML). CR with incomplete count recovery (CRi) and CR with incomplete platelet recovery (CRp) are associated with inferior overall survival post induction therapy (Walter et al, JCO 2010 and Chen et al, JCO 2015). Furthermore, residual cytogenetic disease is associated with a higher relapse compared with patients with cytogenetic CR (CCR; Chen et al, JCO 2011). There is a paucity of literature regarding the impact of CRi, CRp and CCR prior to allogeneic transplantation. Aim:To study the impact of CRi, CRp and CCR and their impact on relapse incidence (RI), non-relapse mortality (NRM) and overall survival (OS) in reduced intensity allogeneic stem cell transplantation (RIC-SCT). Methods:After due IRB approval, patients (pts) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received RIC-SCT at our institution between 2008-2014 were identified. All clinical and pathologic data were retrospectively extracted. CR, CRi, CRp and CCR were defined in accordance to the international working group definition. Categorical and continuous variables were analyzed using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the kaplan-meier and log-rank test. RI was estimated on a competing event analysis using Grey's model. Cox proportional regression was used to compute hazard ratios (HR). Results: A. Baseline characteristics: A total of 134 patients were identified. A total of 70 (52%) were in CR, 40 (30%) in CRi and 24 (18%) in CRp. 129 patients had evaluable cytogenetic data pre-SCT; 81 (63%) were in CCR and 48 (37%) had persistent cytogenetic disease. Baseline patient, disease and transplant characteristics stratified by peripheral count recovery pre-SCT are shown (Table 1). Significantly more patients in CR had higher KPS, higher proportion AML diagnosis, more likely to be in first complete remission (CR1), higher rate of cytogenetic CR and a higher proportion of minor ABO mismatched donor. No other significant variables were identified between the three cohorts. B. Transplant outcomes: Median follow up of the entire cohort was 41.9 months and the 2-yr OS, RI and NRM were 61.7%, 25.7% and 21.9%. Patients in CR, CRi and CRp had a similar 2-year rates of RI (26.3%, 18.4% and 28.9%, respectively; p = 0.66), 2-year NRM (20.5%, 38.8% and 22.1%, respectively; p = 0.18) and 2-year OS (61.8%, 55.1% and 58.6%, respectively; p = 0.82). RI was significantly lower for patients in CCR pre-SCT with HR 0.25 (95% CI 0.11-0.51 p = 0.0001) without a difference in overall survival HR 0.68 (0.41-1.15; p = 0.14). However, we observed a similar RI in CR, CRi and CRp patients who had persistent cytogenetic disease pre-SCT (p = 0.55). The outcome remained similar between strata after excluding MDS patients (data not shown). Conclusion: We observed equivalent post-transplant outcomes between CR, CRi and CRp despite the presence of persistent cytogenetic disease. This suggests that RIC SCT had a role in mitigating the negative prognosis associated incomplete hematologic recovery. These findings have implications as physicians may not need to postpone SCT to await count recovery. This important question should be further validated in a larger cohort of patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding.