Patnaik, Mrinal M.

Abstract Background: AML outcome in elderly patients unfit for intensive chemotherapy continues to be challenging. Hypomethylating agents (HMA) can be effective in these patients but responses are short-lived (Fenaux et al, JCO 2009; Dombret et al Blood 2015). Even though HMAs achieve superior response rates to supportive care alone, complete remissions (CR) are rarely achieved and often quickly lost when they occur. The majority of patients will either have stable disease or progress through therapy. We hereby describe the outcome of these patients at our institution after they fail HMAs. Methods: A total of 56 AML patients' data from Feb 2007 to June 2015 at Mayo Clinic were reviewed after appropriate IRB approval was obtained. All cases had their bone marrow slides reviewed at our institution. Patients were considered for our study if they received HMA as frontline therapy for their AML. Patients who received HMAs after induction chemotherapy failure or for their MDS were excluded. Response was identified based on IWG AML criteria (Cheson et al, JCO 2003). 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: i) Characteristics at Diagnosis: We identified 56 AML patients treated with HMA as frontline therapy with median age of 76 years (range, 59-91), 68% of which were males. Cases were classified as AML with myelodysplasia related changes in 25%, and therapy related myeloid neoplasm in 2%, and not otherwise specific in 73%. Out of 56 cases, 23% were secondary to MDS, 2% ET (Essential Thrombocytopenia), 5% PV (Polycythemia Vera), 5% MF (Myelofibrosis), 4% from CMML (Chronic Myelomonocytic Leukemia); while 61% were de novo AML. Per cytogenetics data, 2% were considered favorable risk, 62% intermediate, and 36% poor (34% had complex karyotype). ii) Clinical outcome to Frontline HMA: Out of 56 patients, 15(27%) patients received azacitidine (AZA) and 41 (73%) received decitabine (DAC) with a median number of cycles of 4 (range 1-62). Median number of cycles was higher for AZA vs DAC (8 vs 4, p =0.3). CR was found in 10 (18%), CR with incomplete count recovery in 3 (5%), partial remission (PR) in 3 (5%) patients, with overall response of 28% and median response duration of 10 months (range, 1-78 months). Thirteen (81%) out of 16 responders relapsed. Therefore, only 53 patients were included in primary or secondary failure analysis. iii) Clinical outcome to Frontline HMA failure: Out of 53 patients, 12 (23%) received subsequent treatments. Out of the 12 patients, 3 (25%) received another HMA (switch), 2 (17%) subcutaneous low dose cytarabine, 4 (33%) intensive chemotherapy, while 3 (25%) received either therapy on a clinical trial or targeted therapy. None of the 12 patients who got first salvage therapy achieved remission. Five out of the 12 patients received second salvage therapy, 2 (40%) of which achieved CR. Only one patient had third salvage therapy and did not respond. No patient was able to proceed to allogenic hematopoietic cell transplantation. Median overall survival (mOS) for this group was 2 months. Median OS for patients who received subsequent salvage therapies was better than those who did not receive any subsequent therapy after failing HMA (9.5 vs 2 months, p = 0.0009). Conclusions: Elderly patients diagnosed with AML who are unfit for intensive chemotherapy have a poor prognosis. HMA can get some patients into remission but most patients will ultimately fail. Outcome for patients who have primary or secondary (relapse) failure is very poor with a median OS of 2 months. Switch of HMA did not result in any response. Response to salvage therapy continues to be low but offering salvage therapies seem to improve OS. Our study provides historical data for future novel therapies, which are sorely needed for these patients. Figure Figure. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Background: Over the last decade there have been three FDA-approved agents available for the treatment of myelodysplastic syndromes (MDS); azacitidine was approved in 2004 for all subtypes of MDS; lenalidomide in 2005 for MDS with del(5q); and decitabine in 2006 for intermediate/high risk MDS. However the ability of these drugs to improve survival outside of clinical trials remains controversial (Neukirchen J, Leuk Res 2015, Bernal T, Leukemia 2015). Objectives : i) Evaluate trends in overall survival (OS) and leukemic transformation (LT) rate amongst primary MDS patients (pts) by year of diagnosis and, ii) Evaluate trends in OS by treatment received. Methods : The Mayo Clinic database was used to identify pts with primary MDS in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and LT. A comparative analysis was performed based on year of diagnosis commensurate with the approval of the aforementioned drugs (Group 1- diagnosis prior to the year 2000, Group 2- year 2001-2004, Group 3- year 2005-2009, and Group 4- year 2010-2014). Results : i) Patient characteristics: A total of 1000 pts met the above-stipulated criteria. 85% of pts were above 60 years of age (median 72 years) with 69% being males. The distribution of pts by year of diagnosis was as follows: Group 1 (n=281)(28%), Group 2 (n=250)(25%), Group 3 (n=264)(26%), and Group 4 (n=205 (21%). Median follow-up of our cohort was 27 months (range; 0-300 months) during which time 808 (81%) deaths and 129 (13%) LT were documented. ii) Comparison of patient characteristics by year of diagnosis: Pts in group 1 and 2 compared with groups 3 and 4 were more likely to present with anemia defined as hemoglobin < 10 g/dl (61%/59% vs 50%/55%)(P =.04). In addition, groups 1 and 2 displayed a higher incidence of RA (5%/4% vs 1% each), and RARS (17%/16% vs 9%/8%), compared to groups 3 and 4 that had a higher incidence of RCMD (37%/44% vs 17%/28%) (P <.001). The IPSS-R risk distribution was not significantly different; 17% very low, 36% low, 21% intermediate, 15% high and 11% very high risk with median survivals of 72, 43, 24, 18 and 7 months, respectively (P <.001). As expected, a higher proportion of pts in groups 3 and 4 (41% and 57% respectively) received "disease-modifying" therapy including allogeneic transplant and hypomethylating agents as opposed to only 6% and 22% in groups 1 and 2 respectively (P <.001). iii) Trends in OS and LT rate by year of diagnosis: The median OS of the entire cohort was 30 months, with median OS and LT rates being similar amongst groups 1 through 4 at 31 vs 33 vs 30 vs 27 months (P =.79) (Figure) and 10% vs 16% vs 12% vs 15% (P =.25), respectively. iv) Trends in OS by treatment received: In univariate analysis survival was significantly better in pts who underwent allogeneic transplant (n=65) with median survival of 55 months vs 26 months for non-transplant pts (P<. 001); and among non-transplant lenalidomide-treated pts (n=44) with median survival of 54 months vs 26 months for the remainder of pts (P =.02). However, these results lost significance on multivariable analysis with the addition of age as a co-variate for transplant pts (P =.28), and IPSS-R as a co-variate for lenalidomide treated pts (P =.10). Excluding transplant pts, pts that received hypomethylating agents (n=158) had similar survival to pts not treated with hypomethylating agents (27 vs 29 months; P =.19, age-adjusted P =.11). In addition, the 54 pts who received other chemotherapeutic agents had similar survival to pts not treated with these agents (33 vs 26 months; P =.57, age-adjusted P =.80). Supportive care alone was utilized in 702 pts that had comparable survival to the 298 pts that received "disease-modifying" therapy (27 months vs 34 months; P =.05, age-adjusted P =.11). Conclusions : In this single center analysis of 1000 pts with primary MDS, stratified by year of diagnosis, the poor outcome of these pts has not improved over the last two decades, in spite of the significantly higher utilization of "disease-modifying" therapy, including hypomethylating agents since 2005. The lack of improvement in survival with hypomethylating therapy is consistent with recently published results from the Spanish MDS registry (Bernal T, Leukemia 2015). However, our retrospective study is not designed to detect marginal survival benefit, which has thus far been reported in only one clinical trial. Figure 1. Figure 1. Disclosures Al-Kali: Novartis: Research Funding. Pardanani:Stemline: Research Funding.

Abstract Background: Addition of sex combs-like 1 (ASXL1) is frequently mutated (mutational frequency 14-29%) and is prognostically relevant in myelodysplastic syndromes (MDS) (Bejar, NEJM 2011, Thol, JCO 2011). The prevalence and prognostic impact of ASXL1 mutation in MDS with ring sideroblasts (MDS-RS) is not known. MDS-RS is defined by the presence of ≥15% RS in bone marrow (BM), with refractory anemia with ring sideroblasts (RARS) being the prototype but may also be seen in other categories. Methods : Our institutional database was reviewed to identify patients with WHO-defined primary MDS with ≥1% BM RS. Pathology slides, including iron stains, were reviewed to accurately quantify BM RS percentage and confirm WHO morphologic categories. All patients were annotated for their mutational status including ASXL1, JAK2, MPL and IDH with a subset for SF3B1 by PCR sequencing performed on BM specimens obtained at diagnosis. Results : i) Patient characteristics: A total of 76 MDS patients displayed ≥1% BM RS (median age 72 years; 76% males); 51 (67%) patients had ≥15% BM RS. IPSS-R risk categories for the entire 76 study patients were 30% very low, 37% low, 14% intermediate, 11% high and 8% very high; IPSS-R karyotype was normal in 63%, very good/good risk 17%, intermediate risk 12%, and poor/very poor in 8%; 3% had monosomal karyotype. ii) Prevalence of ASXL1 mutations: Twenty-one (28%) of the 76 study patients were ASXL1 mutated; ASXL1 mutational frequencies were 25% (16/63 patients) in the absence and 38% (5/13 patients) in the presence of excess blasts (P =0.34). When considering only those patients with ≥15% BM RS (n =51), ASXL1 mutations were detected in 12 (24%) patients with mutational frequencies of 24% (11/46 patients) in the absence and 20% (1/5 patients) in the presence of excess blasts (P =0.84); ASXL1 mutational frequencies were 13% (3/23 patients) in RARS and 37% (7/19 patients) in RCMD-RS (P=0.07). In terms of other mutations, all 76 study patients were wild-type for JAK2 and MPL, whereas IDH2 R140Q mutations were present in 4 (5%) patients, including 3 with concomitant ASXL1 and IDH2 mutations. IDH1 mutation was seen in only 1 patient. 25 of 43 (58%) patients screened were mutated for SF3B1, including 4 (9%) who were mutated for both ASXL1 and SF3B1. Significant associations were evident between ASXL1 and IDH2 mutations (P =0.02) but not between ASXL1 and SF3B1 mutations (P =0.61). iii) Clinical correlates of ASXL1 mutations: Among all 76 study patients, presence of ASXL1 mutation did not correlate with age (P =0.30), hemoglobin level (P =0.17), platelet count (P =0.53), BM blast percentage (P =0.17), WHO morphologic category (P =0.34), transfusion dependence (P =0.84), IPSS-R cytogenetic categories (P =0.93), or IPSS-R risk group (P =0.33). The results were unchanged when analyzing the 51 patients with MDS-RS (i.e. ≥15% BM RS). Amongst the ASXL1 mutated patients (n =21) IPSS-R cytogenetic categories were as follows: 13 patients with normal karyotype (62%), 2 patients with trisomy 8 (10%), 1 patient each with -Y, del(11q), del(5q), del(20q), isochromosome 17 and monosomy 7 (5% each). iv) Prognostic impact of ASXL1 mutations: Median follow-up was 42.5 months, during which time 69 (91%) deaths and 8 (11%) leukemic transformations were documented. ASXL1 mutated patients had a median survival of 29 months, compared to 45 months in ASXL1 wild-type patients (P =0.04). However, the difference in median survival was no longer significant during multivariable analysis, which instead identified only IPSS-R and transfusion need as being independent predictors of inferior survival. Amongst those patients without excess blasts (n =63), presence of ASXL1 mutation predicted inferior survival in univariate analysis (P =.04) and significance was sustained during multivariable analysis that included IPSS-R cytogenetic categories (P =.04) but became borderline when WHO morphologic category was included (P =0.06); ASXL1 mutated patients had a shortened median survival of 43 months compared to 66 months in ASXL1 wild-type patients (P =.04). In the presence of ≥15% BM RS, ASXL1 mutations did not affect survival (P =0.48); the results were the same for RARS (P =0.9) and RCMD-RS (P =0.64). Conclusions : ASXL1 mutations might not affect survival in MDS patients with ≥15% BM RS, including those with RARS or RCMD-RS. Furthermore, an apparent survival disadvantage seen in ASXL1 -mutated MDS patients with ≥1% BM RS was accounted for by IPSS-R. Disclosures Pardanani: Stemline: Research Funding.

Abstract Abstract 2918 Background: Monosomal karyotype (MK) is defined as the presence of two or more distinct autosomal chromosome monosomies or a single autosomal monosomy associated with at least one structural abnormality (Breems DA et al. J Clin Oncol 2008; 26: 4791). In acute myeloid leukemia (AML), MK has been associated with a worse prognosis than otherwise complex karyotype, regardless of the specific type of autosomal chromosome involved (Breems DA et al. J Clin Oncol 2008; 26: 4791). Whether or not these observations also hold true for myelodysplastic syndromes (MDS) is currently unknown. Objective: To determine if MDS with complex karyotype can be prognostically sub-stratified further based on the presence or absence of MK and if prognosis in MDS with MK is in addition affected by the presence or absence of monosomy 7 or monosomy 5. Methods: The Mayo Clinic database for MDS was used to identify consecutive patients with complex karyotype, defined as the presence of three or more numerical or structural cytogenetic abnormalities. World Health Organization (WHO) criteria were used for MDS diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). Overall and leukemia-free survivals were calculated from the time of initial cytogenetic studies documenting complex karyotype. Results: A total of 127 MDS patients (median age 70 years; 79 males) with complex karyotype were identified. Amongst them, 106 (83%) met the above-stipulated criteria for MK and 21 (17%) had complex karyotype without monosomies. The MK in the 106 patients included monosomy 7 and/or monosomy 5 in 73 cases. The three complex karyotype subsets (i.e. complex without monosomies vs. MK that included monosomy 7 and/or 5 vs. MK excluding monosomy 7 or 5) were not significantly different in terms of age and sex distribution, hemoglobin level, leukocyte or platelet count, bone marrow blast percentage or International Prognostic Scoring System (IPSS) risk score. However, survival was significantly inferior in patients with MK compared to those with complex karyotype without monosomies (p=0.01; HR 1.9, 95% CI 1.1–3.3). Multivariable analysis identified MK (p=0.002), advanced age (p=0.0004), increased bone marrow blast percentage (0.04), but not IPSS risk category (p=0.34), as independent risk factors for survival. Interestingly, there was no difference in survival among MK patients further sub-stratified by the presence or absence of monosomy 7 and/or monosomy 5 (Figure 1). Although not statistically significant, leukemia-free survival was also worse in patients with MK compared to those with complex karyotype (p=0.11; HR 2.7, 95% CI 0.8–9.0); none of the aforementioned variables significantly affected leukemia-free survival. Conclusions: Monosomal karyotype in MDS identifies a prognostically worse subgroup of patients with complex karyotype. Furthermore, in the context of MK, autosomal monosomies other than monosomy 7 or monosomy 5 are prognostically as detrimental. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 5226 Background Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder with overlapping features between myelodysplastic syndromes and myeloproliferative neoplasms. Allogeneic stem-cell transplant (SCT) is considered to be a potentially curative option (Eur J Haematol. 2013; 90:355); with karyotype and comorbidity index (CI) being independent prognostic factors. The role of newer CMML prognostic models remains to be elucidated. We carried out this study to analyze the predictive value of the Mayo model (Leukemia 2013; 27:1504) in assessing transplant outcomes for patients with CMML. Methods After due IRB approval, 25 patients with WHO-defined CMML that underwent allo-SCT at Mayo Clinic from 1992 through 2013 were identified. All patients underwent bone marrow examination and cytogenetic evaluation at diagnosis. Clinical features including status at transplant, graft-versus-host disease (GVHD) prophylaxis, donor-recipient HLA-matching, donor-recipient blood types and CMV status were documented. Patients were evaluated for development of GVHD, disease relapse, remission status, and death from all causes. We evaluated the prognostic relevance of clinical and laboratory parameters including those previously identified by the MDAPS (Blood 2002;99:840), Spanish cytogenetic stratification (Haematologica 2011;96:375), and the recently described Mayo model Results Among 25 study patients, 14 (56%) were males and 15 (60%) had WHO defined CMML-1 (6-symptomatic/transfusion dependent, 3-monosomy 7). The median age at transplant was 51 years (range, 18-66 years). Graft sources included: 19 (76%) peripheral blood, 5 (20%) bone marrow, and 1 (4%) double umbilical cord blood. Ten (40%) patients received a reduced intensity conditioning. At last follow up, 15 (60%) deaths were documented while the remainders are alive and disease free. There were six (25%) post-transplant relapses all resulting in mortality. The 5-year OS was 42% and the 5-year non relapse mortality was 35%. Based on the Mayo model, 15 (60%) patients received a high-risk prognostication, 6 (24%) were intermediate and 3 (12%) were low. In an univariate analysis that included: demographics, blood counts at diagnosis and transplant, WHO classification (p=0.19), Spanish karyotypic stratification (p=0.67), prognostication according to the MDAPS (p=0.35) and Mayo model, disease status at transplant, SCT comorbidity index (p=0.06), graft sources, transplant conditioning regimens (p=0.08), development of acute (p=0.64) and chronic GVHD (p=0.06); thrombocytopenia at diagnosis (p=0.04), disease status at transplant (p=0.02), and a high risk prognostication using the Mayo model (p=0.01) were statistically significant. On a multivariable analysis only high risk prognostication by the Mayo model (p=0.02) retained its negative prognostic impact. In an univariate analysis for relapse-free survival, risk stratification by the Spanish cytogenetic system (p=0.04) and the Mayo model were prognostic (p=0.01), with the high risk prognostication by the Mayo model retaining its negative prognostic impact (p=0.01). Conclusions Allogeneic SCT remains a viable treatment option for patients with CMML. The Mayo model serves as a valuable tool, helping with the identification of high risk CMML patients. These patients seem to benefit from allo-SCT in comparison to non-transplant therapeutic options. Given the smaller sample size, validation in a larger patient cohort is needed. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Cytogenetic abnormalities have significant prognostic role in AML at the time of diagnosis. Several prognostic groupings have been recommended including the NCCN and European LeukemiaNet classification. It is still unknown whether cytogenetic abnormalities have any prognostic role at the time of relapse for predicting clinical outcome. In addition, clonal evolution (CE) has been seen in many AML cases, but its prognostic value remains to be identified. Aim To study cytogenetic abnormalities and clonal evolution impact on clinical outcome for patients diagnosed with rAML Method A retrospective, single institution study through chart review of all cases diagnosed with rAML at Mayo Clinic Rochester between 2003 to 2011 was performed. Pts who achieved complete remission and relapsed at our institution were included. Pts with PML-RARA and BCR-ABL rearrangements were excluded from this study. Pts with available cytogenetics data, both at presentation and relapse, were included. Response to treatment was defined as per international working group (IWG) criteria (Cheson JCO 2003). Appropriate IRB approval was obtained in accordance with Helsinki declaration. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V9. Results Out of 192 pts, 74 pts matched our inclusion criteria. The median age at diagnosis is 60 years (range 18-81), 53% were males. At relapse, median white blood cell (WBC) was 3.2 x109, hemoglobin 10.4 g/dL, platelet 59 x109, peripheral blood (PB) blast 2% (range, 0-96), bone marrow (BM) blasts 23% (range, 1-95) and cellularity 60%. Relapse site was mainly in the BM (95%). Flt3 mutation was found in 12/43 (28%), while NPM1 mutation in 2/7 (29%). Upon treatment with salvage therapy, 27 (36%) pts achieved complete remission (CR) and 16 (22%) pts partial remission (PR) for a total overall response (OR) of 58%. Twenty one (28%) pts were able to proceed to allogeneic stem cell transplant (SCT) after achieving remission. Median overall survival (mOS) was 198 days. Pts had a longer mOS if they proceeded to SCT (386 days vs 121 days, p =0.0003). Cytogenetic analysis (CG) were diploid in 32 (43%) of 74 pts at relapse. Five pts had favorable cytogenetics (3 pts with t(8,21) and 2 pts with inv (16)). CG was divided into favorable, intermediate and poor prognosis as per NCCN classification in 5 (7%), 45 (61%), 24 (32%), respectively. As per European LeukemiaNet, there were 4 CG groups divided into: favorable, Intermediate-1, intermediate-2, and adverse in 5 (7%), 33 (45%), 12 (16%), 24 (32%), respectively. Upon comparison of CG at diagnosis and relapse; clonal evolution (a change in CG due to gain or loss of chromosomal abnormalities) was found in 42/74 (57%) of pts. CG reverted back to diploid in 8/42 (19%) or gained additional CG abnormalities at relapse in 32 (76%) pts. CR2 was achieved in 80% of favorable CG (NCCN grouping), 40% (intermediate), and 21% in poor risk (p=0.01). Using NCCN CG grouping mOS was: 435 days (favorable), 266 (intermediate), and 104 (poor) (p value = 0.01). However, using European LeukemiaNet grouping mOS was: 435 days (favorable), 174 (intermeidtae-1), 363 (intermediate-2), and 104 (poor) (p=0.004). CE did not affect mOS (p =0.7). On multivariate analysis, response to salvage therapy (p<0.0001), NCCN CG grouping (p =0.03), wbc (p=0.045), and PB blasts (p=0.01) were significant but not age, BM blast, platelet and CE. Conclusion CG were diploid in 43% of relapsed pts. CE (gain or loss of cytogenetic abnormalities) was seen in 57% of CG at relapse compared to diagnosis but did not affect mOS. NCCN (and not European LeukemiaNet) cytogenetic grouping did affect clinical outcome through both achieving second CR and mOS (both on univariate and multivariate analysis). Our results confirm the prognostic value of CG on relapse, and need to be confirmed by larger studies. Disclosures: No relevant conflicts of interest to declare.

Abstract Background : Gene mutations are common (~90%) in patients with chronic myelomonocytic leukemia (CMML) and involve epigenetic regulators (TET2 ~ 60%, ASXL1 ~40%), spliceosome components (SRSF2 ~40%) and signal pathways (RAS ~30%). Of these, thus far, only ASXL1 mutations have been shown to adversely impact overall survival (OS). In the current study, we used a 27-gene panel assay to identify additional prognostically-relevant mutations in CMML and to also determine if number of mutations carries prognostic relevance. Methods : 175 patients with WHO-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. Paired-end indexed libraries were prepared from individual patient DNA using the NEBNext Ultra Library prep protocol on the Agilent Bravo liquid handler. Capture libraries were assembled according to Nimblegen standard library protocol. Base-calling was performed using Illumina's RTA version 1.17.21.3. Genesifter software was utilized to analyze targeted sequence data. Specific variants were deemed as mutations if they were associated with a hematological malignancy (as identified by COSMIC database), or if they were not associated with a dbSNP Results: Among the 175 study patients, 66% were males and median age was 70 years. 146 (83%) patients were subclassified as CMML-1. At a median follow-up of 23 months, 146 (83%) deaths and 25 (14%) leukemic transformations were documented. Median survivals were 24 months for CMML-1 and 16 months for CMML-2 (p=0.38). Mutational frequencies were; TET2 46%, ASXL1 45%, SRSF2 45%, SETBP1 19%, CBL 14%, RUNX1 14%, NRAS 12%, U2AF1 8%, SF3B1 6%, ZRSR2 6%, Tp53 5%, DNMT3A 5%, IDH2 5%, PTPN11 5%, SH2B3 5%, JAK2 4%, NPM1 3%, CSF3R 2%, IDH1 2%, EZH2 1%, SUZ12 1%, KIT 1%, FLT3 1%, CALR 1%. 172 patients (98%) had at least one mutation, 21 (12%) had 2, 24 (14%) had 3, 20 (11%) had 4, 9 (5%) had 5, while one (1%) patient had 6 concurrent mutations. Risk stratification was based on Mayo prognostic model: 25% high, 32% intermediate and 43 % low risk. In univariate analysis, presence of ASXL1 mutations (p=0.01), absence of TET2 mutations (p=0.005) and presence of DNMT3A mutations (p=0.02) were associated with inferior survival; in multivariable analysis, ASXL1 (p=0.01) and TET2 (p=0.03) mutations remained significant. In order to determine prognostic interaction between these two mutations, patients were stratified into four mutational categories: ASXL1wt/TET2wt (n =56), ASXL1mut/TET2wt (n =31), ASXL1mut/TET2mut (n =50) and ASXL1wt/TET2mut (n =38). Survival data in these four groups showed significant difference in favor of ASXL1wt/TET2mut (median survival 38 months; p=0.016), compared to those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (31 months)and ASXL1mut/TET2mut (16 months); there was no significant difference in survival among the latter three groups (p=0.3) (Figure). The number of mutations per patient did not affect outcome (p=0.3). In multivariable analysis, presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (p=0.003) remained significant when risk factors used in the Mayo prognostic model (HB <10 gm/dl, AMC >10 x 10(9)/L, platelets <100 x 10(9)/L, circulating IMC) were added to the model; the same was true for ASXL1wt/TET2mut (p=0.036). In a separate multivariable analysis that included the Mayo prognostic model as a single variable along with presence of ASXL1 and absence of TET2 mutations; or absence of ASXL1wt/TET2mut mutational status, the respective hazard ratios were 1.4 (95% CI 1.07-2.1; p=0.012), 1.5 (95% CI 1.07-2.1; p=0.03) and 1.8 (95% CI 1.2-2.7; p=0.001). Leukemia-free survival was worse in ZRSR2 -mutated cases (p=0.03). Conclusions: Almost 100% of patients with CMML express one or more myeloid neoplasm-relevant mutations. The current study suggests a favorable prognostic impact from TET2 mutations, unless accompanied by ASXL1 mutations. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 1887 Poster Board I-910 Background: Chromosomal translocations involving 8p11.2 give rise to diverse oncogenic fusion genes including FGFR1 and MYST3. FGFR1 rearrangements have been associated with the stem cell leukemia/lymphoma (SCLL) syndrome, which is a mixed myeloid-lymphoid malignancy characterized by eosinophilia, monocytosis and rapid disease progression into acute myeloid leukemia or lymphoblastic lymphoma. MYST3 is a histone acetyltransferase whose rearrangement has been associated with acute myeloid leukemia (AML; usually monocytic). Methods: The Mayo Clinic cytogenetic database spanning the years 1988–2009 was screened for 8p11.2 translocations. Bone marrow (BM) pathology and cytogenetic results were re-reviewed and relevant clinical information was retrospectively obtained. Archived BM specimens were analyzed by FISH to identify FGFR1 and/or MYST3 rearrangements. BAC clones used for direct-labeled break-apart FISH probes for FGFR1 were CTC-497A2, RP11-90P5 and RP11-513D5 for the 5' portion and RP11-675F6 and RP11-495O10 for the 3' portion; those used for direct-labeled dual color, dual fusion FISH probes for MYST3 were RP11-589C21, CTD-2532C15, RP11-45I11 and RP11-411A18 and for CREBBP (16p13.3) were RP11-737F1, RP11-136I22, Rp11-962J17 and CTD-2514E9. Results: Out of 24,262 unique patient cytogenetic studies, 8p11.2 translocations were identified in 14 (∼0.06%) patients; 6 constituted sole abnormalities. BM specimens for FISH analysis were available in 13 patients (age range 52–75 years; 8 males). Twelve of these 13 patients had myeloid neoplasms and one had lymphoma; the latter patient had a t(8;10)(p11.2;p13) translocation as a subclone of a 14q32 abnormality and neither FGFR1 nor MYST3 were involved. Among the 12 patients with myeloid neoplasms, FISH analysis revealed abnormalities of MYST3 in 4 patients, FGFR1 in 4 patients, and neither in 4 patients. The MYST3 abnormalities included MYST3-CREBBP in 2 patients, MYST3-EP300 in one patient and MYST3 amplification in one patient; specific diagnoses included AML with or without antecedent chronic myeloid malignancy. Only one of the 4 patients with FGFR1 rearrangements displayed peripheral blood eosinophilia; specific diagnoses included chronic myeloid malignancy and AML. Three of the remaining 4 patients with neither FGFR1 nor MYST3 abnormalities had highly complex cytogenetic abnormalities except one who had sole t(8;13)(p11.2,q12) and presented with lymphadenopathy (precursor-T cell lymphoblastic lymphoma), marked leukocytosis, eosinophilia, monocytosis, and a BM morphology consistent with MPN (marked myeloproliferation with granulocytosis and eosinophilia). Survival was uniformly poor in all 8p11.2 translocations. Conclusions: 8p11.2 translocations are rarely encountered in routine clinical practice and are usually associated with aggressive myeloid malignancies. In the current unselected series of patients, peripheral blood eosinophilia was not a typical feature of the myeloid neoplasm phenotype associated with FGFR1 translocation. Conversely, at least by FISH, FGFR1 was not involved in an 8p11.2-associated myeloid neoplasm that exhibited SCLL-like features. Additional molecular studies are planned to validate the current findings. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Tunneled central venous catheters have traditionally been used for administration of chemotherapy (chemo) for acute leukemia treatment. Peripherally inserted central catheters (PICC) are increasingly being used, but there is an increased risk of PICC-associated thrombosis (PAT). There is limited information on management of PAT in this subgroup of patients (pt). Methods In this retrospective cohort study we investigated the primary management of PICC related upper extremity venous thrombosis (TB) in pt with hematologic malignancy undergoing chemo at Mayo Clinic Rochester. Eligible pt were 18 years and older, had documentation of PICC placement at our institution, initiation of chemo within a week of PICC placement, and the TB was objectively documented by compression venous ultrasound (CVU). Superficial venous TB (SVT) was defined as TB of subcutaneous veins (basilic and cephalic) and deep venous TB (DVT) defined as TB of brachial, axillary, subclavian, or innominate superior vena cava and internal jugular veins. We retrospectively stratified initial management (IM) into 1) PICC removal alone (PR), 2) PR and therapeutic anticoagulation (AC), 3) AC alone, and 4) conservative management (CM) consisting of symptomatic care and observation. We also investigated factors influencing IM of PAT. Long term outcomes including incidence of pulmonary embolism (PE), post phlebitic syndrome and recurrence of TB were noted. Results Between 2006 and 2012, 190 pt with AML (n=160), MDS or MDS/MF (n=10), or ALL (n=20) met our study criteria. Overall, 40/190 (21.6%) developed PAT: AML n=38, ALL n=1, MDS/MF n=1. SVT occurred in 16/40 (40%) pt and DVT occurred in 24/40 (60%) pt. IM is shown in Table 1. One pt with SVT received AC for 6 weeks as well as PR. In this pt, IM included AC because of proximity of TB to deep veins. 7 pt had a follow up (f/u) CVU within 3 months demonstrating: TB progression (prog, n=1, IM with PR alone but with prog AC was started); TB stability (stab, n=2, both IM with PR alone) and TB resolution/improvement (R/I, n= 4, 2 IM with PR and 2 IM with CM) In the 5 pt with CM, 2 pt had f/u CVU demonstrating improvement, one pt had charted clinical improvement , and 2 pt had no charted clinical f/u. Of DVT pt on AC (n=14), 5 pt completed at least 2 months of AC. Reasons for early cessation (n=9) of AC included thrombocytopenia (tcp, n=4), hematoma (n=1), hematuria (n=1), subarachnoid hemorrhage (n=1), and unknown (n=1). One pt died 2 days after presence of DVT was noted. Two pt initially treated with PR alone developed a second TB with placement of a new PICC on contralateral arm and AC was subsequently initiated (duration: 3 months (n=1), and 8 days (n=1)). 14 pt with DVT had f/u CVU within 3 months which demonstrated prog (n=2), stab (n= 8), or R/I ( n=4) of TB (Table 2). The 2 pt with TB prog subsequently received longer term AC guided by platelet count. In 5 pt with PICC not initially removed, 3 pt had PR after completion of chemo. (1-4 days), one pt had PR at discharge (27 days from TB), and one pt had PICC in place on discharge. One pt with DVT experienced a PE within one year f/u. This pt had initially completed 3 days of AC which was stopped because of tcp. Conclusion In this cohort of patients with PAT, the most common IM consisted of PR, which appeared to result in a low recurrence rate among pt with SVT. In pt with DVT, the role of AC remains to be defined given the abbreviated course of AC in most pt. Though, the lack of CVU followup in all pt limits conclusions, there appeared to be a low rate of symptomatic prog. Initiation of AC was largely guided by platelet count and degree of occlusive symptoms. Thrombocytopenia was also the most commonly cited reason for discontinuing AC. Close clinical follow up aided by the use of CVU was integral to ensure that PAT did not lead to further adverse events. Disclosures: No relevant conflicts of interest to declare.