Elliott, Michelle A.

Abstract Abstract 2910 Poster Board II-886 Background: Polycythemia vera (PV) and primary myelofibrosis (PMF) are stem cell-derived myeloproliferative neoplasms characterized clinically by increased red cell volume and bone marrow fibrosis, respectively. Phlebotomy is the cornerstone of treatment in PV whereas hydroxyurea has been the traditional drug of choice in both PV and PMF. Over the last 20 years, several new treatment approaches have been introduced and promoted (e.g. interferon-alpha, anagrelide, thalidomide, allogeneic stem cell transplantation) but their benefit in terms of survival has not been confirmed in controlled studies. Methods: Study patients were recruited form the Mayo Clinic database for myeloproliferative neoplasms. Diagnosis was based on 2001 WHO criteria. Follow-up information was updated in July, 2009. In order to assess changes in survival over time, patients were stratified into two groups by year-of-diagnosis: 1970-1990 and 1991-2005. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 652 patients were studied, including 314 with PMF (median age 57 years, range 18-88; 193 males) and 338 with PV (median age 63 years, range 18-93; 183 males). Overall median survivals were 6.5 years for PMF and 12.2 years for PV (p<0.0001); ten- and twenty-year survival rates were 37% and 13% in PMF and 60% and 18% in PV (Figure). Both the International Prognostic Scoring System for PMF (IPSS; Cervantes et al. Blood 2009;113:2895) and the age/leukocyte count-based PSS for PV (Gangat et al. BJH 2007;138:354) were validated in the current series of patients. Considering all patients, there was no significant difference in survival when either PMF (p=0.91) or PV (p=0.73) patients were stratified according to year-of-diagnosis (Figure); median survivals were 4.7 and 6.6 years in PMF patients diagnosed 1970-1990 (n=54) and 1991-2005 (n=260), respectively; the corresponding median survival figures for PV were 11.8 (n=170) and 12.2 (n=168) years. These results did not change when adjusted for age and sex and, in PV, for age/leukocyte count-based PSS. In PMF, however, borderline significance (p=0.05) was noted when IPSS scores were introduced into the Cox model with further analysis showing improved survival in Int-2/high risk patients with PMF diagnosed after 1990 (p=0.01). Conclusion: The current study provides mature survival data in PMF and PV using large cohorts of consecutive patients seen at a single institution. Although median survival is significantly better in PV compared to PMF, their survival curves converge after 20 years of follow-up, underscoring the poor long-term prognosis in PV patients. The study also suggests improved survival for high/intermediate-2 risk PMF in recent years. Disclosures: Off Label Use: hydroxyurea use in myelofibrosis.

Abstract Introduction L-asparaginase therapy results in systemic depletion of antithrombin (AT) and fibrinogen (FG), resulting in thrombotic (TE) and hemorrhagic events (HE). Prophylactic correction of coagulation disturbances have been inconclusive with regard to cost effectiveness, and specifically cost effectiveness of antithrombin concentrate (ATC) replacement has not been evaluated. (Abbott et al, 2009, Mitchell et al, 2003). Currently, AT repletion is recommended for levels less than 60%. (Stock et al, 2012) Several treatment protocols with distinctly different L-asparaginase (LAS) or pegaspargase (PEG) doses complicate the frequency and intensity of ATC replacement. We carried out this study to evaluate the cost effectiveness of ATC replacement, based on our institutional practice. Methods This single center, retrospective, observational study was approved by the Institutional Review Board and conducted at Mayo Clinic, Rochester, MN. Consecutive adult patients with a confirmed diagnosis of ALL receiving LAS or PEG between January 2000 and October 2012 were evaluated. Patients with hereditary or acquired thrombophilias or pre-existing TE or HE, were excluded. Per institutional guidelines, ATC was administered if levels were less than 70%. The Centers for Medicare & Medicaid (CMS) single drug historical pricing guide was utilized for 2000-2004. ATC cost beginning January 1, 2005, was derived from the CMS average sales price, reported quarterly. To adjust for price differences due to regimen utilization trends, each dose was also calculated at the final 2012 cost of 3.05/unit. ATC repletion practices and estimated expenditures were compared between regimens. Results Fifty four patients were treated with LAS or PEG containing regimens. Of these, 47 (87%) received ATC. Twenty-eight patients received LASP, 22 received PEGASP and 4 received both. Distribution across protocols was; CALGB 9111 (n=20, Larson et al, 1998), E2993 (n=13, Goldstone et al, 2008), C10403 (n=9, NLM: NCT00558519), CCG 1941 (n=7, Gaynon et al, 2006) and Augmented HyperCVAD (n=5, Faderl et al, 2005). PEG and LAS dosing schemes are outlined in table 1 . LAS doses were converted to PEG upon specific protocol revision or at discontinuation of LAS availability in 2012. Regimens specified a dose cap with the exception of C10403. A total of 399 LAS and PEG doses resulted in 378 instances of ATC repletion. The reimbursement price of ATC in 2000 was estimated at 1.50/unit U.S. dollars (USD) and 3.04/unit USD by the fourth quarter of 2012. The total estimated average sales price was 2,471,745 USD over the study period. C10403 resulted in the highest median number of PEG doses per patient (n = 5) and a median of 17 ATC doses per dose of PEG. This resulted in C10403 being the most expensive regimen with the median expense for ATC replacement being 118,064 USD (chart 1). This conclusion was also seen after comparing different regimens using the most recent 2012 cost estimates. The overall incidence of TE or HE was 17% and equally distributed between regimens (please see accompanying abstract). Conclusions Repletion of ATC in patients receiving asparaginase containing chemotherapy regimens is very expensive and continues to add to costs at many centers, without clear benefit, especially with regards to TE and HE. A prospective, randomized, multicenter clinical trial looking to answer this question is the need of the hour. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2895 Poster Board II-871 Background: Recent studies have reported a significant association between JAK2V617F acquisition and a specific JAK2 germline haplotype; rs12343867 (located at intron 14 of the JAK2 gene) is one of several SNPs that tag this haplotype. We performed rs12343867 SNP analysis in a consecutive cohort of patients with primary myelofibrosis (PMF) in order to study the clinical and laboratory correlates of the particular JAK2 haplotype and its effect on survival. Methods: Study patients were recruited form the Mayo Clinic database for PMF. Molecular studies were performed on DNA extracted from stored bone marrow. rs12343867 SNP genotyping was performed by a commercially available Taqman assay. Quantitative JAK2V617F analysis was done according to previously published methods. Standard statistical methods were used to test significance of associations between SNP genotype and other variables. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 132 patients with PMF were studied (median age 62, range 28-82; 82 males). Risk distribution according to the International Prognostic Scoring System (IPSS) for PMF were low in 39 (29%) patients, intermediate-1 in 41 (31%), intermediate-2 in 25 (20%) and high in 27 (20%). 77 (58%) patients were JAK2V617F positive; median mutant allele burden was 26% (range 1-85) and 21 patients displayed > 50% mutant allele burden. The rs12343867 genotype distributions were C/C 22%, C/T 44% and T/T 34% . The corresponding figures in JAK2V617F positive/negative cases were 31%/9%, 38%/53%, 31%/38% (p=0.01). Among the 21 patients with > 50% JAK2V617F allele burden, 14 (67%) displayed the C/C allele, 2 C/T and 5 T/T. The specific SNP genotype was not significantly affected by age (p=0.33), sex (p=0.46), leukocyte count (p=0.39), platelet count (p=0.09), or IPSS risk category (p=0.63). Patients were followed for a median of 54 months and during this period 73 (55%) deaths were documented. The T/T SNP genotype was significantly associated with shortened survival, compared to either C/C or C/T (p=0.001; Figure). Multivariable analysis showed this association to be independent of IPSS, JAK2V617F mutational status, age or sex. The adverse prognostic effect of the T/T genotype was also apparent when JAK2V617F negative (p=0.01) or positive (p=0.06) cases were analyzed separately. Conversely, JAK2 mutational status or allele burden did not affect survival in patients with T/T or C/C allele. Conclusion: The current study illustrates the non-random haplotype distribution of JAK2V617F in patients with PMF. More importantly, a non-JAK2 haplotype, tagged by the rs12343867 T allele, was associated with inferior survival that is not accounted for by IPSS or JAK2V617F mutational status. These findings, together with previous observations regarding shortened survival associated with low JAK2V617F allele burden, suggest the presence of molecular events in PMF that are more aggressive than JAK2V617F and not necessarily linked to the JAK2 haplotype. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder that was classified by the World Health Organization (WHO) as a myelodysplastic/ myeloproliferative overlap disease. Cytogenetic abnormalities have a significant prognostic role in many hematologic neoplasms, but their prognostic value in CMML has been debatable. Recently, monosomal karyotype (MK) has been reported to be a marker of poor prognosis in patients with myelodysplastic syndromes (MDS) and primary myelofibrosis, but its value in CMML is unknown. Aim To study MK effect on clinical outcome for patients diagnosed with CMML Method A retrospective study of all cases diagnosed with CMML at Mayo Clinic Rochester between 1994 to 2011 was performed. Only pts with complete cytogenetic analysis at presentation to our institution were included. MK was defined as the presence of ≥ 2 autosomal monosomies or one autosomal monosomy with at least one structural abnormality (Breems et al, JCO 2008). CK was defined as the presence of at least 3 chromosomal abnormalities. 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 A total of 262 pts diagnosed with CMML had available cytogenetic data at diagnosis. Median age was 72 years, 176 (67%) were male. Median hemoglobin 10.5 g/dL, white blood cells (wbc) 12 x109/L, platelet 89 x109/L, peripheral blood (PB) blast 0, and bone marrow (BM) blast 4%. CMML2 was seen in 9% while 47% were proliferative (wbc >13). Leukemic transformation was documented in 34 pts (13%). Median overall survival was 513 days. Cytogenetic (CG) analysis was diploid in 167 pts (64%). Trisomy 8 was the most frequent cytogenetic abnormality at 8% (22), followed by complex karyotype (CK) 5% (14), then -7 at 4% (10) and MK 3% (7, six of which were also CK). Comparing pts with diploid CG to other categories indicates: to abnormal CG pts had lower wbc (0.001), PB blasts (p<0.0001), and BM blasts (p=0.0001); to CK pts had lower PB blasts (p=0.003) and higher platelets (p=0.03); to -7 pts had lower wbc (p=0.005), PB blast (p=0.0004), BM blasts (p=0.03) and higher platelets (p=0.03); to +8 pts had lower PB blast (p=0.02) and BM blasts (p= 0.01); no difference was noted when compared to MK. Median OS was statistically significantly worse in MK+ vs MK- (24 vs 527 days, p= 0.002), but not in other comparisons: -7 vs others (250 vs 527 days, p=0.2), CK+ vs CK- (256 vs 527 days, p=0.05), diploid vs others (570 vs 365 days, p=0.1), +8 vs others (312 vs 527 days, p=0.1). Pts with MK+ only or MK+CK+ did worse than CK+ only or other groups (4, 63, 304, 527 days, respectively, p<0.0001). On a multivariate analysis, MK+ (in addition to platelet, BM blast, hemoglobin, and wbc) did have an impact on OS (p=0.0004), while CK+, -7, +8, diploid CG, age, PB blast did not. Conclusion Cytogenetic abnormalities were not frequent findings in pts diagnosed with CMML (36%), but did affect wbc, PB and BM blasts. The most common cytogenetic abnormality was +8 while MK was present at 3% (less than published data in MDS). Only MK predicted statistically significant shorter mOS between all other cytogenetic categories on both univariate and multivariate analysis. This finding needs to be validated by larger cohorts of pts due to its rare occurrence in CMML. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2893 Poster Board II-869 Background: A specific JAK2 germline haplotype has been associated with the occurrence of JAK2V617F in myeloproliferative neoplasms (MPN). Several SNPs, including rs12343867, tag this haplotype. We performed rs12343867 SNP analysis in a consecutive cohort of patients with essential thrombocythemia (ET) in order to study the clinical and JAK2V617F allele burden correlates of the particular SNP genotype. Methods: Study patients were recruited form the Mayo Clinic database for ET. Molecular studies were performed on DNA extracted from stored bone marrow. rs12343867 SNP genotyping was performed by a commercially available Taqman assay. Quantitative JAK2V617F analysis was done according to previously published methods. Standard statistical methods were used to test significance of associations between SNP genotype and other variables. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 226 patients with ET were studied (median age 57, range 14-91; 145 females). Median hemoglobin, leukocyte and platelet counts at initial diagnosis were 13.8 g/dL, 9.7 × 109/L and 1000 × 109/L, respectively. 118 patients (52%) were JAK2V617F positive and among them, 90 (76%) displayed JAK2V617F allele burden of < 10% (low allele burden group) and the median (range) mutant allele burden in the remaining 28 patients (higher allele burden group) was 12% (12-68). As expected, JAK2V617F-positive cases, compared to their mutation-negative counterparts, were older (p=0.006) and displayed higher hemoglobin (p=0.0001) and leukocyte (p<0.0001) counts and lower platelet (0.03) count. The rs12343867 genotype distributions were C/C 15%, C/T 53% and T/T 33% (expected frequency in the HapMap-CEU listed control population is ∼ 6%, 46% and 48%, respectively). The corresponding figures in JAK2V617F positive/negative cases were 17%%/11%, 53%/53%, 30%/36% (p=0.29). Unlike the case with JAK2V617F mutational status, rs12343867 SNP genotype did not correlate with age (p=0.69), hemoglobin level (p=0.47), leukocyte count (p=0.25) or platelet count (p=0.33). Patients were followed for a median of 7.4 years and during this period 56 (25%) deaths were documented. rs12343867 SNP genotype did not correlate with survival (Figure). Similarly, survival did not correlate with the presence or absence of JAK2V617F. However, patients with higher JAK2V617F allele burden displayed a shorter survival with borderline significance, during multivariable analysis that included age as a covariate. Conclusion: The current study shows the JAK2 haplotype enrichment in a large series of ET patients. However, the particular phenomenon was not significantly different between JAK2V617F positive and negative cases, which suggests specific haplotype association with the disease rather than the mutation. Consistent with this contention, rs12343867 genotype did not correlate with clinical or laboratory variables that typically associate with JAK2V617F mutational status. Furthermore, unlike the case with primary myelofibrosis, rs12343867 SNP genotype did not correlate with survival, an observation that is not surprising considering the lower level of complexity in molecular pathogenesis in ET compared to PMF. Disclosures: Pardanani: TargeGen: Research Funding; Cytopia: Research Funding. Off Label Use: Data from ongoing clinical trial will be presented. Tefferi:TargeGen: Research Funding.

Abstract Background: Treatment-related AML (t-AML) accounts for 10 to 20% of all AML cases and carries an especially poor prognosis (Kayser et al. 2011, Godley et al. 2008). Patients diagnosed with t-AML are likely to have abnormal cytogenetic profiles with chromosome changes that are predictive of an aggressive malignancy, poor response to therapy, and decreased overall survival(Smith et al. 2003). The simultaneous use of multiple chemotherapeutic agents of different classes makes it increasingly difficult to predict risk for developing t-AML and determining disease course. An updated analysis of predictive factors for t-AML is needed so clinicians can more accurately inform patients of their prognosis. The aim of this study was to classify t-AML according to primary malignancy, previous chemotherapy exposure, and cytogenetic profile. Methods: A retrospective chart review of patients that were diagnosed with AML at Mayo Clinic from 7/1/1990 to 5/13/2015 was performed following IRB approval. AML patients found to have a previous malignancy treated with chemotherapy were classified as t-AML. Chemotherapeutics were classified as alkylating agents, antimetabolites, anti-tubulin agents, and topoisomerase II inhibitors. Patients diagnosed with a myelodysplastic or myeloproliferative disorder prior to development of AML were excluded from this study. Previous chemotherapy exposures, duration of chemotherapy exposure, complete blood count, chromosome abnormalities, and survival data were collected for t-AML cases. Cytogenetic changes were classified as favorable, intermediate, and adverse according to the system used by Kayser et al. 2011. JMP 10.0 was used for statistical analysis. Results: Out of 584 patients, 64 patients (11%) had a primary malignancy that was treated with chemotherapy prior to being diagnosed with AML. The most common primary malignancies were breast cancer (31%), non-Hodgkin lymphoma (27%), colorectal cancer (8%), and Hodgkin lymphoma (8%). Laboratory findings showed median hemoglobin 9.6 g/dL (4.7-13.8), median white blood cells 3.2 x109 (0.6-126), median platelets 50x109 (3-320), median peripheral blood blasts of 8% (0-91), and median bone marrow blasts 38% (1-94). 95% of patients diagnosed with t-AML had been previously treated with an alkylating agent. Additional exposure to an anti-metabolite trended towards a more adverse cytogenetic profile (χ2=5.0, p=0.08) but there was not a statistically significant decrease in overall survival (KM analysis, p=0.31). The median overall survival for patients diagnosed with t-AML was 10.2 months compared to 19.2 months for patients with de-novo AML (KM analysis, p=0.04). Adverse cytogenetic profiles were associated with decreased survival (KM analysis, p <0.0001). However, there was no difference in overall survival between patients with t-AML that had intermediate cytogenetics and those with de-novo AML (KM analysis, p=0.36). None of the chemotherapy classes other than antimetabolites were associated with poor cytogenetics or survival when combined with an alkylating agent. Conclusion: Over half of all patients classified as having t-AML in this study received prior chemotherapy for breast cancer or non-Hodgkin lymphoma. Cytogenetic classification of t-AML into favorable, intermediate and adverse groups is useful in predicting disease course. Interestingly, t-AML patients with intermediate risk cytogenetics had similar overall survival to patients with de-novo AML. This suggests that the poor outcomes observed in patients with t-AML is predominantly due to the subset with adverse cytogenetics. Thus, cytogenetic analysis remains the best indicator of overall survival regardless of chemotherapy exposure. Additional work is needed to delineate the risk associated with the aforementioned chemotherapy classes. Disclosures Al-Kali: Celgene: Research Funding.

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.

Abstract Background: Young (age < 60 years) patients with agnogenic myeloid metaplasia (AMM) are potential candidates for curative therapy with allogeneic stem cell transplantation. In such transplant-eligible patients, median overall survival (OS) is reported to be between 78 and 128 months. Because clinical course in an individual patients is markedly heterogeneous (survival ranges of months to decades), objective prognostic variables are essential for transplant decision making. Accordingly, we recently developed a modified Dupriez prognostic scoring system (PSS) that effectively discriminated between high (2 or more risk factors), intermediate (one risk factor) and low (no risk factor) risk patient groups based on the presence or absence of complete blood count (CBC)-derived adverse parameters; hemoglobin < 10 g/dl, leukocyte count < 4 or > 30 × 109/L, and platelet count < 100 × 109/L (Dingli et al. Cancer2006;106:623). In the current study, we identify absolute monocytosis of ≥ 1 × 109/L as an additional independent risk factor for survival in AMM. Methods: A consecutive cohort of WHO-defined AMM patients diagnosed before the age of 60 years was identified. The impact of various clinical and laboratory parameters on overall survival was evaluated with univariate and multivariable analysis. Results: The study included 129 patients (median age 52 years, range 18–60; 69 males) with AMM. An overall median survival of 75 months was univariately affected by platelet count < 100 × 109/L, hemoglobin level of < 10 g/dL, leukocyte count of either < 4 or > 30 × 109/L, monocytosis of ≥ 1 × 109/L, and, where cytogenetic studies were available (n=41), presence of unfavorable cytogenetic abnormalities (p < 0.01 in each instance). On multivariable analysis, all but leukocyte count maintained their significance. The independent prognostic value of monocyte count was also validated against the modified Dupriez score (see above) and thus allowed further refinement of the particular CBC-based PSS that included monocytosis of ≥ 1 × 109/L as a fourth risk factor; low-risk identified patients with none of the 4 risk factors, intermediate-risk with one risk factor, and high-risk with 2 or more risk factors (Figure 1). For comparison, Figure 2 illustrates survival curves according to the original Dupriez PSS. Conclusion: Monocytosis of ≥ 1 × 109/L is an independent risk factor for inferior survival in AMM. Figure 1. Mayo score Figure 1. Mayo score Figure 2. Dupriez score Figure 2. Dupriez score

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is a rare and aggressive hematological malignancy. Unlike B-cell ALL, apart from age and presenting WBC, additional prognostic factors remain largely unknown. Additionally, the prognostic impact of a monosomal karyotype, which has a negative impact on survival in myeloid neoplasms, remains to be determined in T-ALL (Kenderian et al, BCJ 2013) Aim: To study predictors of survival including the role of a monosomal karyotype in T-ALL. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic Rochester were identified. All clinical and pathologic data including FISH studies and cytogenetics were retrospectively reviewed. Chi-square test was used to compare variables. Survival was estimated and compared using the Kaplan-Meier Method and log-rank test. Univariate and multivariate analysis was performed using the Cox regression model. Results: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified, 41 had acute lymphoblastic lymphoma (LBL), and 51 (55%) acute lymphoblastic leukemia (ALL). Median age at diagnosis was 33 years (range; 18-88 years) with 72%males. Median follow up of our cohort was 25 months (range; 0.9-260 months) during which time 42 deaths (45%) were documented. A. Baseline characteristics: Fifty six (67%) had constitutional symptoms, and 63 (77%) had lymphadenopathy at diagnosis. Mediastinal mass was identified in 49 (55%) pts with palpable splenomegaly in 16 (20%) pts. Fifty one (58%) pts had extranodal disease, and 17 (19%) pts had CNS involvement. Pleural and pericardial effusion were evident in 16 (19%), and 6 (7%) pts, respectively. Median laboratory values included; LDH 288 U/L (115-6590), hemoglobin (Hb) 12.8 g/dl (4.5-18.2), WBC 8.65 x109 (1.4-406), platelets 169 x109 (8-485), bone marrow blasts 29% (0-99). B. Treatments: Induction therapies were variable and included; 11 (12%) CHOP like regimens, 7 (8%) modified NHL regimens (Asparginase+CHOP), 54 (58%) ALL like regimens (CALGB 9111, E2993, or HyperCVAD), 13 (14%) Pediatric regimens (ALL 10403, CCG 1961, BFM, Augmented BFM, GRAALL 2003, or Hoelzer regimen), with 7 (8%) patients' receiving palliative care only. Seventy-one (77%) pts achieved complete remission (CR1) during induction therapy while eight pts had refractory disease (8%). Thirty-three (35%) pts underwent stem cell transplant; 7 (21%) autologous and 26 (79%) allogeneic. Forty one (44%) pts had disease relapse and median time to relapse was 10.8 months (range; 8.2-16 months) C. Predictors of survival: In univariate analysis, that included age > 60 years, leukocyte count Hb, Plt, Blast percentage, mediastinal mass, LDH and CNS involvement, only age >60 and CNS involvement were predictors of inferior survival and both retained significance in the multivariable analysis with HR 3.9 (CI 1.5 - 9; p=0.0055) and 2.8 (1.3 - 5.7; p =0.0085), respectively (Figure 1 and 2). In this cohort age >60 was a better stratification that the conventionally used age above 40 (p = 0.1). Among 56 pts with evaluable cytogenetics data, 7 (13%) pts had MK which did not have an impact on survival with HR 1.9 (CI 0.4-5.6; p=0.33). Conclusion: In this large cohort of adult T-ALL patients, we observed that age >60 years and CNS involvement were independent predictors of inferior survival. MK was infrequent, but unlike in myeloid neoplasms, does not seem to impact overall survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Spectrum: Research Funding; Valeant Pharma: Equity Ownership.

Abstract Background : An increased incidence of second skin and visceral malignancies in comparison to the general population has been reported in patients with hematologic neoplasms such as, chronic lymhocytic leukemia (CLL) (~11-36%) (Tsimberidou, JCO, 2009),chronic myeloid leukemia (CML) (4-6%) (Miranda, Leukemia 2016)and multiple myeloma (MM) (3-4.3%) (Palumbo, Lancet Oncol 2014).Diverse etiologies exist for this association. We carried out this study to describe the spectrum of second malignancies in patients with chronic myelomonocytic leukemia (CMML). Methods : Patients with World Health Organization defined CMML were included in the study. All patients had bone marrow (BM) biopsies performed at diagnosis. We only included malignancies that were diagnosed at the time of CMML diagnosis or subsequent to it. Patients that had concomitant systemic mastocytosis (n=18), therapy related CMML (n=19) and those that underwent allogeneic stem cell transplantation (n=23) were excluded. Standard cancer specific diagnostic and staging methods were utilized. Results: The study included 378 patients (median age 71 years; 66% males). Seventy-one concomitant and/or subsequent second malignancies were identified in thirty-two (8%) patients. Age group distribution was; 50-59 years 1 (1%), 60-69 years 21 (30%), 70-79 years 30 (42%) and ≥ 80 years 19 (27%) second malignancies. 22 (69%) patients had 1 second malignancy, 4 (13%) had 2, 2 (6%) had 4 (skin neoplasms), while 4 (13%) patients had ≥ 5 second malignancies (Table one). At a median follow-up of 18 months, 284 (75%) deaths and 54 (14%) leukemic transformations were documented. i) Second hematological malignancies: Thirteen (18%) concomitant (n=7, 54%) and subsequent hematological malignancies (n=6, 46%) were observed in 13 (3.5%) patients. In addition, 10 (3%) pre malignant states including, 7 patients with MGUS and 3 with monoclonal B-cell lymphocytosis (MBL) were seen. In one case each, the MGUS and MBL evolved into multiple myeloma (after 16 months) and CLL (after 30 months), respectively. Concomitant malignancies included: polycythemia vera (n=2, 15%), MM (n=2, 15%), marginal zone B-cell lymphoma (n=1, 8%), splenic lymphoma (n=1, 8%), ALK-rearranged T-cell lymphoma (n=1, 8%), while subsequent malignancies included: MM (n=1, 8%), diffuse large B-cell lymphoma (n=1, 8%), Waldenström's macroglobulinemia (n=1, 8%), CLL (n=2, 15%) and acute lymphoblastic leukemia (n=1, 8%). Four (31%) patients needed chemotherapy, with outcomes including: complete remission in one case (multiple myeloma), progression of disease in 2 (multiple myeloma and diffuse large B cell-lymphoma) and partial response in 1 case (ALK rearranged T cell lymphoma). CMML related cytopenias did not preclude patients from getting chemotherapy. Three patients died from causes related to their second malignancies. ii) Cutaneous malignancies: Fifty-one (71%) concomitant (n=12, 24%) and subsequent cutaneous malignancies (n=39, 76%) were seen in 13 (3%) patients. The concomitant malignancies included: 7 (14%) basal cell carcinoma (BCC), 5 (10%) squamous cell carcinoma (SCC), while subsequent cancers included: 3 (6%) malignant melanoma, 7 (14%) BCC and 29 (57%) SCC. Four cases (8%) were locally advanced and four patients (8%) had recurrent lesions. A concomitant diagnosis of BCC and SCC was made in 8 patients (16%). All patients were treated surgically or with electrodesiccation and curettage. No deaths or metastases were reported. iii) Visceral malignancies: Seven (10%) subsequent visceral malignancies were seen in 6 (1%) patients. These included; colonic adenocarcinoma (n=2, 29%), bladder adenocarcinoma (n=1, 14%), endometrial adenocarcinoma (n=1, 14%), prostate adenocarcinoma (n=1, 14%), clear cell renal carcinoma (n=1, 14%) and papillary thyroid carcinoma (n=1, 14%). All the cases were localized and surgically resected, with two patients (colonic and endometrial adenocarcinoma) needing adjuvant chemo-radiotherapy. All patients achieved complete remission with no mortality related to second malignancies. Conclusions: Approximately 8% of CMML patients have second cutaneous (3.5%), hematological (3.5%) and visceral (1%) malignancies, with most of these occurring in and beyond the seventh decade (~70%) of life. Mortality related to second cancers was low (2%), with most patients receiving appropriate surgical and adjuvant chemo-radiation therapy. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.