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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 : DNMT3A mutations result in epigenetic dysregulation and impart a negative prognostic impact in acute myeloid leukemia and myelodysplastic syndromes. In chronic myelomonocytic leukemia (CMML), DNMT3A mutations are seen in 2-5% of patients. In a large Groupe Français des Myélodysplasies (GFM) study (n=312), DNMT3A mutations were seen in 2% and were not included in further survival analyses (Itzykson JCO 2013). In a prior Mayo Clinic study (n=175), DNMT3A mutations were seen in 5% (n=9) and on univariate, but not multivariate analysis (Patnaik Blood C J 2016), were associated with shortened over-all survival (OS). We carried out this study on a larger CMML cohort (n=261), with more (n=15) informative cases to assess the impact of DNMT3A mutations. Methods : 261 patients with World Health Organization (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, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. The 2016 WHO diagnostic criteria were used. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations (LT) were documented. Mutational frequencies ≥4% were encountered in; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. i) DNTM3A mutated CMML: phenotypic and molecular correlates DNMT3A mutations were seen in 15 (6%) patients; 64% male with a median age of 64 years. DNMT3A amino acid substitutions included; R882H 50%, R882C 29%, R910P 7%, R598* 7% and R320* 7%. The median variant allele frequency burden was 45%. Concurrent gene mutations were detected in; TET2 43%, ASXL1 21%, SF3B1 21%, U2AF1 14%, RUNX1 14%, SETBP1 14%, NRAS 14%, SRSF2 7%, JAK2 7% and Tp53 7%. There was no difference between DNMT3A mutated and wild-type patients in terms of age and gender distribution, hemoglobin level, leukocyte, monocyte (AMC), and platelet counts, peripheral blood (PB) or BM blast content. Concurrent gene mutations were equally distributed with the exception for a higher prevalence of SF3B1 (p=0.003) and a lower prevalence of SRSF2 (p=0.004) mutations in DNMT3A mutated CMML. Four (29%) patients underwent leukemic transformation. ii) Impact on OS and leukemia-free survival (LFS): Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wild-type (median 27 months) patients (p=0.0007; HR 2.9, 95% CI 1.5-5.7; Figure 1A). Other variables of significance, in univariate analysis, included lower hemoglobin (p=0.002), higher leukocyte count (p=0.0009), higher AMC (p=0.0012), PB blast % (p=0.001), circulating immature myeloid cells (IMC, p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), and ASXL1 (p=0.01) mutations. Survival was also adversely affected by the presence of either (n=133) or both (n=3) ASXL1/DNMT3A mutations (0=0.007, Figure 1B). In multivariable analysis (MVA) excluding ASXL1 and DNMT3A mutations, hemoglobin (p=0.03), IMC (p=0.013) and AMC (p=0.02) retained significance. When ASXL1 mutations were added to the MVA, ASXL1 (p=0.01) mutations, AMC (p=0.012) and IMC (p=0.03) retained significance. Similarly, when only DNMT3A mutations were added to the MVA, DNMT3A (p=0.003) mutations, IMC (p=0.01) and AMC (p=0.02) retained significance. When both DNMT3A and ASXL1 mutations were added to the MVA, only DNMT3A (p<0.0001) and ASXL1 (p=0.004) mutations remained significant. DNMT3A mutations predicted shortened OS, independent of the ASXL1 inclusive GFM model (p<0.0001) and Mayo Molecular Model (p=0.002). DNMT3A mutations (p=0.0018), along with low hemoglobin levels (p=0.003) independently predicted for a shorter LFS. Conclusions: DNMT3A mutations are seen in ~5% of patients with CMML and impart a negative prognostic impact on both OS and LFS. This finding warrants inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Disclosures No relevant conflicts of interest to declare.

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.

Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

Abstract Background In myelodysplastic syndromes (MDS), we have previously shown the adverse prognostic effect of ALC <1.2 x 10(9)/L (Nisha et al. Am J Hematol 2010;85:160). In the current larger study of 889 patients with MDS, we sought to validate and expand on our previous observations and also examine the effect of lymphocyte-to-monocyte ratio (LMR). Methods We retrospectively recruited 889 consecutive patients with primary MDS who were untreated at the time of referral to our institution, and in whom ALC and absolute monocyte count (AMC) at time of referral was documented. The diagnosis of MDS and leukemic transformation (LT) was according to WHO criteria (Blood. 2009;114:937). Complete follow-up information was updated in January 2015. Comparison of laboratory and clinical features was made between patients with subnormal and normal ALC; patients with above normal ALC were considered separately. Overall and leukemia-free survivals of patients with normal ALC was compared to those with either subnormal ALC or, in order to validate our previous observation, with ALC <1.2 x 10(9)/L. Results Patient characteristics: Median (range) values for the 889 study patients (69% males) included: age 72 (18-98), hemoglobin 9.6 g/dL (5.4-15.7), leukocyte count 3.4 x 10(9)/L (0.4-35), AMC 0.2 x 10(9)/L (0-1.7), platelet count 106 x 10(9)/L (2-1804), circulating blasts 0% (0-18) and bone marrow blasts 3% (0-19). Transfusion need was documented in 33% of patients and abnormal karyotype in 49%. Risk stratification by the revised international prognostic scoring system (IPSS-R) was very high in 10%, high in 16%, intermediate in 20%, low in 36% and very low in 16%. The median (range) ALC for the entire study population of 889 patients was 1.16 x 10(9)/L (0.02-8.9). The normal range of ALC at our institution was 0.9-2.9 x 10(9)/L; the number of patients with subnormal, normal and above normal ALC was 261 (29%), 598 (67%) and 30 (4%), respectively. In addition, 442 (50%) and 417 (47%) patients had ALC below 1.2 x 10(9)/L and ALC between 1.2 and the upper limit of normal, respectively. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformations were documented. Comparison of patients stratified by absolute lymphocyte count Compared to patients with normal ALC, patients with subnormal ALC displayed lower hemoglobin (p=0.002), higher red blood cell transfusion need (p=0.0003), lower leukocyte count (p<0.0001), lower monocyte count (p=0.002) and lower platelet count (p<0.0001), whereas borderline association was also apparent for older age (p=0.06). In univariate analysis, survival was adversely affected by lower ALC, treated as a continuous variable (p=0.01). Similarly, when compared to patients with normal ALC, patients with subnormal ALC (p=0.001; HR 1.3, 95% CI 1.1-1.5) and those with ALC <1.2 x 10(9)/L (p=0.0002; HR 1.3, 95% CI 1.2-1.6) experienced significantly shortened survival. There was no difference in survival between patients with above normal ALC and those with either subnormal (p=0.58) or normal (p=0.41) ALC; accordingly, patients with above normal ALC were excluded from subsequent analysis. In multivariable analysis, the adverse effect of subnormal ALC was shown to be independent of age, gender, anemia, thrombocytopenia, neutropenia , circulating blast percentage, bone marrow blast percentage or cytogenetic risk stratification by and IPSS; the same held true for ALC <1.2 x 10(9)/L. The association with IPSS-R was of borderline significance for both ALC <1.2 x 10(9)/L (p=0.06) and subnormal ALC (p=0.1). The adverse effect of ALC was most apparent in patients with very low or low risk disease per IPSS-R (p=0.0007 for subnormal ALC and 0.0003 for ALC <1.2 x 10(9)/L), compared to those with higher risk status (p=0.67 and 0.7, respectively). Neither subnormal ALC (p=0.4) nor ALC <1.2 x 10(9)/L (p=0.1) affected leukemia free survival. Analysis using LMR in place of ALC showed similar but not necessarily superior results. Conclusions Compared to those with normal ALC, MDS patients with either subnormal ALC or with ALC below 1.2 x 10(9)/L experienced shorter overall, but not leukemia-free, survival; this adverse effect was most apparent in lower risk patients and was independent of most of the currently established risk factors for survival in MDS. The observations from the current study suggest the possible therapeutic value of augmenting host immunity in lower risk MDS. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

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 Background Increased serum levels of lactate dehydrogenase (LDH) typically accompany primary myelofibrosis (PMF) and might be linked to increased cell turnover from clonal myeloproliferation, including leukocytosis, low grade hemolysis and extra-medullary hematopoiesis in the liver. Despite the fact that serum LDH has been extensively utilized as a prognostic marker in both lymphoid neoplasms and solid tumors, there are limited studies in PMF that have systematically examined the clinical significance of the degree of serum LDH elevation in PMF. Methods Study patients fulfilled the 2016 WHO criteria for the diagnosis of PMF, including both pre-PMF and overt PMF (Blood. 2016;127:2391). Additional selection criteria included the availability of serum LDH at time of referral. Marked elevation of serum LDH was defined as a value of ≥1000 U/L (i.e. over 4-fold increase from the upper limit of the normal range for our institution, which was 122-222 U/L), based on preliminary analysis of the threshold for prognostic effect. Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of initial referral to the Mayo Clinic. Results LDH values in overt PMF versus pre-PMF: The entire study population consisted of 357 patients, including 311 with overt PMF and 46 with pre-PMF. The median serum LDH level was 514 U/L (range 136-2263): overt PMF 532 U/L (range 136-2263); pre-PMF 401 U/L (range 180-1237) (p=0.0003). Accordingly, in order to avoid the confounding effect of the difference in serum LDH level between overt PMF and pre-PMF, and considering the small number of patients with pre-PMF, further analysis was limited to the 311 patients with overt PMF. Patient characteristics: The 311 patients (median age 64 years; 66% males) with overt PMF included 205 (66%) JAK2, 49 (16%) type 1/like CALR, 13 (4%) type 2/like CALR, 16 (5%) MPL mutated cases and 28 (9%) were "triple-negative". DIPSS-plus risk distribution was 31% high, 43% intermediate-2, 15% intermediate-1 and 12% low; 30% displayed red cell transfusion-dependency and 37% abnormal karyotype, including 14% with unfavorable karyotype. 184 patients were screened for ASXL1 mutations with 42% mutated and 205 for SRSF2 mutations with 16% mutated. Clinical correlates of markedly elevated LDH (≥1000 U/L): Among all 311 study patients with overt PMF, 37 (12%) displayed marked elevation of LDH (≥1000/L). Patients with marked elevation of LDH displayed significantly higher leukocyte count (p=0.005; R-squared = 0.05), circulating blast percentage (p=0.03; R-squared = 0.07) and SRSF2 mutational frequency (44% vs 12%; p<0.0001). Survival analysis: After a median follow up of 3 years, 199 (64%) deaths and 31 (10%) leukemic transformations were documented. In univariate analysis, increased serum LDH level was associated with inferior survival, both as a continuous variable (p=0.002) and as a categorical variable with the cutoff level of 1000 U/L (HR 2.02, 95% CI 1.3-3.1; p=0.001); the survival effect LDH ≥1000/L was independent of DIPSS-plus (HR 1.6, 95% CI 1.1-2.5). Other variables that were significantly associated with shortened survival, on univariate analysis, included all 8 DIPSS-plus variables (p≤0.01 in all instances), absence of CALR type 1/type 1-like (p<0.0001) and presence of ASXL1 (p<0.0001) or SRSF2 (p=0.0006) mutations. In multivariable analysis that included only genetic risk factors, serum LDH retained its significance (HR 2.2, 95% CI 1.3-3.6), along with absence of CALR type 1/type 1-like, or presence of ASXL1 or SRSF2 mutations or unfavorable karyotype. In multivariable analysis that included only clinical variables, serum LDH ≥1000/L was again independently predictive of poor survival (HR 1.7, 95% CI 1.1-2.6), along with age >65 years, hemoglobin <10 g/dL, platelets <100 x 10(9)/L, leukocyte count >25 x 10(9)/L and constitutional symptoms. Patients with marked LDH elevation were also more likely to undergo leukemic transformation (HR 3.1, 95% CI 1.2-7.6). Conclusion The current study suggests that marked elevation of serum LDH in PMF indicates aggressive tumor biology that is currently not accounted for by established clinical or genetic risk factors; the low R-squared values seen in relation to leukocyte count and circulating blasts are consistent with this assumption. Disclosures No relevant conflicts of interest to declare.

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: 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.