Gangat, Naseema

Abstract Background: Myeloid sarcoma is a tumor mass consisting of myeloid blasts occurring at anatomical site other than the bone marrow (Arber et al. Blood 2016;127(20):2391-2405). It is a subgroup of acute myeloid leukemia, which can be localized or disseminated and may involve multiple organs. It can present with or without a positive bone marrow. It may precede or follow bone marrow involvement. It may be identified at diagnosis or relapse, and is not uncommon after stem cell transplantation (Koc et al. Cancer 1999;85(3):608-615; Yoshihara et al. Biol. Blood Marrow Transplant 2012;18(12):1800-1807). Objective: To describe the clinical characteristics, cytogenetics, prognosis and outcome of patients with myeloid sarcoma with or without bone marrow involvement. Methods: The Mayo Clinic database was interrogated using the ICD-9 codes 205.0, 205.2, 205.3, as well as terms "myeloid sarcoma," "chloroma," and "extramedullary sarcoma" in clinical notes and pathology reports. Patients' follow up information was collected until July 2016. Results: Ninety six patients with a diagnosis myeloid sarcoma were identified. The diagnosis was based on biopsy results and in some cases imaging studies in addition to bone marrow biopsy. The median age was 53 (range 17-83) years, and 64 (67%) patients were males. Myeloid sarcoma with de novo (primary) and secondary acute myeloid leukemia (with antecedent hematologic malignancy and therapy related) accounted for 64% (61) and 36% of the cases respectively. The sites involved based on their frequency of occurrence included integumentary system (skin and soft tissues) in 37 (38%), lymphatic system in 17 (18%), the gastrointestinal and genitourinary system in 14 (15%), the nervous system in 9 (9%), the breast in 3 (3%) and multiple and other single sites in 16 (17 %). Bone marrow cytogenetics findings were documented in 74 (77%) patients; favorable, intermediate, and poor cytogenetic abnormalities account for 7 (9%), 45 (61%), and 22 (30%) cases respectively. After a median follow up of 135 weeks, 57 (59%) patients died. The median survival of primary and secondary acute myeloid leukemia with myeloid sarcoma was 52 and 11.5 months (P<0.0001); and that of favorable, intermediate and unfavorable cytogenetics abnormalities was 169, 52 and 17.5 months (P=0.04) respectively. Twenty six (27%) patients had no bone marrow involvement; and 18 (69%) of them were primary myeloid sarcoma (without antecedent malignancy or therapy). The median (range) age of those with and without bone marrow involvement was 53 (17-83) and 56 (17-81) years (P=0.6). At diagnosis patients with and without bone marrow involvement have a median (range) hemoglobin (gm/dL) (10.3 (6.2-15.4) vs 13.1 (9.9-15.2) P=0.0002), white blood cell count (X109/L) (21.4 (1.1-182.5) vs 5.8 (2.4-23.2) P<0.0001), and platelet count (X109/L) (71 (8-437) vs 250 (17-561) respectively. Aggressive chemotherapy therapy was given to 58 (83%) and 20 (77%) of patients with and without bone marrow involvement (P=0.6). The median survival was 17 and 20 months with and without bone marrow involvement (P=0.4). Of those with bone marrow involvement, 49 (70%) achieved complete remission, and 26 (53%) of those individuals subsequently relapsed. Conclusion: The treatment outcome of patients with myeloid sarcoma with or without bone marrow involvement seems the same. The conventional risk factors, antecedent hematological neoplasms and cytogenetic findings, have significant impact on survival. Disclosures Al-Kali: Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding.

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for primary myelofibrosis (PMF). Reduced intensity conditioning (RIC) allows otherwise ineligible patients to proceed with HSCT. Host factors in PMF such as bone marrow (BM) fibrosis, massive splenomegaly, and transfusion related allo-immunization increase the risk of engraftment failure, especially with RIC. Spleen directed therapy (SDT) is often used in PMF patients with splenomegaly to help with engraftment, however little data exists supporting this practice. This study was carried out to investigate the role for SDT and the predictors of outcomes with RIC HSCT for PMF. Methods :After IRB approval, the Mayo Clinic HSCT registry was queried for patients with PMF that underwent RIC allo-HSCT from 2005-2014. Disease and transplant related data were retrospectively abstracted and analyzed for HSCT related outcomes. SDT was defined as a therapeutic strategy with specific intent to overcome an enlarged spleen prior to HSCT and included splenectomy, splenic artery embolization, splenic irradiation, or JAK inhibitor therapy that was stopped <30 days before HSCT. Survival estimates were calculated using the Kaplan-Meier method and means were compared using the log-rank test. Univariate and multivariate analyses were performed using Cox regression modeling. Results :51 patients (67% males) with WHO defined PMF with palpable splenomegaly that underwent RIC allo-HSCT were included in the study; median age 57 years (range, 35-68). The median follow-up was 12.2 months, and at last follow up, 19 deaths (37%) and 4 relapses (8%) were documented. The median OS for the group was not reached (mean 34.2 months); 88% at 100 days and 60% at 2 years. 17 deaths were attributed to non-relapse mortality (NRM). There were 3 engraftment failures (6%). 32 patients (63%) developed acute GVHD (grades II-IV) and 24 patients (47%) developed chronic GVHD (all grades). Twenty-one patients (41%) received SDT; 10 (48%) splenectomy, 2 (9%) splenic irradiation, and 9 (43%) JAK inhibitor therapy (ruxolitinib). The SDT group had a median spleen size of 14.5 cm (range, 1-29 cm) below the left costal margin (LCM) and 13 patients (62%) with spleen size >10 cm below LCM, while the no SDT group had a median spleen size of 7 cm (range, 1-19 cm) and 12 patients (40%) with spleen size >10 cm below LCM; p = 0.01. Seven (64%) of 11 patients receiving splenic irradiation (n = 1) or JAK inhibitor therapy (n = 6) were eligible for IWG-MRT spleen response, and 2 (29%) responded (both in JAK inhibitor group). Of the remaining 5 patients, 2 had a response not meeting IWG-MRT criteria. There were no differences in age (p = 0.09), gender (p = 1.0), DIPSS + score (p = 0.35), or HCT-CI (p = 0.61) between the two groups. There was a statistically significant difference in engraftment failure, with all 3 engraftment failures occurring in the SDT group (2 splenectomy patients, 1 splenic irradiation patient; p = 0.02). Engraftment failures were not attributable to insufficient cell dose, donor specific antibodies, or identifiable host factors. The patient with engraftment failure who underwent splenic irradiation had persistent massive splenomegaly. There were similar outcomes with regards to relapse rates, NRM, and acute and chronic GVHD. In the SDT group, the median OS was 13.3 months; 81% at 100 days and 33% at 2 years. In the no SDT group, the median OS was not reached; 94% at 100 days and 68% at 2 years; p=0.13. In a univariate survival analysis that included age, gender, SDT, DIPSS+ score, HCT-CI, CMV status, ABO status, HLA matching, donor source, graft source, engraftment status, and acute and chronic GVHD, predictors of survival were engraftment failure (p = 0.02) and major/bidirectional ABO incompatibility (p = 0.02). Similar results were obtained when JAK inhibitor therapy was considered separately from other forms of SDT. In a multivariate analysis, engraftment failure (HR 8.2, 1.8-27.2; p = 0.01) and major/bidirectional ABO incompatibility (HR 4.1, 1.4-10.9; p = 0.009) retained independent prognostic significance. Discussion:In patients with PMF and splenomegaly, there was no demonstrable benefit from SDT. Predictors of post-HSCT survival included engraftment failure and major/bidirectional ABO incompatibility. These findings need validation in a larger cohort of patients. Disclosures Al-Kali: Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding.

Abstract Background : Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) is a provisional entity in the MDS/MPN overlap syndromes, with diagnostic features of RARS, along with a platelet count > 450 x 10(9)/L and large atypical megakaryocytes. Mutations involving SF3B1 (~80%), JAK2 (~60%), TET2 (~25%) and ASXL1 (~15%) have been reported. The frequency of thrombotic events in RARS-T is thought to be similar to that of essential thrombocytosis (ET) (3.6 vs 3.9/100 patient years; Hematologica 2012; 1036-41). However, unlike in ET, it remains unclear as to whether thrombotic events in RARS-T impact overall (OS) or thrombosis-free (TFS) survival. Methods : 82 patients with WHO-defined RARS-T were included in the study. All patients had bone marrow (BM) biopsies, iron stains for detection of BM ring sideroblasts (RS) and cytogenetics performed at diagnosis. Mutational analysis for JAK2, CALR, MPL, SF3B1, SRSF2 and ASXL1 was carried out on BM DNA obtained at the time of diagnosis. Details of type of thrombotic event and cardiovascular (CV) risk factors including; hypertension, diabetes, smoking and dyslipidemia were obtained by careful review of the medical record. OS was calculated from time of initial diagnosis to the time of last follow-up or death. TFS was calculated from the time of diagnosis of RARS-T to development of thrombosis in uncensored patients and date of last follow up or death in patients censored for thrombosis. Conventional statistics were utilized for all analyses. Results: Among the 82 study patients, 46 (56%) were males and median age was 72 years (range, 48-93). At a median follow-up of 26.5 months; 48 (59%) deaths and 2 leukemic transformations were documented. Median OS was 44 months. Karyotype was diploid in 61 (74%) and analyzed mutational frequencies were; SF3B1 67% (28/42), JAK2 V617F 40% (25/61), ASXL1 21% (9/41), SRSF2 6% (2/31), MPL 1% (2/41) and CALR 0, respectively. Cardiovascular risk factors were present in 52 (63%). a) Thrombotic events and their impact on thrombosis free survival: Eight (10%) patients had a thrombotic event prior to or at the time of diagnosis of RARS-T (venous-8, arterial-0). Nine (11%) patients developed subsequent thrombotic events (venous-7, arterial-2), with no fatalities. In univariate analysis, lower hemoglobin level (p=0.008), lower BM RS % (p=0.04), history of thrombosis (p=0.02), and absence of SF3B1 mutations (p=0.017) were associated with an inferior TFS. Age (p=0.07), JAK2 mutation status (p=0.56) and CV risk factors (p=0.95) did not have prognostic impact. Given the association between SF3B1 mutations and BM RS, in a multivariable model that included these two as covariates, only the absence of SF3B1 mutations retained prognostic significance (p=0.02). Absence of SF3B1 mutation remained significant when history of thrombosis or lower hemoglobin level were introduced into the multivariable model. b) Risk factors for overall survival: In univariate analysis, hemoglobin <10 gm/dl (p=0.007), presence of circulating blasts (p=0.002) and presence of CV risk factors (p=0.04) were associated with an inferior OS. Neither history of thrombosis (p=0.59) nor SF3B1 (p=0.12) mutations affected OS. In multivariable analysis, hemoglobin <10 gm/dl (p=0.03) [HR 1.9; 95% CI 1.1-3.5] and circulating blasts (p=0.002) [HR 1.3; 95% CI 1.1-1.6] remained significant. Conclusions: In contrast to what is observed in ET, thrombosis history does not appear to affect either overall or thrombosis-free survival in RARS-T. The current study suggests a lower thrombosis risk in SF3B1 -mutated patients with RARS-T, compared to their SF3B1 wild-type counterparts. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two commonly used reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT). A recent analysis showed that both regimens had similar overall survival (OS) but relapse incidence (RI) was significantly higher with FB with a trend towards higher non-relapse mortality (NRM) in FM (Baron et al., Cancer 2015). However, that cohort included patients treated with oral and intravenous busulfan without pharmakokinetic targeting of intravenous which may impact anti-leukemic activity. Aim: Compare transplant related outcomes of FB vs. FM using intravenous (IV) busulfan targeted to the area under the curve (AUC). Methods: After due IRB approval, patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) receiving RIC-SCT from 2008-2014 were identified. All baseline and laboratory features were retrospectively extracted. Busulfan dose in FB was 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L (min). All patients received T-cell replete grafts. Categorical and continuous variables were compared using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier method and curves were compared using the log-rank test. Cumulative incidence was computed as competing events using Grey's model. Univariate and multivariate analyses were performed using Cox regression modeling. Results: A. Baseline characteristics and AUC monitoring: 134 pts were identified (47 FB and 87 FM). Median follow up of the entire cohort was 40 months (0-63.3) and at last follow up, 60% and 29% have died or relapsed, respectively. Baseline characteristics stratified according to conditioning regimen are shown in table 1. Younger age (60 yrs FB vs. 61 yrs FM, p = 0.015) and a trend towards a higher CMV R-/D- status (28% FB vs. 14% FM p = 0.064) were the only significant differences identified. All patients in the FB group received intravenous busulfan and 46/47 patients had evaluable AUC data with a range of 732-1354 mcmol/L (min). A total of 19 patients were outside of range, all <900 mcmol/L (min) and required a median dose increase of 28.1% (3.3-50.2%) B. Engraftment and toxicity data: The median time for platelet engraftment was 19 days (0-48) for FB vs. 16 days (14-183) for FM (p = 0.0023) whereas the median time to absolute neutrophil count (ANC) engraftment was 18 days (7-30) for FB and 15 days (11-40) for FM (p = 0.077). Cumulative incidence of grade II-IV, III-IV acute GVHD and chronic GVHD at 2-yr was 57.3%, 11% and 52.8% for FB and 48.6%, 17% and 63.4% for FM (p = 0.73, 0.4 and 0.21, respectively). Two patients in the FM group died of cardiac causes (heart failure and sudden cardiac arrest). No cases of sinusoidal obstructive syndrome were observed in either arm C. Transplant outcomes: A significantly higher 2-yr relapse incidence (RI) was associated with FB vs. FM at 35.6% vs 17.3%, respectively (p = 0.0058). 2-yr progression free survival (PFS) was also significantly lower in the FB vs. FM at 51.2% vs. 65.1%, respectively (p 0.031). However, 2-yr OS and NRM was similar for FB vs. FM (53.1% and 22.9% vs 63.9% and 21.9%, respectively p = 0.26 and 0.89). Necessitating a dose adjustment based on AUC did not increase the risk for relapse or affect NRM. In multivariate analysis, FB was associated with increased RI with hazard ratio (HR) 2.29 (1.07-4.88; p = 0.033). Other factors significantly associated with RI on multivariate analysis were secondary/therapy related disease with HR 2.84 (1.34-6.02; p = 0.0067) and CR1 vs. other with HR 0.39 (0.17-5.32; p = 0.019). The significance of the results remained unchanged after exclusion of MDS patients (data not shown) Conclusion: Despite AUC dose adjustment, FB compared to FM was associated with increased RI with a similar OS and NRM. AUC dose adjustment did not impact transplant outcomes and its routine use in RIC should be further evaluated. Given the wide use of FB as a conditioning regimen, these important observations should be prospectively studied in a randomized fashion. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding. Wolf:Janssen Scientific Affairs, LLC: Consultancy.

Abstract Background: The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms has specifically categorized germline mutations that are associated with myeloid clonal evolution (Arber et al. Blood 2016). This group consists of myeloid neoplasms with an isolated germline predisposition (CEBPA, DDX41), myeloid neoplasms associated with congenital thrombocytopenia (ETV6, RUNX1, ANKRD26) and germline myeloid neoplasms with multi-organ dysfunction (GATA2, chromosomal breakage disorders, telomere biology disorders etc). We carried out this study to describe the clinical spectrum of germline disorders with predisposition to myeloid neoplasms as categorized by the 2016 WHO classification revision. Methods: After Institutional Review Board (IRB) approval, the adult and pediatric bone marrow failure syndrome database (1990-2016) and the electronic medical record were queried for germline disorders involving GATA2, CEBPA, DDX41, ETV6, RUNX1, ANKRD26, Down syndrome and Noonan syndrome. Chromosomal breakage assays (Diepoxybutane/Mitomycin-C), flow-fluorescent in-situ hybridization (FISH) for telomere length assessment, Fanconi anemia complementation assays and Sanger/Next Generation sequencing (NGS) for the aforementioned germline disorders with myeloid predisposition were carried out in Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. These disorders were then classified based on the 2016 WHO classification revision. Results : 54 individuals (37 families) were included in the study. Eleven (20%) patients belonging to 5 families were identified as having germline mutations with a preexisting platelet disorder: ETV6 (n=1), ANKRD26 (n=5), RUNX1 (n=5). Forty-three (79%) patients (32 families) had inherited syndromes with multi-organ dysfunction: GATA2 (n=11, 26%), bone marrow failure syndromes (n=14, 33%) and telomere biology disorder (n=14, 33%). There was one patient with neurofibromatosis with a germline PTPN11 mutation who developed juvenile myelomonocytic leukemia, while there were three patients with Down syndrome; 2 with transient abnormal myelopoiesis and one who developed acute megakaryocytic leukemia. The clinical phenotype, prevalence and characteristics of myeloid clonal evolution and outcomes are presented in Table 1. No patients with germline CEBPA or DDX41 mutations were identified. Patients with germline platelet disorders did not have any prominent non-hematological manifestations. Erythrocytosis (20%) with long-standing thrombocytopenia (100%) was a unique feature associated with ANKRD26 mutations. Non-hematologic clues such as human papillomavirus (HPV)-driven warts, primary lymphedema (Emberger syndrome) and frequent atypical infections with monocytopenia were seen in patients with germline GATA2 mutations, and preceded myeloid clonal evolution (morphologic, cytogenetic and molecular). Notably, the age at presentation and penetrance of myeloid transformation was variable, with individuals from the same family developing symptoms during the first decade of life and others remaining asymptomatic to date (fifth decade). Somatic ASXL1 mutations were detected in all 3 (100%) patients with GATA2 mutations and in one patient with ANKRD26 mutation that developed myeloid clonal evolution. In our study myeloid clonal evolution was seen in 40% with RUNX1 mutations, 27% with GATA2 mutations, and 20% with ANKRD26 mutations. We could not calculate the same for bone marrow failure syndromes as the total number of cases seen are still being assessed. Outcomes with allogeneic stem cell transplantation were favorable in appropriately selected patients (Table 1). Conclusion : The 2016 WHO revision to the classification of myeloid neoplasms highlights the importance of recognition and molecular characterization of germline mutations (syndromic and non-syndromic) with risk for myeloid clonal evolution. While some of these disorders (GATA2, Fanconi anemia, telomere biology disorders) may have important non-hematological clues, many present with isolated thrombocytopenia (RUNX1, ETV6). The age and frequency of myeloid evolution is highly variable. Acquisition of somatic ASXL1 mutations at the time of clonal myeloid transformation highlights the role of epigenetic dysregulation in disease evolution. Disclosures Kenderian: Novartis: Patents & Royalties, Research Funding.

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4104 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) uses five predictors of inferior survival: age > 65 years, hemoglobin < 10 g/dL, leukocytes > 25 × 109/L, circulating blasts ≥ 1% and constitutional symptoms (Cervantes F et al. Blood 2009; 113: 2895). The dynamic IPSS (DIPSS) utilizes the same prognostic variables but can be applied at any time during the disease course (Passamonti F et al. Blood 2010; 115: 1703). IPSS-independent risk factors for survival have since been described and include unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L. Objectives: i) To determine if the aforementioned IPSS-independent risk factors for survival in PMF (i.e. unfavorable karyotype, red cell transfusion need and platelets < 100 × 109/L) are also DIPSS-independent. ii) To develop and validate a refined DIPSS model that incorporates DIPSS-independent prognostic factors for survival. iii) To establish a prognostic model for leukemia-free survival in PMF. Methods: The Mayo Clinic database for PMF was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of their referral. WHO criteria were used for PMF diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). None of the patients in the current study were included in the original group of patients used to describe DIPSS (Passamonti F et al. Blood 2010; 115: 1703). Results: A total of 793 patients met the above-stipulated criteria. The study population was divided into two groups based on whether or not patients were seen at the Mayo Clinic within (n=428; training set) or beyond (n=365; test set) their first year of diagnosis. i) Objective 1: Multivariable analysis that included DIPSS risk category (low, intermediate-1, intermediate-2 and high risk), karyotype (favorable or unfavorable), platelet count (≥ or <100 × 109/L) and transfusion status (independent or dependent) was performed using the training set and all four variables were found to be significant as independent predictors of survival (p<0.0001, <0.0001, 0.0008 and 0.01, respectively). ii) Objective 2: Using the respective hazard ratios (HR) obtained during the multivariable prognostic analysis in the training set, HR-weighted adverse points were assigned: 3 points for high-risk DIPSS, 2 points for intermediate-2 risk DIPSS, and 1 point each for intermediate-1 risk DIPSS, unfavorable karyotype, platelets < 100 × 109/L or transfusion need. Accordingly, a refined DIPSS model (i.e. DIPSS-plus) was devised using the training set (Figure 1) and subsequently validated in the test set (Figure 2): low-risk (0 adverse points), intermediate-1 risk (1 adverse point), intermediate-2 risk (2-3 adverse points) and high-risk (4-6 adverse points). Considering the entire group of 793 study patients, the respective median survivals were 185, 78, 35 and 16 months (p<0.0001). ii) Objective 3: Multivariable analysis identified platelet count (p=0.0007) and karyotype (p=0.04) but not DIPSS or transfusion status as independent predictors of leukemia-free survival. We used these two variables to classify patients into a low (favorable karyotype and platelets ≥ 100 × 109/L) or high (unfavorable karyotype or platelets < 100 × 109/L) risk category for leukemic transformation; the respective 5- and 10-year risk of leukemic transformation were 6% and 12% vs. 18% and 31%, respectively (p<0.0001; HR 3.3, 95% CI 1.9–5.6). Conclusions: DIPSS-plus effectively incorporates prognostic information from karyotype, platelet count and transfusion status into the DIPSS prognostic model for PMF. Unfavorable karyotype or platelets <100 × 109/L is associated with a significantly higher risk of leukemic transformation in PMF. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Adult T-cell acute lymphoblastic leukemia / lymphoma (T-ALL) is an rare and aggressive hematological malignancy with overall survival (OS) according to the UKALL XII/E2993 of 48% at 5 years (Marks et al, Blood 2009). Over the last decade, the incorporation of L-asparaginase, dose intensification (similar to pediatric protocols), availability of newer agents such as clofarabine (Dec 2004) and nelarabine (Oct 2005) have been shown to improve outcomes. We carried out this study to see if the above mentioned changes in treatment have translated to an OS benefit. Methods: After due IRB approval, adults diagnosed with T-ALL from 1990-2014 at Mayo Clinic were identified. All clinical and pathologic data was retrospectively reviewed Comparative analysis was performed based on year of diagnosis before and after 2005 (Group 1, diagnosis prior to 2005, and Group 2, diagnosis post 2005). Survival was estimated using the Kaplan-Meier Method and log-rank test. Chi-square test was used to compare variables. Results: A. Patient Characteristics: Between 1990 and 2014, a total of 92 consecutive patients (pts) with T-ALL were identified. Median age at diagnosis was 33 years (range; 18-88 years) with 72% males. Distribution of pts by year of diagnosis was as follows: Group 1(n= 47) (51%), and Group 2 (n=45) (49%). Median overall survival was 97.2 months. Median follow up for Group 1 was 50 months, during which time 23 (39%) deaths were documented, and 22.8 months (0.9 - 115.4) for Group 2 at which time19 deaths (42%) were documented (p= 0.04). Pts in Group 2 were older than Group1 (median age 41 vs 27 years (p= 0.004). Apart from age, the two groups were similar in other characteristics (Table 1). B. Therapy received by patient groups: We observed a high use of L-asparaginase containing regimens in Group 1 vs Group 2 [35(74%) pts vs 19 (42%), p=0.0013]. In contrast there was an increase in use of Hyper-CVAD in Group 2; 23(51%) vs. 3 (6%) (p<0.0001). There was no difference in the use of intensive pediatric protocols (p=0.11). There was a trend of increased use of nelarabine in Group 2, however clofarabine usage was not different (p=0.09, and p=0.6 respectively) (Table1). Allogenic stem cell transplant was offered more in Group 2 compared to Group 1, 16 (36%) patients vs. 10 (21%) patients (p=0.0009). In contrast, 7 (19%) patients underwent autologous transplantation in group 1 vs. none in group 2 (p=0.0009). C. Overall outcome by patient groups: We did not observe any difference in CR, or relapse rates among the two groups. The median OS and time to relapse were also not statistically different among Group 1 and 2 [102.6 vs 61.8 months Figure A, and 7.1 vs 14.1 months respectively]. Furthermore, age adjusted survival analysis was also not statistically significant. Conclusion: In this large cohort of adult T-ALL patients, in spite of significant advances in treatment strategies over the last two decades, we observed no difference in overall and relapse free survival prior to and after 2005. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding. Witzig:Spectrum: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Valeant Pharma: Equity Ownership.

Abstract Background: There is demonstrated benefit when administering fluoroquinolones as infection prophylaxis in neutropenic patients; however, side effects, drug interactions and increasing drug resistance necessitate investigation toward safe and effective alternative therapies. This study investigates the use of oral third generation cephalosporins as antibacterial prophylaxis during chemotherapy-induced neutropenia to establish knowledge on alternative treatment options. Methods: A retrospective chart review was performed to compare incidence of febrile neutropenia and documented infection rates in Acute Myeloid Leukemia (AML) and intermediate to high International prognostic scoring system (IPSS) risk myelodysplastic syndrome (MDS) patients receiving antibacterial chemoprophylaxis at Mayo Clinic between January 2006 and April 2016. Patients were included if they were 18 years or older, had a diagnosis confirmed on bone marrow biopsy, received induction or first relapse induction-remission chemotherapy regimens and then subsequently were prescribed fluoroquinolone or an oral third generation cephalosporin prophylaxis for anticipated profound and prolonged neutropenia. The main regimens prescribed were cytarabine + anthracycline (7+3), daunorubicin + cytarabine + nilotinib, mitoxantrone + etoposide + cytarabine, all-trans-retinoic acid (ATRA) + anthracycline, all-trans-retinoic acid (ATRA) + arsenic, clofarabine + cytarabine, or an investigational trial. After meeting inclusion criteria the treatment arms were matched via Charlson comorbidity index ( ± 3) and age ( ± 5). Patients with a documented infection 48 hours after switching from either broad spectrum antibiotics to antibacterial prophylaxis, or from levofloxacin prophylaxis to an oral third generation cephalosporin were excluded from the study. All patients provided consent for review of their medical records for research purposes. This study was approved by the Mayo Foundations institutional review board. Results: A total of 565 patients admitted to Mayo Clinic inpatient leukemia service for chemotherapy and concurrently prescribed antibacterial prophylaxis with either levofloxacin or an oral third generation cephalosporin were screened between January 1, 2006 and April 1, 2016. Of those screened 397 patients met the inclusion criteria, and subsequently 123 patients were matched via Charlson comorbidity index and age. Patient characteristics are presented in Table I. Of the 123 study patients, 80 (65%) were male, and the median age was 58.6 years (IQR: 53.3-68.5). The population was comprised of 115 (93.5%) patients with AML, and 8 (6.5%) patients with MDS. By 30 days after prophylaxis start 109 of the 123 patients developed febrile neutropenia (89.9%, 95% CI: (82.8-94.1)). There was no difference in the risk of febrile neutropenia between those on levofloxacin and those on an oral third generation cephalosporin (hazard ratio [HR] = 1.057, 95% CI: 0.64-1.75, p=0.83). The mean ANC value at the time of febrile neutropenia was 0.47 (SD: 1.4). Documented reasons that patients did not receive an oral fluoroquinolone were QTc prolongation (34.2%), rash (21.1%), tendonitis (2.6%), anaphylaxis (5.3%), drug interaction with a treatment study drug (23.7%), or other (13.1%). Three patients died 30 days or less after the last dose of chemoprophylaxis (40 day survival: 96.6%, 95% CI: 92.7-100); two of the reported deaths were due to infection. Of the 111 patients who had a documented febrile episode, 40 (36%) had a culture positive infection. Gram positive organisms caused 27 (71.1%) of the infections, 11 (28.9%) were gram negative organisms, and 1 (2.6%) infection was due to an anaerobic organism. There were 3 (7.5%) polymicrobial infections, and 36 (90%) monomicrobial infections. The majority of the patients had bloodstream as the documented site of infection. Of the documented culture positive infections 15 (39.5%) showed resistance to levofloxacin and 6 (15.8%) had resistance to third generation cephalosporins when susceptibility testing was reported. Conclusions: These findings demonstrate comparable safety and efficacy of oral third generation cephalosporins compared to fluoroquinolones and contribute to the growing body of literature surrounding antibacterial prophylaxis during chemotherapy-induced neutropenia. Further prospective, randomized investigation is warranted. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 4122 Background: We have previously identified sole +9, 13q- or 20q- as “favorable” and sole +8 or complex karyotype as “unfavorable” cytogenetic abnormalities in primary myelofibrosis (PMF) (Blood 2010; 115: 496). The purpose of the current study, which includes more than twice the number of patients included in previous studies, was to identify additional prognostically-relevant cytogenetic abnormalities in PMF and refine cytogenetic risk categorization for overall and leukemia-free survival. Methods: Clinical and laboratory data were collected from consecutive patients with PMF seen at our institution and in whom cytogenetic information at or within 1 year of diagnosis was available. Diagnosis of PMF and acute myeloid leukemia were according to the World Health organization (WHO) criteria. Results: A total of 433 patients with PMF were included in the current study. Median age at diagnosis was 65 years. IPSS risk distributions were low in 12% of patients, intermediate-1 in 25%, intermediate-2 in 24% and high in 39%. JAK2V617F mutational frequency was 60%. Cytogenetic findings were normal in 275 (64%) patients. Among the 158 (36%) patients with abnormal karyotype, 109 (69% of abnormal cases) represented sole abnormalities, 23 (15%) two abnormalities and 26 (17%) three or more (i.e. complex) abnormalities. In an effort to identify cytogenetic categories of similar prognosis, each one of 12 operational cytogenetic categories was separately compared with both normal and complex karyotype. Accordingly, we were able to devise a two-tired cytogenetic risk stratification with highly significant differences in overall and leukemia-free survival (Figures 1 and 2): unfavorable (complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement) and favorable (all other cytogenetic findings including normal karyotype). Median survivals of patients with favorable and unfavorable karyotype were 5.2 and 2.0 years, respectively (p<0.0001). The corresponding 5-year survival rates were 51% and 8% (HR 3.1, 95% CI 2.2–4.3; p<0.0001). Multivariable analysis confirmed the IPSS-independent prognostic value of cytogenetic risk categorization (p<0.0001; HR 2.1, 95% CI 1.5–3.1) and also identified thrombocytopenia (platelet count < 100 × 109/L) as another independent predictor of inferior survival (p<0.0001; HR 1.9; 95% CI 1.4–2.6). A similar multivariable analysis showed that cytogenetic risk profile (p=0.001; HR 4.1, 95% CI 1.7–9.6) and platelet count (p=0.04; HR 2.3, 95% CI 1.0–5.0), but not IPSS (p=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable and favorable karyotype were 46% and 7%, respectively (HR 5.5, 95% CI 2.5–12.0; p<0.0001). These results, in terms of both overall and leukemia-free survival analysis, did not change when patients receiving allo-SCT were censored at the time of their transplant. Among patients with favorable karyotype; the incidences of leukopenia and thrombocytopenia were highest in patients with sole 20q- (41% and 38%, respectively) and lowest in those with sole 13q- (0% and 0%, respectively). Conclusions: The current study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF. The study also revealed a highly significant association between sole 20q- and both leukopenia and thrombocytopenia, which suggests a 20q- haploinsufficient gene effect. Disclosures: No relevant conflicts of interest to declare.