Citations

Abstract Abstract 3795 Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (IL-2R, IL-8, IL-12, IL-15 and CXCL10) and large cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). In order to examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex ELISA to measure 30 plasma cytokines in 78 patients with primary MDS. Compared to normal controls (n =35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (p<0.01), IL-7 (p=0.02) and IL-6 (p=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the international prognostic scoring system (IPSS), age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (p<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (p=0.01). Comparison of plasma cytokines between MDS (n =78) and primary myelofibrosis (n =127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically-relevant plasma cytokine signatures in hematologic malignancies.Figure:Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).Figure:. Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002). Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Relapse after ATRA-based induction therapy is relatively uncommon in patients with acute promyelocytic leukemia (APL). Long term follow up studies have estimated a 15-25% relapse rate. Autologous and allogeneic hematopoietic stem cell transplantation (HCT) has been used as an effective salvage strategy. We present a single institution study of the outcomes of patients with relapsed APL that underwent HCT. Methods: After due IRB approval, the Mayo Clinic Transplant Database was retrospectively reviewed to identify all patients across three Mayo Clinic sites with relapsed APL that underwent HCT from 1995-2013. Data was abstracted at diagnosis and at relapse. The aims of this study were to report the descriptive characteristics of patients, with a focus on HCT outcomes. Results: Baseline Patient Characteristics A total of 15 patients (9 (60%) males) with relapsed APL that underwent HCT were identified. Median age was 36 years (range: 19-63) and median follow up from diagnosis was 8.8 years (range: 1.7-17). 2 (13%) deaths (1 from relapse) were recorded. 14 (93%) received ATRA and anthracycline-based induction therapy and 1 received anthracycline-based induction without ATRA. All relapsed patients achieved a complete remission (CR) after induction. Median time to relapse was 1.6 years (range: 0.6-3.9). 10 (67%) patients had a medullary relapse (hematologic-7(70%), cytogenetic -2 (20%) and molecular-1(10%)), 3 (20%) had additional extramedullary (EM) disease (CNS-2, myeloid sarcoma-1), while 2 (13%) presented with EM disease only (CNS-2). Salvage regimens included ATRA in 5 (33%) patients and arsenic trioxide (ATO) in 8 (53%) patients. 12 (80%) patients were transplanted in CR2 and 1 in CR3 (7%), while 2 (13%) had persistent disease (PD) at time of HCT. Allogeneic HCT 4 (27%) patients with a median age of 37 years (range: 33-49) underwent allogeneic HCT. 2 (50%) patients received myeloablative (MA) conditioning and 2 received reduced-intensity conditioning (RIC). 2 patients who underwent MA HCT had PD at time of transplant, while 1 patient in CR3 received a RIC. 2 (50%) patients developed acute GVHD while 2 (50%) had extensive stage chronic GVHD. At a median follow up of 2.6 years (range: 0.3-10.9), 3 (75%) patients remain alive and disease-free. 1 patient died of infectious complications within 100 days of transplant. Autologous Transplantation 11 (73%) patients with a median age of 40 years (range: 23-68) underwent autologous HCT with MA conditioning. 7 (64%) patients were in molecular remission at time of HCT, 3 (27%) patients transplanted before 2004 were in cytogenetic remission and information about type of remission was unavailable in 1 patient. At a median follow up of 6.8 years (range: 0.5-16) since HCT, 1 (9%) patient had a documented relapse at 175 days after HCT and died of disease-related complications. 10 (91%) are alive and in remission. Conclusions: Our single-institution study reaffirms the efficacy of HCT for APL patients with medullary and EM relapse. Autologous HCT has excellent long-term results in selected patients in CR2. Allogeneic HCT was mainly reserved for patients with high risk disease (CR3) and persistent disease at time of HCT. Table 1: Baseline Patient Characteristics N (%) Number of patients 15 Follow up (years) (median, range) 8.8 (1.7-17) Age at diagnosis (years) (median, range) 36 (19-53) Gender Male 9 (60%) Female 6 (40%) Sanz risk score High 4 (29%) Intermediate 8 (57%) Low 2 (14%) Induction Regimen ATRA + anthracycline 14 (93%) Anthracycline-based 1 (7%) Response to induction therapy CR 15 (100%) Time from diagnosis to relapse (years) (median, range) 1.6 (0.6 - 3.9) Type of relapse Hematologic 7 (47%) Cytogenetic 2 (13%) Molecular 1 (7%) Hematologic and EM 3 (20%) CNS only 2 (13%) Salvage regimen ATRA-based 5 (33%) ATO-based 8 (53%) Chemotherapy only 2 (13%) Table 2: Outcomes at HCT N (%) Age at HCT (years) (median, range) 38 (23-68) Disease status at HCT CR2 12 (80%) CR3 1 (7%) PD 2 (13%) Type of HCT Allogeneic 4 (27%) Autologous 11 (73%) Conditioning regimen Myeloablative 13 (87%) Non-myeloablative 2 (13%) Follow up since HCT (years) (median, range) 4.5 (0.3 - 16.3) Disease status at last follow up CR 13 (86%) Relapsed disease 1 (7%) Unable to assess 1 (7%) Alive at last follow up 13 (87%) Disclosures No relevant conflicts of interest to declare.

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 Introduction Isolated myeloid sarcoma is a rare form (<1%) of acute myeloid leukemia presenting as extramedullary tumor. Contemporary clinical data are mostly limited to institutional case series. Using the National Cancer Database, the largest public cancer registry covering >70% of all newly diagnosed cancers in the United States, we determined the patterns of anatomical presentation and clinical outcome of myeloid sarcoma. Methods We identified patients with a histologically confirmed diagnosis of isolated myeloid sarcoma from 2004-2013 using International Classification of Diseases for Oncology version 3 (ICD-O-3) code: 9930. To allow at least 1 year of follow-up, only patients diagnosed from 2004-2012 were included in the survival analysis using Kaplan-Meier estimates. Results A total of 746 patients were included in the study. The median age of patients was 59 years (range, 41 to 73) and 56% were males. The anatomical distribution and median overall survival of patients are depicted in the Table. The top 3 most common sites of presentation were connective/soft tissues (31.3%), skin/breast (12.3%), and digestive system (10.3%). Compared to other races, Blacks were more likely to have presentation in bones/joints (11.8% vs 6.3% in others), lymph nodes/spleen (22.1% vs. 9%), and less likely in skin/breast (4.4% vs. 13.8%). Asians were more likely to present with cardiopulmonary/mediastinal disease as compared to other races (13.6% vs. 4.2%). According to outcomes, we can categorize the patients into 3 groups: good (median overall survival >30 months: reproductive and digestive systems), intermediate (median overall survival 15-30 months: head/neck and kidney/bladder/retroperitoneum/adrenal), and poor (median overall survival <15 months: nervous system, connective/soft tissue, and bones/joints). There was no significant difference in overall survival between males and females (P =0.06). Among the races, Blacks had the worst overall survival (P =0.02; Figure). Conclusions This is the largest registry-based study on isolated myeloid sarcoma in the United States. Isolated myeloid sarcoma has a diverse anatomic clinical presentation and the overall survival varied significantly according to sites of presentation and racial subgroups. The results of our study may aid the prognostication of patients for treatment decision making and in the understanding of the biological differences by anatomic sites of presentation. Table Anatomical distribution and median overall survival of isolated myeloid sarcoma Table. Anatomical distribution and median overall survival of isolated myeloid sarcoma Figure Overall survival by sex and race in isolated myeloid sarcoma Figure. Overall survival by sex and race in isolated myeloid sarcoma Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

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 Myeloid neoplasms (MN) occurring secondary to treatment of non-malignant disease, especially autoimmune diseases (AID), and the overlap between them, is an increasing clinically important observation. Confounding variables for myeloid transformation include the nature of autoimmune disease as an incessant, chronically activated inflammatory cascade that has been associated with an increased risk of myeloid malignancy, and disease modifying therapies, often with cytotoxic and immunosuppressive drugs. Thus, the addition of therapeutic agents for treatment of AID theoretically amplifies the opportunity for MN to develop in genetically susceptible individuals. To our knowledge, there is no large study evaluating a comprehensive primary AID population that developed MDS or AML with detailed assessment of therapeutic interventions for AID. The presented study queries the association of cytotoxic, anti-inflammatory, and immune-modulating agents to treat AID as risk factors for developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Methods In a 10-year period from 2004-2014, a total of 40,011 patients with an ICD-9 coded diagnosis of AID were seen at Mayo Clinic Arizona and Florida campuses; 311 patients from this population had a concomitant coded diagnosis of MDS and/or AML. In an IRB approved, retrospective chart review, we confirmed 86 cases meeting strict inclusion criteria for AID and confirmed MDS or AML. We performed a case-control match from the same primary autoimmune population for age, gender, and autoimmune specific diagnosis at a 2:1 ratio querying for therapeutic interventions. Results Myeloid neoplasm specifics in our case cohort of 86 patients were 55 MDS, 21 de novo AML, and 10 AML with history of MDS. Average age was 72 years with a slight male predominance (57%). Rheumatoid arthritis (26.4%), psoriasis (20.7%), systemic lupus (13.8%), was the most common autoimmune profiles. Median onset of autoimmune disease to diagnosis of myeloid neoplasm was 6 years (range 1-54 years). Up to 26% controls documented no systemic agent for treatment of autoimmune disease and similarly 12.8% of the case cohort (p=0.142). Case and control populations treated with systemic therapies had similar exposures by category for immune-modulating agents (33.7% and 37.8% respectively) and cytotoxic therapies (47.7 and 44.8% respectively). A total of 57/86 cases (66.3%) received either a cytotoxic or immune-modulating agent. In comparison, 105/172 (61.1%) controls received either agent; p=0.495. Azathioprine was the only statistically significant agent exposure observed more frequently in the study cohort than controls with an OR of 7.05 (p= < 0.001). There was no increased incidence of MDS or AML in TNF-antagonist treated patients. No significant correlation for duration of agent exposure by drug category was observed. Discussion In a large primary AID population, azathioprine exposure was associated with a 7 fold risk of MDS or AML (p=< 0.001). Notable, but not statistically significant case cohort trends among cytotoxic agents was exposure to cyclophosphamide (OR 3.58) followed by mitoxantrone (OR 2.73). Methotrexate, mercaptopurine, and mycophenolate had favorable odd ratios, but these were not statistically significant. No association was found for TNF-inhibitory agents. Finally, there was no association of drug exposure time to the incidence in development of MDS or AML. Disclosures Dueck: Bayer: Honoraria. Mesa:Gilead: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Research Funding; Galena: Consultancy; Ariad: Consultancy; CTI: Research Funding; Promedior: Research Funding. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Foran:Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding.

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 Abstract 2525 Background: Patients with relapsed AML have a very poor outcome. The molecular signature at diagnosis has emerged as a significant marker for prognostic, and possibly therapeutic, values in newly-diagnosed AML. FLT3 mutations are found in about 25–30% of AML pts. In the absence of FDA-approved agents for FLT3, the prognostic value of FLT3 mutation on clinical outcome for relapsed AML (rAML) is not well documented. Aim: To study clinical implications of FLT3 status on rAML. Methods: All adult pts with AML diagnosed and treated at Mayo Clinic between 2003–2011were studied. Retrospective data collection included pts' demographics, laboratory tests, bone marrow biopsies, FLT3 mutation (internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutation), and survival information. IRB approval was obtained in accordance with Helsinki declaration. Chi-Square and T-test were used for comparatives between groups and Kaplan-Meier test was applied for survival estimates using JMP 9.0 software. Results: A total of 192 pts with newly-diagnosed with AML were identified. Sixty percent (115) were males, 88% (168) were Caucasians, 26% (49) had antecedent hematological disease (AHD), and 13% (25) had previous exposure to chemo- or radiotherapy. Forty-seven percent had a normal chromosomal analysis, and 18% (35) had FLT3 mutation (28 ITD, 7 TKD). In FLT3-mutated pts, median WBC was 70 x109/L (p=0.0016), hemoglobin 9.5 g /dL, and platelets 48 x109/L, compared to 8.8 x109/L, 9.1 g/dL, 50 x109/L in the rest of pts, respectively. Peripheral blood blasts were elevated in FLT3-mutated group compared to rest of pts (p 0.0059). A total of 128 pts achieved complete remission (CR), with 79 (62%) subsequently relapsed. Of the relapsed patients, 93% (74) were Caucasians, 54% (43) males, 22% (17) had AHD, and 8% (6) had prior chemo- or radiotherapy. Cytogenetics were diploid in 49% (39) and complex in 15% (12). Hematopoietic stem cell transplantation was performed in 30% (24) of pts. Eleven of 79 (14%) pts were FLT3-mutated at relapse (Group 1); with 1 pt having TKD-mutation. Forty-eight percent (38) of pts had unmutated-FLT3 (Group 2), and 38% (30) pts were FLT3-unknown (Group 3). In group 1, median WBC was 9.9 x109/L, hemoglobin 10.55 g /dL, platelets 55 x109/L, compared to 3.2 x109/L (p=0.0034), 10.55 g/dL, and 58 x109/L in group 2, respectively. Peripheral blasts were significantly elevated in group 1 compared to group 2 (38% vs 4%, p <0.0001). Surprisingly, 3/11 pts (27%) with FLT3 mutation at relapse were unmutated at diagnosis. CR was achieved in 2/11 (18%) pts in group 1 compared to 15/38 (39%) in group 2 (p=0.19). Median overall survival in rAML was significantly lower in group 1 compared to group 2 (90 days vs 229 days, p 0.0076). This survival difference was statistically more significant in pts with diploid cytogenetics at relapse compared to the rest (p 0.0009 vs 0.48, respectively). Within 1.5 years, all pts in group 1 died, compared to 21% survived in group 2. Conclusion: FLT3-mutated AML pts had a significantly higher peripheral WBC and blasts at both diagnosis and relapse. Importantly, FLT3 at relapse was found to be mutated in one quarter of pts who were wild-type FLT3 at diagnosis; raising the importance of assessing FLT3 gene on all relapses. FLT3 mutation significantly predicted worse median overall survival in rAML raising the need for novel agents, such as FLT3 inhibitors, in this population. Disclosures: No relevant conflicts of interest to declare.

Abstract Background L-asparaginase (LASP) depletion of asparagine reduces antithrombin (AT) and fibrinogen and is associated with thromboembolic (TE) and hemorrhagic events (HE). AT replacement in pediatric ALL patients demonstrated safety and potential benefit as thromboprophylaxis in a prospective, randomized trial.(Mitchell et al, 2003) Current consensus supports AT replacement when AT activity is below 60%.(Stock et al, 2011) The incidence of TE and HE in adults receiving AT repletion during LASP or pegylated asparaginase (PEGASP) requires further investigation. Methods This single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board. Consecutive adult patients with a confirmed diagnosis of ALL receiving LASP or PEGASP containing chemotherapy regimens between January 2000 and October 2012 were evaluated. Patients with documented thrombophilia and pre-existing TE or HE were excluded. Patients receiving AT concentrate (ATC) compared to those that did not and were evaluated up to 60 days after the last LASP or PEGASP dose for objectively confirmed TE and HE. Results Of the 74 patients screened, 54 (73%) met inclusion criteria. Forty-seven (87%) received ATC and were evaluable. The remaining 7 (13%) did not meet follow up duration and were excluded from further analysis. Twenty-three (49%) patients received LASP, 20 (42%) received PEGASP and 4 (9%) received both. Distribution per treatment protocols was; CALGB 9111 (n=16 (34%), Larson et al, 1998), E2993 (n=12 (25%), Goldstone et al, 2008), C10403 (n=8 (17%), NLM: NCT00558519), CCG 1941 (n=6 (13%), Gaynon et al, 2006) and Augmented HyperCVAD (n=5 (11%), Faderl et al, 2011). A total of 1465 AT activity levels were analyzed, resulting in 378 doses of ATC. Ten patients (21%) experienced a clinical event, with all events occurring during cycle 1 of chemotherapy (table 1). Median time from last LASP or PEGASP dose to TE was 13 days (range 3-56) with a median of 4 days (range 3-13) from last ATC dose to TE. Median AT activity level at time of TE was 56% (range 47-72). Thrombotic events included; line-related deep vein thrombosis (LRDVT, n=7), cerebral venous sinus thrombosis (CVST, n=1) and pulmonary embolism (PE, n=1). One patient with cerebral hemorrhage constituted the only HE. All LRDVT occurred in central venous catheters and management included; line removal (n=3), anticoagulation (n=1), line removal and anticoagulation (n=2) and no intervention (n=1). The single case of PE was managed with anticoagulation. Two patients had a recurrent LRDVT in different locations during subsequent chemotherapy in spite of ongoing ATC supplementation. Conclusions The incidence of TE in adult ALL patients receiving LASP or PEGASP during induction chemotherapy with AT thromboprophylaxis was 19%. LRDVT was the most common TE with a comparable incidence to adult ALL patients not receiving ATC (15%) (Grace et al 2011). There was a small incidence of non-LRDVT (4%) and HE (2%). As induction-phase chemotherapy and placement of central lines are independent risk factors for thrombosis, the cost-effectiveness of AT replacement for prevention of TE during adult ALL treatment requires prospective evaluation. Disclosures: No relevant conflicts of interest to declare.