bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant BCL2 Co-Operates with CBFβ/PEBP2β-MYH11 to Promote Expansion of Leukemia Initiating Cells with a Predominantly Pro-Apoptotic Mechanism Via Recruitment of Ras-GTP In a Mouse Model of Progressive Acute Myeloid Leukemia.
Authors: Omidvar Nader , Pogam Carole Le , Beurlet Stephanie , Noguera Maria-Elena , Janin Ann , Kogan Scott C. , Weissman Irving L. , Pla Marika , Chomienne Christine , Padua Rose Ann 
Published: October 2019

Abstract
Abstract 1050
Mutations and translocation of the core binding factor complexes frequently co-operate with other lesions in Acute Myeloid Leukemia (AML). In order to study the molecular mechanisms and develop therapeutic platforms we have developed highly penetrant and tractable mouse models.
We crossed single transgenic mice that express the human (h)BCL2 or NRASD12 under the control of the myeloid promoter MRP8 with single transgenic mice that express the protein fusion CBFβ/PEBP2β-MYH11 (Inv16) under the same promoter. Whereas single transgenic mice have a normal lifespan, the double transgenic mice develop rapid and fatal hematologic disease. The NRASD12/Inv16 mice are already known to develop strong features of dysmyelopoiesis, developing severe thrombopenia and anemia associated with leucocytosis (Kogan SC, et al. PNAS USA 95:11863-11868). Here within marrow and spleen cells we find abnormal eosinophils with Charcot-Leydan crystals associated with an increase of myeloid blasts, features that are found in human AML4 with eosinophilia. The hBCL2/Inv16 mice develop anemia and leucopenia, with greater than 30% bone marrow blast cells associated with enlarged infiltrated liver and spleens. Consequently hBCL2/Inv16 animals demonstrated significantly reduced survival as compared to litter mate controls (median 65 days; p<0.001). Immunophenotyping of circulating myeloid cells revealed lack of differentiation; namely a raised Mac-1hi/Gr-1lo profile. We further demonstrate that there is an expansion of the primitive Lin-/Sca-1+/c-Kit+ compartment for both NRASD12/Inv16 and hBCL2/Inv16 models in comparison with the singles. The colony assays performed show an increase of all myeloid progenitors for the hBCL2/Inv16 mice whereas NRASD12/Inv16 assays revealed a strong increase of CFU-M. The diseases are transplantable into irradiated syngenic recipients, supporting the expansion of the leukemic initiating cell compartment.
To further elucidate signaling mechanisms we employed phospho-interrogation of spleen samples using the capillary isoelectric focusing methodology via NanoPro CB1000 (Cell Biosciences). Novel data reveals the balanced role of ERK/BCL2 phosphorylation states illustrating pro versus anti-apoptotic signaling. Surprisingly during disease progression, hBCL2/Inv16 recruits endogenous Ras, with a pro-apoptotic phenotype, providing tangible targets for the treatment of progressive AML.

Disclosures:
Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Identification of Recurring Tumor-Specific Somatic Mutations In Acute Myeloid Leukemia by Transcriptome Sequencing.
Authors: Greif Philipp A , Eck Sebastian H , Konstandin Nikola , Benet-Pages Anna , Dufour Annika , Vetter Anna , Popp Henning , Lorenz-Depiereux Bettina , Meitinger Thomas , Bohlander Stefan K , Strom Tim M 
Published: October 2019

Abstract
Abstract 1059

Aims:
Genetic lesions are crucial for cancer initiation. Recently, whole genome sequencing using next generation technology was used as a systematic approach to identify mutations in genomes of various types of tumors including melanoma, lung and breast cancer as well as cytognetically normal acute myeloid leukaemia (CN-AML). Despite its technical feasibility, whole genome sequencing is still time consuming and cost intensive. As an alternative approach, here we identify tumor-specific somatic mutations by sequencing transcriptionally active genes.

Methods:
Mutations were detected by comparing the transcriptome sequence of a CN-AML with the corresponding remission sample. In a single Genome Analyzer II run, we generated 4.35 Gbp of CN-AML and 5.54 of remission transcriptome sequence from the same patient. 63% of AML reads and 74% of remission reads mapped to exon regions. 10,152 genes had an average read depth of at least 7-fold and 6,989 genes an average read depth of 20 or greater in both samples. By comparing the 8,978 coding Single Nucleotide Variants (SNVs) discovered in the CN-AML sample with the remission sample, we identified 5 non-synonymous mutations specific to the tumor sample.

Results:
We found 5 tumor-specific somatic mutations. Among them is a nonsense mutation affecting the RUNX1 gene, which is a frequent mutational target in AML, and a missense mutation in the putative tumor suppressor gene TLE4, which encodes a RUNX1 interacting protein. A second missense mutation was identified in SHKBP1, which acts downstream of FLT3, a receptor tyrosine kinase mutated in about 30% of AML cases. The frequency of mutations in TLE4 and SHKBP1 in a cohort of 95 CN-AML patients was 2%.

Conclusion:
Our study demonstrates that whole transcriptome sequencing leads to the rapid detection of recurring point mutations in the coding regions of genes relevant to malignant transformation.

Disclosures:
No relevant conflicts of interest to declare.
Pediatric Experience with Low Dose Decitabine In Very High Risk Relapsed AML.
Authors: Phillips Christine L , Davies Stella M. , McMasters Richard , O'Brien Maureen , Absalon Michael J. , Moscow Jeffrey A. , Smolarek Teresa , Perentesis John P. 
Published: October 2019

Abstract
Abstract 1070

Background:
Children with relapsed AML and organ dysfunction or fungal infections rarely tolerate intensive retrieval therapies and have a very poor prognosis. Low-dose decitabine has encouraging clinical activity for adults with AML and a favorable toxicity profile. Experience regarding the use of decitabine in children and young adults with relapsed/refractory AML is lacking.

Methods:
We report the use of decitabine in a cohort of children and young adults with refractory/relapsed AML, who had either failed multiple standard retrieval regimens and/or were not candidates due to prior toxicities (e.g. severe cardiomyopathy, invasive fungal infections). Patients received decitabine at 20 mg/m2 IV for days 1–10 at four week intervals. Patients who responded to therapy but had prolonged myelosuppression received 5 days of therapy in subsequent course.

Results:
Eight patients were treated with median age of 4 years [range 2–26]. One patient was refractory to primary induction therapy. The remaining patients were in first through fifth relapse. Five patients had at least one previous bone marrow transplant. One patient had normal karyotype, 2 patients had complex karyotype (≥3 abnormalities). Three others had unfavorable cytogenetics including monosomy 7; 5 q deletion, t(11;17) with MLL rearrangement. None of the patients had low risk cytogenetics (t(8;21), inv 16). A total of 24 cycles to were administered to 8 patients (mean number of cycles = 3). Six of 8 total patients (75%) achieved at least partial response with 3 patients (38%) achieving CR, CRp or CRi. One responder who did not meet CRi criteria had no evidence of leukemic blasts on a hypocellular marrow following the second cycle of decitabine and remained in peripheral blood remission with 100% donor chimerism for two additional months. Of the 2 non-responding patients, 1 had stable disease, and 1 had progressive disease. In responders, best response was seen after a median of 3 cycles [range 1–4 cycles]. Of the 5 patients with prior transplantation, donor chimerism improved in the three responders by a mean of 57% with treatment. Therapy was well tolerated with neutropenia being the most common toxicity. There were only two documented bacterial infections in 24 cycles, with no fungal infections or treatment related deaths.

Conclusions:
Decitabine administered at low doses has activity in this cohort of heavily pre-treated children and young adults with relapsed/refractory AML. The toxicity profile is very favorable compared with conventional chemotherapy. These encouraging results warrant further investigation of decitabine in prospective pediatric studies of high risk relapsed/refractory AML.

Disclosures:
Off Label Use: Decitabine is not FDA approved for the treatment of pediatric acute myeloid leukemia.
High Body Mass Index (BMI) as a Predictor of Differentiation Syndrome (DS) In Acute Promyelocytic Leukemia (APL).
Authors: Jeddi Ramzi , Achour Béchir , Guerci-Bresler Agnès , Ghédira Héla , Dombret Hervé , Huguet Françoise , Chevallier Patrice , Vey Norbert , de Botton Stephane , Bordessoule Dominique , Muller Beatrice U. , Eclache Virginie , Gardin Claude , Meddeb Balkis , Adès Lionel , Fenaux Pierre 
Published: October 2019

Abstract
Abstract 1078

Background:
High BMI was recently identified as a new predictor of differentiation syndrome (DS) in a relatively small Tunisian series of 39 APL patients (pts) treated with ATRA and anthracycline based chemotherapy (Leuk Res 2010; 34: 545–547). We analyzed this parameter in a larger pt cohort included in European APL 93 and APL 2000 trials.

Methods:
Between 1993 and 2006, 1196 APL patients (pts) were included in APL93 and 2000 trials, of whom 1016 APL had BMI determination (524/576 in APL 93 and 492/620 in APL 2000). In both trials, induction treatment consisted of ATRA and DNR + AraC except in one arm of APL 2000 trial where standard risk pts (ie low and int risk using Sanz score) received no AraC. Chemotherapy (CT) was started on day 1 of ATRA treatment in high risk (Sanz score) pts and on day 3 of ATRA treatment in standard risk pts except in one arm of APL 93 where standard risk pts received CT after ATRA. In APL 2000 (but not APL 93) trial, high risk patients received prophylactic dexamethasone from day 1 of ATRA.

Results:
Median age was 45 years (range: 1–80). 260 (25.6%) pts were high risk, 420 (41.3%) int risk and 336 (33%) low risk. Median BMI was 25.8 kg/m2 (range: 10–38). CR was achieved in 92.9% pts. Overall incidence of DS (according to Frankel's criteria) was 23.3%. Prognostic factors associated with an increased risk of DS were baseline WBC > 3×109/l (p=0.03) (best cut-off for WBC count), inclusion in APL2000 trial (p<0.0001) and randomization arm without AraC (p=0.028). When focusing on the low risk group, univariate analysis and multivariate analysis showed BMI > 25.5 (p=0.031) and inclusion in APL 2000 (p=0.002) to be significantly associated with occurrence of DS whereas age, sex, baseline WBC and absence of AraC had no prognostic impact. In low risk pts, occurrence of DS was associated with a trend for shorter survival (p=0.051). BMI however lost its prognostic value for DS in intermediate and high risk pts.

Conclusion:
High BMI may be associated to a higher risk of DS, at least in low risk APL, suggesting that those patients may have to be monitored closely during induction treatment of APL.

Disclosures:
Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
Arsenic Containing Triple-Agent Therapy for Acute Promyelocytic Leukemia-Comparison of Tetra-Arsenic Tetra-Sulfide vs. Arsenic Trioxide in the Long-Term Follow-up at a Single Hospital.
Authors: Wu Shu-Lan , Lu Dao-Pei , Zhao Yan-Li , Liang Lan-Qing , He Jun-Bao , Zou Wei , Fei Xin-Hong , Jiang Bin , Shan Fu-Xiang , Yang Ping-Di , Zhao Jie , Tong Chun-Rong 
Published: October 2019

Abstract
Abstract 1081
Our previous study has demonstrated that oral tetra-arsenic tetra-sulfide (As4S4) alone is highly effective and safe in both induction and maintenance therapy in acute promyelocytic leukemia (APL) (Dao-Pei Lu et al., Blood 2002; 99: 3136). Triple-agent treatment with As4S4, all-trans retinoid acid (ATRA) and low-dose chemotherapy has achieved expeditiously consecutive complete remission (CR) without death during induction, and it has also improved leukemia-free survival (LFS) (Tong Wu et al., ASH abstract 591 2007). To learn the efficacy and safety of As4S4 and arsenic trioxide (ATO), a total of 88 consecutive cases of newly diagnosed APL patients who have been treated with triple-agent regimen with arsenic, either As4S4 (n=42) or ATO (n=46), ATRA and low-dose chemotherapy at Beijing Dao-Pei Hospital were analyzed retrospectively. Major clinical characteristics in two groups were similar. Purified natural oral As4S4 (Dao-Pei Lu's Lab) or commercially available intravenous ATO were used. The regimens for induction, consolidation and maintenance therapy have been reported previously. All 88 patients attained hematological CR (HCR) after induction therapy without early death. A total of 84 cases were monitored for PML/RARA fusion transcript by RQ-PCR. Molecular CR (MCR) reached in all evaluable cases (100%) in As4S4 group and 93.5% of cases in ATO group. In As4S4 group, 3-year and 5-year LFS rates were all 100% with a median follow-up of 57 months (range, 12–103 months). In ATO group, however, 5 cases relapsed and 2 patients died with a median follow-up of 36 months (range, 12–96 months). The 3-year and 5-year LFS rates were both 86.6%. The difference of LFS between As4S4 and ATO groups were remarkable (p=0.028). Three-year and 5-year overall survival (OS) rates were all 100% in As4S4 group, 96.7% and 88.6% in ATO group respectively. Statistically there was no significant difference (p=0.1015). The side effects in As4S4 group were mild and all patients could continue the therapy. However, a total of 15 side events in ATO group including hepatic, cardiac or lung complications led to discontinuation of therapy. Our encouraging clinical results indicate that arsenic, either As4S4 or ATO in combination with ATRA and low-dose chemotherapy is highly effective in the induction of both HCR and MCR in newly diagnosed APL patients. As4S4 containing triple-agent protocol has better results in the prevention of relapse and improvement of LFS, and has less toxicity. Our clinical study has shown for the first time that all consecutive newly diagnosed cases of APL have achieved long-term LFS with As4S4 containing triple-agent regimen, which are significantly better than that of ATO containing one.

Disclosures:
No relevant conflicts of interest to declare.
Incidence of Secondary Neoplasms In Patients with Acute Promyelocytic Leukemia Treated with All-Trans-Retinoic Acid (ATRA) with Chemotherapy or with Arsenic Trioxide (ATO).
Authors: Eghtedar Alireza , Faderl Stefan , Kantarjian Hagop , O'Brien Susan , Garcia-Manero Guillermo , Ferrajoli Alessandra , Kadia Tapan , Pierce Sherry A. , Shan Jenny , Cortes Jorge E. , Ravandi Farhad 
Published: October 2019

Abstract
Abstract 1085

Background:
Progress in the treatment of patients (pts) with acute promyelocytic leukemia (APL) with the use of modern all-trans retinoic acid (ATRA)-containing regimens has resulted in the majority of pts achieving long-term disease-free survival. There is little data on the incidence and patterns of secondary neoplasms in pts treated with these regimens.

Objective:
To compare the incidence of secondary neoplasms in pts with APL treated with two different ATRA-containing regimens.

Methods:
We retrospectively examined the charts of 160 pts with APL treated with ATRA plus chemotherapy (n=54) or ATRA plus arsenic trioxide (ATO)(n=106) as their initial induction regimen at the University of Texas – M. D. Anderson Cancer Center from 1991 to 2009. Twenty seven (17%) pts had a remote history of a prior unrelated cancer. Pt characteristics and the incidence of secondary cancers per unit time of follow-up were compared.

Results:
The median age at diagnosis of the entire population was 44 years (range, 13 – 81) and the median age for the chemotherapy plus ATRA group was 38 years (range, 13–67) vs. 46 years (range, 14 – 81) for the pts treated with ATO plus ATRA (p= 0.001). Thirty (55%) and 54 (50.9%) in each cohort were women (p=0.52) and 2 (3.7%) and 26 (24.5%) were older than 60 years of age, respectively (p= 0.001). Twenty (37%) and 30 (28.3%) had high risk disease (WBC > 10 × 109/l)(p= 0.3), and 34 (62.9%) and 76 (71.6%) had low risk disease (WBC ≤ 10 × 109/l), respectively. Fifty one (94.4%) and 105 (99%) pts treated using the two regimens achieved a CR. The median follow-up time for the two cohorts was 136 and 29 months [ranges, (5 to 193) and (1 to 93), respectively]. Nine and 2 pts in the two groups developed secondary cancers including 2 breast cancers, 3 MDS/AML, 1 vulvar cancer, 1 prostate cancer, 1 colon cancer and 1 soft tissue sarcoma in the chemotherapy group vs. 1 melanoma and 1 pancreatic cancer in ATO group. The cumulative incidence of secondary cancers in the two cohorts is shown in figure 1.

Conclusion:
Treatment of pts with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time exposure.

Disclosures:
Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Ravandi:Cephalon: Honoraria, Research Funding, Speakers Bureau.
Thromboprophylaxis In Multiple Myeloma Patients Undergoing Immunomodulatory Therapy with Thalidomide and Lenalidomide: A Systematic Review and Meta-Analysis.
Authors: Carrier Marc , Gal Gregoire Le , Tay Jason , Wu Cynthia M. , Lee Agnes Y. 
Published: October 2019

Abstract
Abstract 1090

Background:
The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) is high in patients treated with thalidomide (T)- and lenalidomide (L)-based regimens containing dexamethasone (D) and/or cytotoxic chemotherapy (C). Consensus guidelines recommend routine thromboprophylaxis but reliable data from randomized controlled trials are lacking. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population.

Purpose:
To determine the absolute rates of VTE with and without different thromboprophylactic agents (ASA, warfarin, low-molecular-weight-heparin [LMWH]) in patients with newly diagnosed or previously treated MM receiving T- or L-based regimens.

Data Source:
A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to Jan 2010.

Results:
A total of 66 studies were included in the analyses. Of these, 61 (4264 patients) and 5 (1119 patients) assessed T- and L-based regimens, respectively.
Thalidomide-based regimens
The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with T-based regimens:
The rates of VTE (per 100 patient-months) in patients with previously treated MM managed with T-based regimens:
Lenalidomide-based regimens
The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with L-based regimens:
The rate VTE (per 100 patient-months) in patients with previously treated MM managed with L-based regimens:
None of the studies reported major bleeding events.

Limitations:
The definition for VTE varied across studies. Most studies did not outline the diagnostic criteria for VTE. Data are not available (NA) for all prophylaxis regimens.

Conclusion:
Patients with newly diagnosed or previously treated MM receiving T- or L-based regimens are at high risk of VTE. It is uncertain whether thromboprophylaxis provides a clear benefit, especially in those receiving L-based therapy or have previously treated disease. Randomized controlled trials are needed to address this important clinical need.

Disclosures:
Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.
Thrombin Generation Is a Sensitive Measure of Low Molecular Weight Heparin Anticoagulant Activity.
Authors: Gatt Alexander , Riddell Anne , Lanning Lesley , Aghighi Saman , Kanagasapathy Pamala , Chowdary Pratima 
Published: October 2019

Abstract
Abstract 1099
Current guidelines recommend monitoring of low molecular weight heparins (LMWHs) using the anti-Xa assay in high risk patients like those with renal impairment, pregnancy or overweight and in children. However, it is well accepted that this test does not accurately predict the anticoagulant effect of these drugs1. This is understandable since the various LMWHs available affect the coagulation cascade in different ways relative to their different molecular structure. Notoriously, the larger LMWHs like Tinzaparin have a higher anti-IIa to anti-Xa ratio that is not detected by the anti-Xa assay.
We hypothesized that thrombin generation (TG) is a better, more sensitive way how to monitor LMWH anticoagulant activity since it is a measure of the interplay of all coagulation proteins.
Blood samples from patients with acute thrombosis, pregnancy and other conditions and having LMWH monitoring were analysed using a chromogenic anti-Xa assay and a TG assay as per Hemker et al2 together with a chromogenic anti-IIa and FVIII clotting assay (FVIII:C). A tissue factor trigger of 10pM Innovin was used for the TG experiments. Patient samples were divided into 2 groups: those on Tinzaparin (n=45) or Enoxaparin (n=39).
There was no difference between the FVIII:C levels of the Tinzaparin and Enoxaparin groups (mean 250 vs 327IU/ml P>0.05). A higher lower mean anti-Xa and a higher mean anti-IIa level was achieved with Tinzaparin (0.48 vs 0.63 U/ml P= >0.05 for anti-Xa and 0.3 vs 0.15U/ml P=0.005 for anti-IIa respectively). The endogenous thrombin potential (ETP) was significantly lower with Tinzaparin than Enoxaparin despite a higher anti-Xa (705 vs 1216nM.min P=0.006). Linear regression analysing TG with anti-Xa of the two LMWHs shows that 1.0U/ml antiXa activity for Enoxaparin is as potent as 0.7U/ml Tinzaparin in suppressing TG to similar levels. Significant inter-individual variation in TG suppression was noted with both LMWHs.
This study demonstrates that anti-Xa results achieved for different LMWHs do not have the same anticoagulant significance. Using TG, we achieved similar therapeutic anti-Xa levels as achieved from the individual LMWH clinical trials3. It is clear that TG is a better test to predict LMWH anticoagulant activity. This needs to be proven in clinical studies.
1. Baglin T et al British Journal of Haematol. 2006; 133(1): 19–34.
2. Hemker HC et al Pathophysiol Haemost Thromb, 33, 4-15.
Boneu B and de Moorloose P. Semin Thromb Hemost 2001; 27(5): 519–522.

Disclosures:
No relevant conflicts of interest to declare.