bluuebunny/crossref_metadata_2025_split huggingface dataset:
FLT3-ITD Internal Tandem Duplication Confers Poor Prognosis In Patients With Acute Promyelocytic Leukemia Treated With The AIDA Protocols. Long-Term Follow-Up Analysis
Authors: Breccia Massimo , Loglisci Giuseppina , Loglisci Maria Giovanna , Ricci Roberto , Diverio Daniela , Latagliata Roberto , Foà Robin , Lo Coco Francesco 
Published: October 2019

Abstract
Although previous studies in APL have revealed that the FlT3-ITD mutation is associated with an elevated presenting WBC count, hypogranular variant (M3v) morphology and the short (bcr3) isoform of PML-RARA, the prognostic significance of FlT3 mutations in APL has not been firmly established. We report an update of these patients with a median follow-up of 9 years in which we observed that the presence at baseline of the FlT3-ITD mutation confers a very poor overall survival (OS). One hundred and forty-seven patients with newly diagnosed APL were observed and treated with the AIDA (73 patients) and AIDA2000 protocols (74 patients) at the Sapienza University of Rome during the period April 1993-October 2010. Diagnosis was initially established morphologically and subsequently confirmed in all cases by RT-PCR. The following clinical characteristics at diagnosis were analyzed according to the FlT3 status: age, sex, FAB classification, peripheral WBC and platelet count, hemoglobin, karyotype, PML/RAR isoform and relapse risk. For statistical analysis, the Wilcoxon-Mann-Whitney test was used to compare non-parametric series and the Fisher’s exact test to compare categories. OS was estimated using the Kaplan-Meier method, whereas relapse-free considered as events relapse and death in CR. Thirty-three patients were identified as FlT3+, 19 were males (57%) and 14 were females; 27% had a variant type according to the FAB classification and 36% were classified as high-risk. Twenty-one FlT3+ patients (63%) presented the bcr3 transcript compared to 37/114 (32%) FlT3- patients (p=0.002). Eight FlT3+ patients (24%) experienced a differentiation syndrome compared to 14 (12%) in the negative cohort (p=0.02). After a median follow-up of 9 years (range 5-19), we could document a significant worse long-term outcome for FlT3+ patients: OS was 96% in the FlT3- cohort compared to 39% in the FlT3+ cohort (p=0.0001), relapse-free survival (RFS) 90% in FlT3- patients vs 30% in the FlT3+ ones (p=0.017), CIR at 9 years was 4% (95% CI, 1,279-6,238) for the FLT3-negative cohort and 60% (95% CI,22.632-81.236) for the FLT3-positive subset (p=0.0001). While this study confirms that there is no difference in response to induction with the AIDA schedule in FlT3+ APL patients, the longest follow-up so fare reported has allowed to demonstrate the significantly worse long-term outcome for this subset of APL, in terms of OS, RFS and DFS. Further studies aimed at investigating whether other clonal mutations may play a role in this unfavorable subset of patients are needed.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Significance Of The Cytogenetic Evolution After The Hematopoietic Stem Cell Transplantation In Adult Acute Myeloid Leukemia
Authors: Yuasa Mitsuhiro , Uchida Naoyuki , Kaji Daisuke , Ota Hikari , Ishiwata Kazuya , Tsuji Masanori , Yamamoto Hisashi , Yamamoto Go , Asano-Mori Yuki , Makino Shigeyoshi , Yoneyama Akiko , Wake Atsushi , Izutsu Koji , Taniguchi Shuichi 
Published: October 2019

Abstract

Background
Cytogenetic abnormalities at diagnosis have significant impacts on disease outcome and clonal evolution at cytogenetic level is considered to be associated with relapse and refractoriness to chemotherapy. Relapse of AML was reported to be associated with cytogenetic clonal evolution in 40% of patients who have received chemotherapy. However, little is known about the association of cytogenetic clonal evolution and relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study was conducted to see the karyotypic changes of the AML relapsed after allo-HSCT and to see whether the presence of the cytogenetic evolution has a prognostic impact.

Patients and Methods
We retrospectively reviewed patients diagnosed as AML who underwent allo-HSCT for the first time at our institute from Jan. 2006 to Dec. 2012 consecutively and analyzed the cytogenetic evolution patterns in patient at relapse of AML after HSCT.

Results
Three hundred and thirty patients were included in this study. We identified fifty-seven (17%) relapsed in bone marrow after HSCT. We excluded two patients, because of that one patient was not performed bone marrow aspiration after relapse and the other received auto-PBSCT after allo-HSCT due to an engraftment failure. So, we analyzed the bone marrow karyotypic changes before and after transplantation of 55 patients. Thirty-eight (69%) were male, and median age at allo-HSCT was 56 years (range, 21-82). Eight (14%) are still alive. Thirty-four (61%) received umbilical cord blood transplantation (UCBT), ten (18%) did related HSCT, and eleven (20%) did unrelated HSCT. Eleven (20%) had normal karyotype, fourteen (25%) had one chromosomal abnormality, eleven (20%) had two abnormalities, and nineteen (35%) had more than three abnormalities before HSCT. Median observation time after HSCT was 16 months (1-75). Thirty (55%) showed gain or loss of chromosomal abnormalities from original one (group1), sixteen (29%) showed no karyotypic change between HSCT, and nine (16%) showed totally different karyotype. We defined the cytogenetic evolution group as group 1, and the others as group 2. Median day of relapse after HSCT was not different between group 1 and 2 (4 months (range 1-73), 6 months (range 1-26), P=0.29). Shorter survival time after relapse was observed in group 1 (5.9% vs. 16.8% at 2 year post-relapse, P= 0.04) (figure. 1).

Conclusion
Although durations from HSCT to relapse were comparable between group 1 and 2, survival time after relapse was significantly shorter in group 1 than in group 2, which indicates that cytogenetic clonal evolution may confer resistant characters against treatments, and needs novel therapeutic applications.

Disclosures:
No relevant conflicts of interest to declare.
Trends In Survival Outcome Of Elderly Patients With B-Lineage Acute Lymphoblastic Leukemia : Analysis Of SEER Database
Authors: Guru Murthy Guru Subramanian , Mehta Paulette , Venkitachalam Raji 
Published: October 2019

Abstract

Background
B-lineage Acute Lymphoblastic Leukemia (B-ALL) is the commonest form of ALL in elderly age. Prognosis in this group is generally considered poor due to higher incidence of t(9,22) and other mutations which increase with age and presence of higher comorbidities. It is unclear if the survival has improved over time in this high risk group with addition of newer agents like tyrosine kinase inhibitors and monoclonal antibodies along with chemotherapy.

Methods
Patients were selected from the 13 SEER registry sites (1992 onwards) in the Nov 2012 submission data. Patients included were 60 years and above, with microscopy confirmed B-ALL as the first primary malignancy diagnosed between 1992-2010. We excluded patients diagnosed only at autopsy/death certificate and without survival or demographic data. Patients were evaluated by period of diagnosis (1992-2001 and 2002-2010) and age at diagnosis (60-69 years, 70 years and above). Baseline characteristics were noted (age, sex, race including white, black, Native American, Asian/Pacific Islander). Descriptive statistics were used for comparison of baseline characteristics. One-year and 5-year overall survival (OS) were estimated by Kaplan-Meier method and compared by log rank test. Determinants of OS were analyzed with Cox-regression method. Statistical analyses were done with significance level of p < 0.05.

Results
Among 646 patients who were ≥60 years with B-ALL, 239 patients were in 1992-2001 group and 407 patients were in 2002-2010 group. Mean age was 71.7 years for patients in 1992-2001 group and 70.8 years for patients in 2002-2010 group (p=0.12). Both groups had similarly more males than females, more whites than blacks and other races (Table 1). Patients between 60-69 years had 1-year OS of 50.3 % in 2002-2010 group compared to 32.3 % in the 1992-2001 group (p=0.01). Five-year OS in 2002-2010 group was 20.2% compared to 8.1% in 1992-2001 (p<0.01)(Figure 1). Patients 70 years or older had no significant improvement in 1 year OS or 5 year OS over this period of time (5 year OS 5.5 % in 1992-2001 vs. 12.2 % in 2002-2010, p-NS) (Figure 2). In multivariate analysis, 2002-2010 group was associated with lower mortality (HR 0.77, P=0.004) and age >70 was associated with higher mortality (HR 1.56, P=0.001).

Conclusion
Patients between the ages of 60 and 69 years with B-lineage ALL treated after 2001 had improved 1-year OS and 5-year OS compared to those treated prior to 2001 reflecting efficacy of new therapies in this age group. However, patients above 70 years of age need more effective and safe therapeutic options to improve the survival outcome.

Disclosures:
No relevant conflicts of interest to declare.
Elimination Of Minimal Residual Disease (MRD) In AML Patients With a Novel Fc-Optimized FLT3 Antibody (4G8-SDIEM)
Authors: Salih Helmut R. , Hofmann Martin , Grosse-Hovest Ludger , Nuebling Tina , Bamberg Maximilian , Aulwurm Steffen , Buehring Hans-Joerg , Bethge Wolfgang A. , Kanz Lothar , Jung Gundram 
Published: October 2019

Abstract
Chemotherapeutic treatment induces a morphological complete remission (CR) in the majority of leukemia patients, but minimal residual disease (MRD) remains detectable by sensitive methods and constitutes the basis for relapse. Immunotherapeutic strategies are rarely sufficient to eliminate large tumor burden, but can successfully eliminate MRD. This is exemplified by the efficacy of donor lymphocyte infusion (DLI) and allogeneic stem cell transplantation (SCT) in leukemia. Here we report the first clinical experience with a novel Fc-optimized antibody directed to the receptor tyrosine kinase FLT3 expressed on the surface of leukemia cells. This antibody may potently eliminate MRD after conventional therapy and achieve this goal with less toxicity (i.e. GvHD) than DLI and SCT. After in vitro characterization of the antibody, which revealed its markedly increased ability to mediate antibody dependent cytotoxicity (ADCC), in particular of NK cells, against leukemic cells (Hofmann et al, Leukemia 2012), the antibody (4G8SDIEM) was produced in a university owned unit and applied on a compassionate need basis. Upon application in AML patients with active disease, potent NK cell activation and anti-leukemia activity were observed, but effects were rather short lived, most likely due to unfavorable NK:leukemia cell ratios in the bone marrow. Consecutively we applied 4G8SDIEM to AML patients in morphological CR after SCT which displayed increasing MRD levels (mutNPM1) indicative of imminent relapse and for which no other treatment options were available. In 3 of the 4 patients treated so far, a single application of 4G8SDIEM (in 2 cases followed by treatment with one dose of DLI) resulted in rapid elimination of MRD. The non-responsive patient displayed high titers of preexistent anti-Fab antibodies capable of binding 4G8SDIEM, which provides a potential explanation for the lacking response. One patient that had received subsequent DLI died of complications due to GvHD after reaching and maintaining a molecular CR. The other two patients (1 with, 1 without DLI) remained in molecular CR for at present 17 and 12 months after 4G8-SDIEM application without further specific treatment. No stem cell toxicity was observed. Our results imply that 4G8SDIEM is capable to reduce or eliminate MRD after conventional therapy. Based on these observations, a phase I/II trial enrolling AML patients in CR with detectable MRD is in preparation.

Disclosures:
Hofmann: Synimmune, GmbH, Tuebingen, Germany: Employment. Grosse-Hovest:Synimmune, GmbH, Tuebingen, Germany: Employment. Aulwurm:Synimmune, GmbH, Tuebingen, Germany: Employment. Jung:Synimmune GmbH, Tuebingen, Germany: Equity Ownership, Honoraria.
Parenteral CoQ10 Formulation (BPM31510) Significantly Improves Survival In Animal Model Of Leukemia Including The Resolution Of Paraplegia Due To Brain Metastasis
Authors: Narain Niven R , Mauro Lucia M , Akmaev Viatcheslav R , Benaim Ely , Sarangarajan Rangaprasad , Jimenez Joaquin J 
Published: October 2019

Abstract
Leukemia cells exhibit alterations in intermediary metabolism similar to other cancers, wherein ATP sourcing is shunted from mitochondrial oxphos towards glycolytic preponderance (Warburg Effect) to meet oncogenic proliferative demands. A consequence of this metabolic switch is the simultaneous short-circuit of the programmed death pathways, leading to a immortalization program in cancer cells including leukemia. Delivery of high levels of CoQ10 in a lipid nanodispersion mixture (BPM31510) has been demonstrated to preferentially shift metabolic networks from glycolysis towards mitochondrial-centric oxphos and recapitulation of apoptotic pathways in various cancers in vitro and in vivo models. Given the centrality of the Bcl-2 involvement in the etiology of leukemia, this study focused on investigation of the effectiveness of BPM31510 in animal models of erythroid and myeloid leukemia. Human acute erythro-leukemia (K562) and acute myeloid leukemia (KG1) models were developed in immune-compromised mice. The mice (total n=120 for each model respectively) were randomized into four (n=30/group) treatment groups: Untreated (control); BPM31510 (75 mg/kg, once/day); chemotherapy (Adriamycin [5mg/kg; once/wk]+AraC [25mg/kg; 5 days] and BPM31510+chemotherapy. All dosing were intravenous and followed a protocol of 3wk treatment followed by 1wk rest. In both leukemia models, combination of BPM31510 with chemotherapy was associated with significant increase in survival compared to other groups. BPM31510 alone improved survival compared to chemotherapy in myeloid leukemia, not in erythroleukemia model. In a separate study, a rat (Fisher 344) chloroleukemia (MIA C51) model of CNS leukemia was developed that demonstrated paraplegia and urinary retention as a result of brain metastasis. Administration of BPM31510 (50 mg/kg/day, IP) was associated with complete resolution of limb paralysis demonstrating the ability of BPM31510 in penetrating into the CNS. Moreover, BPM31510 (50 mg/kg/day, IP) administration was associated with significant increase in survival in animals with metastasis to the lungs and liver. The data provides encouraging evidence of the potential translational use of CoQ10 containing BPM31510 in the treatment of leukemia. A Phase 1 study in relapse acute leukemia is to be started shortly.

Disclosures:
Narain: Berg: Employment. Akmaev:Berg: Employment. Benaim:Berg: Employment. Sarangarajan:Berg: Employment. Jimenez:Berg: Membership on an entity’s Board of Directors or advisory committees.
Arginine Deprivation With Pegylated Arginine Deiminase Induces Death Of Acute Myeloid Leukaemia Cells In Vivo
Authors: Miraki-Moud Farideh , Ariza-McNaughton Linda , Ghazaly Essam A , Hodby Katharine A , Luong Phuong , Clear Andrew , Sohrabi Fareeda , Bomalaski John , Gribben John , Bonnet Dominique , Szlosarek Peter , Taussig David C 
Published: October 2019

Abstract

Introduction
Malignant cells require amino acids for a wide range of core functions. Amino acid deprivation using enzymatic degradation has been used to induce remission in acute lymphoblastic leukemia for decades. Amino acid deprivation may also benefit patients with acute myeloid leukemia (AML). We have previously shown that AML cells lack of argininosuccinate synthetase 1(ASS1), a key enzyme in the pathway that produces arginine (1). Here we tested the effect of an arginine depleting agent, pegylated arginine deiminase (ADI-PEG 20) on primary AML cells in a xenograft model of AML.

Methods
NOD/SCID/interleukin 2 gamma chain null (NSG) mice were transplanted with 6 primary AML samples. 12 weeks after transplantation of AML mice received either ADI-PEG 20, cytarabine, ADI-PEG 20 plus cytarabine or vehicle. ADI was administered weekly for 4 doses and cytarabine was given for 10 consecutive days (0.2mg per day, roughly equivalent to 40mg in humans). Five weeks after treatment started, mice were killed and the percentage of AML in the bone marrow was determined by flow cytometry. Blood was collected to quantify plasma arginine using liquid chromatography-mass spectrometry/mass spectrometry.

Results
Plasma arginine levels were depressed following ADI-PEG 20 administration confirming that arginine depletion was achieved in vivo. In all six experiments the combination of ADI-PEG 20 and cytarabine induced a significant reduction in levels of AML compared to control (Figure 1). Critically the combination of ADI-PEG 20 and cytarabine was significantly better than cytarabine alone in three of six experiments.

Conclusion
Our experiments show that arginine deprivation by ADI-PEG 20 can decrease the leukemic burden in mice transplanted with primary AML cells. The combination of ADI with cytarabine had a greater effect than cytarabine alone in half the experiments. These results provide the rationale to test ADI-PEG 20 with cytarabine in clinical trials.
1. Peter W. Szlosarek, Fiona Luong, Andrew Clear, David Taussig, Simon Joel, Maria Calaminici, Silvana Debernardi, Jude Fitzgibbon, John S. Bomalaski, Arthur E. Frankel, and Dominique Bonnet. Pegylated arginine deiminase (ADI-PEG 20) as a potential novel therapy for argininosuccinate synthetase-deficient acute myeloid leukemia. Cancer Research: April 15, 2011. AACR 102nd Annual Meeting 2011, (AACR Abstract # 467)
F. M-M and L. A-M contributed equally
D.B., P.W.S. and D.C.T contributed equally

Disclosures:
Bomalaski: Polaris Group: Employment, Equity Ownership. Szlosarek:Polaris Group: Research Funding.
GADD45a Is a Tumor Suppressor In BCR-ABL-Driven Leukemogenesis
Authors: Mukherjee Kaushiki , Sha Xiaojin , Bhatia Ravi , Skorski Tomasz , Hoffman Barbara , Liebermann Dan 
Published: October 2019

Abstract
The BCR-ABL fusion oncogene which encodes a fused deregulated tyrosine kinase causes chronic myelogenous leukemia (CML) in humans. Imatinib, a small molecule ABL kinase inhibitor has been highly effective in treating chronic phase (CP) CML patients. However, a substantial number of patients undergo relapse due to development of resistance to imatinib therapy that leads to blast crisis (BC-CML), which is invariably fatal within weeks to months. Additional genetic aberrations assist in progression and identification of key players that are responsible for transformation is of utmost importance from a therapeutic point of view. Growth arrest DNA damage 45a (Gadd45a) gene, a member in the gadd45 family of genes including Gadd45b & Gadd45g, was identified as a myeloid differentiation primary response gene. There is evidence consistent with it’s involvement in G2/M cell cycle arrest and apoptosis in response to multiple stressors, including genotoxic and oncogenic stress. To investigate the effect of Gadd45a in the development of CML, adaptive bone marrow transplantation experiments with either wild type or Gadd45a null myeloid progenitors expressing 210-kD BCR-ABL fusion oncoprotein revealed that loss of Gadd45a accelerated BCR-ABL driven CML resulting in the development of a more aggressive AML/BC like disease. Recent newly obtained data indicate that number of Gadd45a deficient Leukemic stem cells (LSC) harboring BCR-ABL increased as disease progressed confirming Gadd45a as a crucial tumor suppressor in CML. Recent data also indicate, that transformed Gadd45a deficient progenitors exhibit increased proliferation and decreased apoptosis, associated with enhanced PI3K-AKT-mTOR-4E-BP1 signaling and upregulated oncogenic p30C/EBPα. More importantly, newly obtained data indicate that Gadd45a transcript levels in peripheral blood of human blast crisis (BC-CML) samples was found to be reduced compared to accelerated phase (AP-CML), chronic phase (CP-CML) and normal controls, assessed by Quantitative real time PCR analysis. Collectivly these data strongly suggest that Gadd45a expression is a novel prognostic indicator of CML progression, implicating Gadd45a as a downregulated target of BCR-ABL associated with progression to more aggressive stages. To conclude, our findings provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven myeloid leukemogenesis, & that suppresion of Gadd45a is associated with CML progression. These data provide the impetus to further elucidate the role Gadd45a plays in suppressing the development of CML, and explore how its loss contributes to the progression of CML to more aggressive leukemic phenotypes.

Disclosures:
No relevant conflicts of interest to declare.
Protein-Coding and Non-Coding RNA Expression Profiles Of Mesenchymal Stem Cells In Patients With Myelodysplastic Syndromes
Authors: Zhao Youshan , Chang Chunkang , Li Xiao 
Published: October 2019

Abstract

Background
A few reports have suggested chromosomal and gene expression abnormalities in mesenchymal stem cells in patients with MDS. Recently years, there is growing evidence for a role of the non-coding RNA in the transcriptional control of gene expression. Characterization of protein-coding and non-coding RNA expression in mesenchymal stem cells of MDS patients could be strategic for understanding gene expression regulation and role of marrow microenvironment in the pathophysiology of MDS.

Methods
In this study, gene expression profiles of MSC in 10 patients with MDS were compared with 5 healthy individuals using human transcriptome array. This array allows comprehensive examination of gene expression and noncoding transcripts, as well as detection of coding SNPs and genome-wide identification of alternative splicing. Real-time RT-PCR was performed to confirm the expression levels of selected transcripts.

Results
In MSC of MDS patients, 2628 genes were significantly differentially expressed (p≤0.01) in comparison to healthy individuals, of which 945(36%) were protein-coding transcripts. Gene ontology and pathway analysis were performed on those protein-coding genes. The significant significant ontology themes for up-regulated gene in MDS include cell division, mitosis, DNA repair and regulation of transcription, and for down-regulated genes include cytokine-mediated signaling pathway, inflammatory response and positive regulation of mitosis. Pathway analysis identified the deregulated gene pathway were main associated with purine metabolism, cytokine-cytokine receptor interaction, toll-like receptor signaling pathway, and so on. In non-coding RNA, 79 were long noncoding RNA (LncRNA), which were reported in database. We used gene coexpression networks to cluster thousands of transcripts into phenotypically relevant coexpression modules. The coexpression patterns of lncRNAs and protein-coding RNAs in MDS and controls were different. In the MDS coexpression network, differentially expressed lncRNAs were mainly focused on gene function related to ribosome biogenesis, tRNA processing, and so on.

Conclusions
These results demonstrated the differential RNA expression profile between MDS and healthy individuals, suggesting that lncRNAs may play an important role in dysfunctional microenvironment in MDS.

Disclosures:
No relevant conflicts of interest to declare.