bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence and Characteristics of Survivors from Adult Acute Myeloid Leukemia (AML) in Sweden 2014
Authors: Juliusson Gunnar , Lazarevic Vladimir , Antunovic Petar , Derolf Asa Rangert , Garelius Hege , Lehmann Sören , Myhr-Eriksson Kristina , Möllgård Lars , Uggla Bertil , Wahlin Anders , Wennström Lovisa , Höglund Martin 
Published: November 2019

Abstract
The prevalence of survivors of adult AML has previously been calculated, but the prevalent population has not been characterized. We analysed all 6289 patients diagnosed with adult AML from 1997-2013 as reported in the Swedish AML registry, with a complete survival follow-up. We found 1148 patients, 563 males and 585 females, who were alive on January 1, 2014, constituting 18% of the total, and of them 204 (18%) were diagnosed during 2013. Patients who had their initial treatment at pediatric departments, and people diagnosed with AML before 1997 are not included. The mean age of survivors was 53.4 years at diagnosis and 59.3 years in 2014, and 303 (26%) were 70 years or older in 2014. The overall prevalence of patients diagnosed at age 20 or more was 15.2 per 100,000 (males 15.0 and females 15.4 per 100,000). There were 124 with prior acute promyelocytic leukemia (APL) (11%), 54 with inv(16) (5%), 44 with t(8;21) (4%), and 82 with NPM1 mut/FLT3 wt (7%), 75 with FLT3 -ITD (7%), and 82 with complex karyotype (7%). Karyotype results were not available in 10%, and molecular data only since 2007. Four hundred two (35%) had undergone allogeneic stem cell transplantation, out of which 32 (8%) had had complex karyotype, 43 (11%) FLT3-ITD, 136 (34%) normal karyortype, and 41 (10%) good risk but were transplanted after relapse. Among the 426 non-transplanted prevalent patients who had survived at least 3 years, 94 (22%) had prior APL, 25 (6%) t(8;21), 24 (6%) inv(16), 126 (30%) normal karyotype, and 11 (3%) complex karyotype, including eight monosomal karyotypes and two with del(7) and one del(5q). Among non-complex karyotypes there were four MLL abnormalities, two del(5q) and two monosomy 7.
Although long-term survivors more often have pretreatment good-risk features, this patient group is still heterogeneous, and also contains older people and those with intermediate/high risk cyogenetics.
Figure 1. Prevalence in January 1, 2014 of Swedish people with a previous diagnosis of AML by sex and current age per 100,000 inhabitants in 2014, and mean incidence 1997-2014 per 100,000 inhabitants in Sweden 2005. Figure 1. Prevalence in January 1, 2014 of Swedish people with a previous diagnosis of AML by sex and current age per 100,000 inhabitants in 2014, and mean incidence 1997-2014 per 100,000 inhabitants in Sweden 2005.

Disclosures
No relevant conflicts of interest to declare.
Combination of Cladribine, Cytarabine and Topotecan (CLAT) for Relapsed or Refractory Acute Myeloid Leukemia
Authors: Chen Xiaomei , Weng Jianyu , Wang Yulian , Deng Chengxin , Luo Chengwei , Liao Pengjun , Li Minming , Huang Xin , Lai Peilong , Huang Lisi , Cao Zhi , Wan Changchun , Zhong Liye , Wu Suijing , Lu Zesheng , Zou Xiaoli , Du Xin 
Published: November 2019

Abstract
Xiaomei Chen and Jianyu Weng contributed equally to this study.
The outcomes ofrelapsed or refractory acute myeloid leukemia (RR-AML) are poor and effective salvage regimens are urgently needed. We present a study of 14 patients with RR-AML (median age 42years, range 18-65years; male n=12, female n= 2) treated with CLAT regimen, which consisted of cladribine 5mg/m² per day i.v. 2-3 hour on days 1-5, cytarabine 1.0g/m² per day i.v. 4 hours after cladribine on days 1-5, topotecan 1.25mg/m² per day i.v. 4 hours after cytarabine on days1-5 and G-CSF 300ug per day subcutaneous injection on days until neutrophile granulocyte recovery. Total of fourteen patients were included into the study from June 2013 to June 2015, Two (14.3%) patients were relapsed and twelve (85.7%) patients were refractory, 4 of 14 patients were relapsed or refractory after allogeneic-HSCT. Two patients died of invasive fungal infection before the assessment. Seven patients (58.3%) achieved complete remission (CR), and one patient (8.3%) achieved partial remission (PR), the rest patients (33.3%) did not respond (NR). The overall response rate was 66.7%. Following CLAT treatment, four patients with CR underwent allogeneic hematopoietic stem cell transplantation (HSCT) or microtransplantation. The median relapse-free survival (RFS) for RR-AML patients receiving CLAT regimen was 8.6 (range 2-16) months. Thirteen patients developed grade 4 granulocytopenia and thrombocytopenia, the median duration was 13(range 2 to 21) days and12 (range 2 to 21) days, respectively. The most common non-hematological side effects included nausea, vomiting, diarrhoea, and were grade 1/2. The CLAT regimen seems promising for the treatment of patients, and it was well tolerated. This regimen offers an alternative treatment for those patients with RR-AML who have received severe intensive treatment, especially with anthracycline-containing chemotherapy.
The project was sponsored by grants from National Natural Science Foundation of China (No. 30972790; No.81270648; No.81370665; No.81300446) Provincial Natural Science Foundation of Guangdong (No. S2012010009560) Provincial Science and Technology Planning Project of Guangdong (No.2013B021800186; No.2013B021800201), and Science and Technology Planning Project of Guangzhou (No. 201400000003-4, 201400000003-1).

Disclosures
No relevant conflicts of interest to declare.
Intensive Treatment Versus Azacitidine for Acute Myeloid Leukemia in Elderly: Retrospective Evaluation
Authors: Bolaman Zahit 
Published: November 2019

Backround: Most of patients with acute myeloid leukaemia (AML) are elderly and older age is an negative prognostic factor for AML. There is no consensus about treatment of elderly patients with AML. In this study, we evaluated intensive treatment with cytosine arabinoside and idarubicine versus azacitidine treatment. Primary objectives were evaluation of disease free (DFS) and overall survival (OS), the rate of complete remission and the remission duration.
Methods: 45 patients with AML were evaluated retrospectively. We examined peripheral blood smear, bone marrow aspirate and trephine, immunophenotyping and cytogenetic analysis, biochemical evaluation of renal and liver function and coagulation profile in pre-treatment period. Intensive treatment consisted of cytosine arabinoside 200 mg/m2/day for 7 days and idarubicin 12 mg/m2/ for 3 days. Bone marrow examination was done between 14-28 days for intensive treatment and 2-6 cyclus for azacitidine treatment. Consolidation treatment (1-3) was done after intensive treatment if the patients were remission. All patients were ≤ECOG 2. Growth factors were not routinely administered before, during or after chemotherapy. Statistical analyses, differences in baseline characteristics between groups were analyzed using the Student's t-test for continuous variables and differences in OS between groups were then analyzed using the likelihood ratio or log-rank tests.
Table 1. The main properties of patients with elderly AML Treatment arm Mean age Sex M/F Leucocyte mean Hb gr/dl FAB (n) MDS history(n) LDH Complete remission Total 73±9 26/19 34.029 ±6870 8.53±1,2 M0:15, M1:6, M2:15,M4:4,M5:2 Yes:21 No:24 276±151 15 Intensive 72±7 18/10 44.176±12390 6.91±2 M0:6, M1:4, M2:12, M4:3, M5:1 yes: 14 299±101 13 Azacitidine 74±8 8/9 31.289±4013 8,95±1.6 M0:9, M1:2, M2:3, M4:1, M5:1 yes:7 256±72 2
Results: Total patient number were 45 and they were ≥ 65 years (yrs). Male/female ratio was 29/16. Two patients rejected leukemia treatment. One patient were not evaluated for treatment response. Intensive arm consisted of 26 patients and azacitidine arm 16 patients. Disease free survival and overall survival for intensive arm and azacitidine arm were 12,1±9,4, 16,7±22,4, respectively. The most importance factors were leucocyte counts, hb level.
Picture 1-2: Disease free survival and overall survival for intensive arm and azacitidine arm
Conclusions: These results showed that intensive treatment is more effective than azacitidine in elderly AML patients with ECOC≤2. There is need for large studies which include higher number of patients with AML in order to evaluate efficiency of intensive treatment.
Figure 1. Figure 1. Figure 2. Figure 2.

Disclosures
No relevant conflicts of interest to declare.
FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia: An Evaluation of Efficacy of Target Inhibition and Relationship to Disease Progression
Authors: Cloe Adam , Larson Richard A. , Cheng Jason X. 
Published: November 2019

Abstract
Introduction
FLT3 is a receptor tyrosine kinase that plays a role in hematopoietic stem/progenitor cell proliferation and survival and is frequently found to be mutated in patients with acute myeloid leukemia (AML). Mutations that lead to constitutive activation of FLT3 (such as internal tandem duplications of the juxtamembrane domain or point mutations involving the kinase domain) are associated with a poor prognosis. This poor prognosis is in part due to an increased relapse rate after allogeneic hematopoietic cell transplant (HCT). Several compounds that inhibit the activity of FLT3 in vitro, including ASP2215, midostaurin and quizartinib, are now being studied in clinical trials for the treatment of AML. Inhibition of the formation of phospho-FLT3 has been correlated with clinical anti-leukemia effects and remissions.
Methods
In this pilot study we use immunohistochemistry to measure the levels of activated FLT3 in bone marrow biopsies of patients prior to and during treatment inclinical trials at our institution to determine the efficacy of these FLT3 inhibitors and correlate it with patient outcomes.
Results
The different FLT3 compounds tested had a heterogenous effect on activated FLT3 levels. In some patients, ASP2215 caused a decrease in levels of activated FLT3 (indicated by brown nuclear staining), which corresponded to a decrease in leukemic blasts (Fig 1). Other patients, however, showed similar amounts of activated FLT3 both before and after treatment, which corresponded with no significant change in leukemic blasts. (Fig 2).
Other FLT3 inhibitors also showed differences in their effects. Midostaurin reduced activated FLT3 levels, which correlated with a positive clinical response. In contrast, one patient receiving quizartinibshowed little to no decrease in activated FLT3 levels, despite remaining in clinical remission. This suggests that this FLT3 inhibitor may have alternative targets, such as the tyrosine kinases AXL or LTK.
Conclusions
The heterogeneity in the responses to ASP2215, midostaurin, and quizartinib suggests that there may be other targets for these compounds that are not currently accounted for in the clinical studies. Immunohistochemicalmeasurements of activated FLT3 in bone marrow sections before and after treatment with FLT3 inhibitors was not predictive for clinical response.
Figure 1. Activated FLT3 levels in patient responsive to ASP2215; pre-treatment (A) and post-treatment (B) Figure 1. Activated FLT3 levels in patient responsive to ASP2215; pre-treatment (A) and post-treatment (B) Figure 2. Activated FLT3 levels in patient not responsive to ASP2215; pre-treatment (A) and post-treatment (B) Figure 2. Activated FLT3 levels in patient not responsive to ASP2215; pre-treatment (A) and post-treatment (B)

Disclosures
Larson: Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy.
Distinct Clinical and Cytogenetic Characteristics and Poor Prognosis in Children with Acute Erythroid Leukemia: A Report from the JPLSG AML-05 Study
Authors: Tomizawa Daisuke , Tawa Akio , Kiyokawa Nobutaka , Kinoshita Akitoshi , Miyachi Hayato , Yamashita Yuka , Horibe Keizo , Iwamoto Shotaro , Deguchi Takao , Shiba Norio , Moritake Hiroshi , Shimada Akira , Hasegawa Daisuke , Taga Takashi , Ishii Eiichi , Adachi Souichi 
Published: November 2019

Abstract
BACKGROUND: Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) that represents less than 5% of AML in children. However, its clinical picture is not fully understood.
PATIENTS & METHODS: We conducted a retrospective analysis on AEL using data from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study (registered at http://www.umin.ac.jp/ctr/index.htm as UMIN000000511) in which patients were enrolled between 2006 and 2010. Morphological, immunophenotypic, cytogenetic, and molecular diagnoses were confirmed by the integrated prospective central diagnostic system.
RESULTS: Among the 443 children (age 0 to 18 years old at diagnosis) with de novo AML (acute promyelocytic leukemia and Down syndrome patients are excluded), ten AEL patients (2.2%) were identified. All the cases were classified as M6 in French-American-British classification (eight as M6a, one as M6b, and one as M6). Notably, 8 were classified as AML with myelodysplasia-related changes (5 with morphological dysplasia and 3 with myelodysplasia-related cytogenetic abnormalities) and 2 as AEL in World Health Organization classification (ver.4). There were 6 males and 4 females. Median age and leukocyte count at diagnosis was 3.5 years old (range, 1-15 years old) and 4.7 x 109/L (1.1-16.1 x 109/L), respectively. Cytogenetically, 3 had complex karyotype, 2 had monosomy 7, and 5 had normal karyotype. Molecular analysis showed one case with NRAS mutation, one with both mutated KIT and WT1, and one with MLL-PTD. No case was FLT3 -ITD positive. Eight cases achieved complete remission after initial induction but 3-year event-free survival and overall survival rates were 30.0% (SE 14.4%) and 41.1% (SE 17.5%), respectively.
CONCLUSIONS: AEL has distinct features such as high frequency of myelodysplasia- related features and poor risk cytogenetics. Because the outcome seems poor, further genetic analysis is required for development of effective novel therapy.

Disclosures
No relevant conflicts of interest to declare.
The Expression and Mechanism of Tim3 and PD-1 in Patients with Acute Myeloid Leukemia
Authors: Li Caixia , Yu Xiao , Gu Caihong , Ma Chao , Liu Hong , Tong Wang , Zou Qiu , Ye Lu , Chen Xiaochen , Depei Wu 
Published: November 2019

Abstract
Objective: To investigatethe expression and the role of Tim3 and PD-1 on T cells of peripheral blood in patients with acute myeloid leukemia(AML). Consistently discuss the clinical significance of Tim3 and PD-1 co-expression on these cells and the mechanism of Tim3-mediated immune escape.
Methods: Collectedclinical data of 36 patients who had been diagnosed with AML by bone marrow MICM classification, and then gathered their heparin anticoagulation peripheral blood before any treatment. The heparin anticoagulation peripheral blood from 20 healthy volunteers was gathered as normal control. We used the methods of immune fluorescence labeling and flow cytometry to detect expression of Tim3 on T cells. Then detected co-expression of Tim3 and PD-1 on T cells, consistently with IFN-γ secreting level on T cells.
Results: 1.The proportions of CD4+ T cells and CD8+ T cells on lymphocytes in AML patients were (15.28±10.99)% and (9.19±7.54)% respectively, which were significantly lower than the proportion of normal controls [(31.12±2.22)% and (21.59±4.22)% respectively] (P<0.05). 2.The levels of Tim3 expression on CD4+ T cells and CD8+ T cells in AML patients were (4.77±3.560)% and (5.90±4.91)% respectively, which were significantly higher than the levels of normal controls [(0.73±0.62)% and (0.96±0.54)% respectively] (P<0.05). 3.Tim3 and PD-1 were co-expression on CD4+ T cells and CD8+ T cells in AML patients. 4.The IFN-γ secreting level in Tim3+ CD8+ T cells was significantly decreased than Tim3- CD8+ T cells (P<0.05).
Conclusion: 1.The high expression of Tim3 on peripheral blood T cells in AML patients mediate T cell exhaustion/dysfunction, which can be an important mechanism of immune escape in leukemia. 2.PD-1 and Tim3 co-expression On CD4+ T cells and CD8+ T cells in AML patients which were dificient in there ability to produce IFN-γ. Further investigations are needed to explore the correlation of co-expression PD1 and Tim3 with process of AML, thus probably making Tim3 become another new immunotherapy target.

Disclosures
No relevant conflicts of interest to declare.
IL-6 Released from BMSCs Suppresses Cytotoxic Effect of Ara-C and IL-6 Mediated Signaling Enhances Re-Growing of HEL Cells Following Ara-C Treatment
Authors: Park Hyejoo , Kim Daeyoon , Lee Chansu , Bae Eunkyung , Ahn Kwang-Sung , Koh Youngil , Lee Hyun Jung , Kim Hyo Jung , Lee Junglim , Yoon Hwi-Joong , Yoon Sung-Soo 
Published: November 2019

Abstract
Various factors released from BMSCs regulate the biologic behaviors of AML cells involving in responsiveness of chemotherapeutic treatment. Cytotoxic effect of Ara-C decreased when AML cells co-cultured with BMSCs. IL-6 expression was prominently increased when HEL cells were co-cultured with BMSCs. Even though IL-6 did not affect the growth of HEL cells, Ara-c mediated apoptosis was suppressed by BMSCs. Also, IL-6 induced the phosphorylation of AKT and its downstream gene (mTOR). Ara-C mediated H2AX mRNA was suppressed when Ara-C was treated with co-cultured HEL cells with BMSCs. Also, its expression was down-regulated in HEL cells co-treated with Ara-C plus 25 nM IL-6. Prevention of IL-6 mediated signaling by gp130 shDNA slightly suppressed Ara-C induced H2AX expression when gp130 shDNA transfected HEL cells were co-cultured with BMSCs under 10-6 M Ara-C treatment. In vivo model, we found that IL-6 expression levels in serum of mice detecting AML cells following Ara-C treatment were higher than in serum of mice not detecting residual AML cells. Even though somatic mutation of gp130 gene was not detected in the genome analysis of AML, the overall survival was statistically different depending on the IL-6 levels in serum of bone marrow. Our findings suggest that IL-6 releasing from BMSCs help AML cells to survive against Ara-C treatment resulting in developing relapase from enhancing the growth of minimal residual cells.
Figure 1. IL-6 suppresses Ara-C mediated apoptosis of HEL in vitro assay. Figure 1. IL-6 suppresses Ara-C mediated apoptosis of HEL in vitro assay. Figure 2. IL-6 suppresses Ara-C mediated H2AX expression in HEL cells. Figure 2. IL-6 suppresses Ara-C mediated H2AX expression in HEL cells. Figure 3. Survival curve depending on IL-6 level of AML patients bone marrow serum. Figure 3. Survival curve depending on IL-6 level of AML patients bone marrow serum.

Disclosures
No relevant conflicts of interest to declare.
Analysis of flt3 in Adult AML
Authors: Adnan Shady , Kandeel Eman Z , Ghareeb Mohammed , Eldessouki Ihab A. 
Published: November 2019

Abstract
FLT3 gene encodes a tyrosine kinase receptor, which is involved in proliferation and differentiation of hematopoietic stem cells. FLT3 mutations are frequently encountered in all AML subgroups specially in AML with t(15;17)- Acute Promyelocytic Leukemia (APL)-, and infers poor prognostic effect. FLT3-ITD mutations represent about 80% of FLT3 mutations. In this study, we aimed to assess frequency and correlation of FLT3-ITD mutation with different AML cytogenetic subgroups, also with MPAL cases and to study the prognostic role of this mutation with focusing on APL.
Between 2011 and 2014 in NCI, Cairo University, 212 newly diagnosed acute leukemia patients [198 AML (10 M0, 47 M1, 56 M2, 30 M3, 49 M4, 4 M5, 1 M6 and 1 M7) and 14 MPAL] were included in this study. Thorough Morphological, Immunophenotypic and cytogenetic analysis were done at initial presentation and fixed follow up time points (Day 14, 28, 36) with subsequent monitoring and follow up of patients. FLT3-ITD mutation was detected using RT-PCR.
FLT3-ITD mutation was detected in 44/198 AML patients (22.2%) and in 2/14 MPAL patients (14.3%). Correlation with cytogenetic subgroups show significant higher incidence in M3 patients 13/30 (43.3%, P=0.0371) in comparison to other types (20% M0, 20.6% M1, 20.1% M2, 13.4% in Monocytic Leukemia -M4 and M5-). In non-APL patients, favorable cytogenetic changes are more common in FLT3 wild group (19.7%)[27/137 (21 patients with t(8;21) and 6 with inv 16] than in FLT3 mutant group (6.5%) [2 with t(8;21) and none with inv 16]. There were insignificant difference between FLT3 wild and mutant group regarding achieving Compete Remission (CR) by Day 36 (P= 0.261), However Overall Survival (OS) of the wild group was high significantly better than that of mutant group (P=0.002). By the end of the 1st year only 10% of patient with mutant FLT3 were alive versus 30% of those with wild type, with 4 months median survival of mutant group versus 8 months of the wild group.
In APL patients, again there was no significance between both groups regarding achieving CR by Day 36 (P=0.06) and still OS of APL patients with wild FLT3 was significantly better than in those with mutant FLT3 (P=0.0182). By the end of 1st year, about 90% of patients with wild group are still alive while only 46% of the mutant group are alive with 2 months median survival.
We conclude that FLT3-ITD mutations infers poor prognostic effect even in the presence of favorable cytogenetic changes like t(15;17); which indicate that patient with such mutations should be assigned to aggressive therapy.

Disclosures
No relevant conflicts of interest to declare.
Identification of the Microrna Signature of Acute Myeloid Leukemia Patient s Regulatory T Lymphocytes
Authors: Rouas Redouane , Merimi Makram , Badram Bassam , Burny Arsene , Bron Dominique , Lewalle Philippe , Fayyad Kazan Hussein 
Published: November 2019

Abstract
There is a clear evidence of elevated numbers of CD4 regulatory T lymphocytes (Tregs) in solid and hematological malignancies in addition to possessing an increased suppressive function. This important feature has urged the scientific community to search for ways to interfere with Treg function during or after cancer therapy. But the underlying molecular mechanisms remain largely unknown. Thus, a special focus on microRNA regulation was the goal of our study.
In our previous study, we investigated the molecular profile of circulating Tregs in the peripheral blood (PB) of healthy volunteers and identified several miRs differentially expressed between CD4+CD25+CD127low (Tregs) and CD4+CD25-CD127low T cells using the TLDA technique.
In fact, a human Treg microRNA signature of AML patients at diagnosis has not been described yet. We thus investigated human CD4+CD25+CD127 low Tregs purified from the peripheral blood of AML patients and identified a signature composed of ten differentially expressed miRs (miR-18a, miR-101, miR-133a, miR-135a, miR-302c, miR-324, miR-511, miR-542, miR-618, and miR-758) in comparison to their negative counterpart. Among those miRs, six were upregulated (miR-18a, miR-101, miR-133a, miR-135a, miR-511, miR-618) whilst four were downregulated (miR-302c, miR-324, miR-542, miR-758). Many potential miRs potential targets were identified in the 3'UTR of genes indispensable for Treg function and are presently under investigation. Moreover, we are comparing Tregs from AML patients to those from healthy individuals in term of microRNA signature and biology.

Disclosures
No relevant conflicts of interest to declare.