bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Prevalent, Features and Prognostic Impact of Deletion p16 in Patients with Adult Acute Lymphoblastic Leukemia
Authors: Xu Na , Li Yulin , Zhou Xuan , Xiaoli Liu , Zhou Hongsheng , Huang Fen , Xu Bing , Liu Qifa , Sun Jing , Feng Ru , Meng Fanyi 
Published: October 2019

Abstract
Background and objective: Deletion of chromosome 9p21 is a crucial event for acute lymphoblastic leukemia (ALL). 9p21.3 genes encode three cell cycle inhibitory proteins: p15INK4b, p16CDKN2A, and p14ARFT. Recently studies show that p16 (CDKN2A) alleles were hypermethylated at CpG islands in ALL patients and delation p16 was associated with poor prognosis in childhood ALL. However, the prognostic significance of the deletion p16 in adult ALL leukemia is controversial, so the aim of the present study was to investigate the prevalence, feature and specific prognostic relevance of delation p16 in Chinese ALL patients from a single center in China.
Patients and Methods: A total of 513 newly diagnosed adult ALL patients were identified retrospectively from the database of ALL between January 2008 and December 2013 at our center. We Detected delation p16 by interphase fluorescence in ituhybridization (I-FISH) and analyzed their clinical data retrospectively.
Results: Of 513 cases, the prevalence of having either heterozygous or homozygous p16 deletions was 32%. p16 deletion were identified in 27% of newly diagnosed Philadelphia positive(Ph+) patients by univariate analysis, patients with p16 deletion had no significant difference compared with wild-type patients in terms of sex, age, white blood cells (WBC) count at diagnosis,BM blast percentage,chromosome karyotype,extra infiltration and CR I rate. The patients with p16 deletion was more likely to relapse comparaed with wild-type patients (P=0.03), and at relapse, we found a strong trend in the detection rate of p16 loss (41%) compared with diagnosis (P=0.01), suggesting that loss of this genomic region may be involved in disease progression. Of note, in newly diagnosed Ph+ALL with delation p16 were likely relapse even in the patients who treated with allogeneic hematopoietic stem cell transplantation (P=0.03). In addition, deletion p16 were significantly associated with poor outcomes in terms of overall survival (P=0.01), disease free-survival (P< 0.001), and cumulative incidence of relapse (P< 0.001).
Conclusion: In our study, the absence of p16 expression seems to a poor prognostic marker in adult ALL patients. However, how to improve the survival of these patients need further study.

Disclosures
No relevant conflicts of interest to declare.
Modeling the Epidemiology of Indolent Non-Hodgkin Lymphoma (iNHL) in France
Authors: Troussard Xavier , Herrera Alain , Cornet Edouard , Solal-Céligny Philippe 
Published: October 2019

Abstract
As of 2014, there were few reliable publication sources of epidemiology data for Non-Hodgkin Lymphoma (NHL) in France, particularly with regard to indolent forms such as Follicular Lymphoma (FL), Waldenström Macroglobulinemia (WM) and Marginal Zone Lymphoma (MZL). In addition, epidemiology registries provide useful data on disease incidence but no information can be directly obtained on the number of relapsed patients, especially in the rare iNHL subtypes. At the same time, many new and effective drugs will be made available to the Hematologist/Oncologist community. As a consequence, there will be an increase in the complexity of therapeutic algorithms.
We undertook an innovative modeling approach to address the need for a greater understanding of the number of relapsed patients available to these new therapies. The objective of the model was to determine the yearly incidence of first line and later lines of therapy patients from 2014 to 2018 and in consequence, provide relevant data to determine precisely which population might be in need for the new compounds and bring accurate data that could be implemented into a prospective economic model.
First, we used the Registre Régional des Hémopathies Malignes de Basse-Normandie (RRHMBN) to collect real world patient characteristics, such as patient subgroups and tumor staging. The RRHMBN is dedicated to Hematological malignancies and supported by official Health Authorities: Institut National du Cancer(INCA) and Institut National de Veille Sanitaire (INVS). Then, we applied these data to the French National Network of Registers FRANCIM incidence and survival data (table 1 below).
Table 1 Yearly number of patients newly diagnosed Table 1. Yearly number of patients newly diagnosed
Finally, we applied the results from medical literature to progression free survival for each standard of care treatment in our epidemiological model.
The table below shows yearly the number of patients in need for treatment in first and subsequent lines of therapy as produced by our model.
Table 2 Yearly number of patients in need for treatment in first and subsequent lines Table 2. Yearly number of patients in need for treatment in first and subsequent lines
Our modeling approach compensates for a lack of real world information on relapsed iNHL. We have shown that there is a significant number of relapsed patients who are in need of new treatments in France. The model is able to answer the question of how many patients are in need of novel therapies in later lines through 2018 and provide for iNHL investigators efficient prospective data that can be integrated into medico-economic model development.
Furthermore, these data address a current medical need for the development of a new iNHL algorithm, necessitated by the expected arrival of new treatment options for patients in the relapsed setting.

Disclosures
No relevant conflicts of interest to declare.
Bendamustine-Rituximab (BR) Combination in Low Grade B-Cell Lymphoproliferative Disorders (LPD): A Community Oncology Experience
Authors: Shahab Aarish , Chin Janet , Yunus Saadia 
Published: October 2019

Abstract
Introduction:
Low-grade B-Cell LPDs are indolent Non-Hodgkin’s Lymphoma (NHL) that are incurable with current therapeutic options. BR chemoimmunotherapy has demonstrated remarkable effectiveness in these patients. Here we report our experience with BR in low-grade B Cell LPD subtypes.
Method:
Between October 2011 and May 2014, we treated 25 patients with a diagnosis of low-grade B-Cell LPD with a planned BR regimen of 6 cycles. The median age was 64 years (range 41-91), 15/10 M/F – a ratio of 3:2. LPD subtype included Chronic Lymphocytic Leukemia (CLL) 5, Small Lymphocytic Lymphoma (SLL) 3, Follicular Lymphoma (FL) 6, Marginal Zone Lymphoma (MZL) 2, Mantle Cell Lymphoma (MCL) 2, Mucosa-associated Lymphoid Tissue (MALT) 3, and Lymphoplasmacytic Lymphoma (LPL) 4. Twenty two (88%) were stages III or IV. Ten had received prior treatments. 15 had BR as first treatment. The regimen consisted of Bendamustine (B) 90 mg/m2 (on days 1&2 and Rituximab (R) 375 mg/m2 on day1 given every 28 days.
Results:
Seventeen (68%) completed the entire 6 planned cycles. 14 (56%) required treatment delays due to various toxicities. In 5 (20%) chemo was discontinued early for toxicity. The most common non-hematologic toxicity was fatigue 11 (44%), and skin rash 5 (20%). The grade III/IV hematologic toxicity was as follows neutropenia (3) anemia (9) and thrombocytopenia (2).
The overall response rate (ORR) was 92% (23 pts) with 18 (72%) Partial Responses (PR), and 5 (20%) Complete Responses (CR). Twenty four (96%) continued to have remission with no progression noted during follow-up. One patient with 17p del CLL progressed after 3 months with Richters transformation to diffuse large B cell NHL. The median duration of response was 17 months, with a range from 2 months – 38 months.
Conclusion:
In all LPD subtypes, despite the observed toxicities requiring treatment delays and dose modifications, 96% patients attained significantly long lasting remissions. Although this review included a comparatively small number of patients, our experience shows that BR is a highly effective chemo immunotherapy in all subtypes of Low-Grade B-Cell LPD – suggestive of altering the natural biology of this disease. For more definitive results, the study should be inclusive of a larger number of patients and prolonged follow-ups.

Disclosures
No relevant conflicts of interest to declare.
Vemurafenib As First Treatment of Hairy Cell Leukemia
Authors: Cheng Gregory , Cheng Gym , Chan Natalie Pui Ha , Wong Chris , Wong Raymond S 
Published: October 2019

Abstract
44 years old lady presented with fever and pancytopenia in March 2014.CXR showed bilateral pneumonia. Hb 7.5xg/dl, plt 42x x109/l, wbc 1.2 x19neutrophils22%, lymphocytes75%.Circulating lymphocytes with hairy cytoplasmicprojections and indented nuclei were noted. Flow cytometry showed these abnormal lymphoid cells were CD19+ve, CD5-ve, CD 23-ve, FMC7+ve, CD25+ve, CD11c+ve and CD103+ve.Bone marrow biopsy revealed a hypercellular marrow with dense infiltration of lymphoid cells of the same immunophenotype. Braf V600 mutation was detected. Cladribine or pentostatin was out of stock and import of these drugs would take at least 2 months. In view of the severe pancytopenia and on -going infection, various treatment options were discussed with, the patient .Patient decided to start on vemurafenib 960mg twice daily while awaiting cladribine. After 8weeks of treatment, the peripheral blood counts were normalized. Hb 12.2g/dl, plt 153x x109/l, wbc 3.1x109/l, neutrophils 53%,lymphocytes 40%. Braf V600 mutation was no longer detected. Vemurafenib was well tolerated and the patient received treatment mainly as outpatient. Vemurafenib was discontinued after 8 weeks and the patient then received a 5-day course of cladribine. She remained in complete remission
Discussion
Vemurafenib had shown to be safe and effected in hairy cell leukemia patients who were refractory to or who relapsed after purine analogs.1,2 Still to be determined are the correct vemurafenib dosing strategy, the best timing , duration and scheduling of vemurafenib. Due to unusual circumstances, our patient received 8 weeks of vemurafenib as first line therapy. The patient achieved a complete remission with minimal residual disease. Follow data is needed to see how long the patient remains in remission
1. N Engl J Med 2014; 370:286-288
2. 19th Congress of the European Hematology Association (EHA): Abstract S696.

Disclosures
Off Label Use: Vemurafenib as first treatment of Hairy Cell Leukemia. Wong:johnson &johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer, MSD, Roche, BMS, Baxter, Amgen, Alexion: Research Funding.
Pre-Clinical Evaluation of a Novel DNA Crosslinking Agent, Bo-1055 in B-Cell Lymphoma
Authors: Caldas Lopes Eloisi , Correa Fabian , Peguero Elizabeth , Ambati Srikanth R. , Shieh Jae Hung , SU Tsann Long , Moore Malcolm A.S. 
Published: October 2019

Abstract
Some B-cell lymphoma including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) remain incurable using conventional chemotherapeutic approaches. Therefore it is important that new treatment strategies be developed. We have evaluated the efficacy of a number of novel, third generation, DNA-directed alkylating agents that have DNA specific binding domain by linking DNA-affinic molecules to N-mustard pharmacophore via a urea, carbamate or hydrazinecarboxamide linker (Kapuriya et al. Bioorganic & Medicinal Chem. 19:471–485; 2011). One of these, the water-soluble ureidomustine BO-1055, was screened for toxicity against a panel of human lymphoma cell lines including MCL (JEKO-1, Z-138, HBL-2), DLBCL (OCILy10, OCILy19) and a spontaneous murine B-cell lymphoma. We also screened BO1055 against a panel of normal human cells including mesenchymal stromal cells (IC50 >10uM), bone marrow-derived endothelium (IC50 >10uM) lung basal epithelium, bronchial epithelium and myofibroblasts (IC50s >10uM) and purified cord blood CD34+ cells in suspension culture or colony-forming assay (for hematopoietic progenitor cells) (IC50 >10uM) and in cobblestone area-forming assay (for hematopoietic stem cells) (IC50 9.1uM). The mean IC50±SD (uM) in MCL cell lines was JEKO-1 (0.266±0.27), Z-138 (0.182±0.15), HBL2 (0.161±0.34), In DLBCL lines OCILy10 (0.117±0.21), OCILy19 (0.287±0.17) and murine B-cell lymphoma (0.463±0.39). Our results indicated that BO-1055 has a significant therapeutic window (50-100-fold) between its toxicity against human B-cell lymphomas compared to various normal human cell types. We evaluated BO-1055 cardiotoxicity in the HL-1 cardiomyocyte line and observed a 227-fold less cytotoxicity compared to Doxorubicin. Treatment with BO-1055 resulted in accumulation of cells in S-phase and up-regulation of proteins involved in DNA repair [MRE11, p-P95/NBS1 (ser343), RAD50, p-ATR (ser428)] while Bcl-6, an important B-cell lymphoma biomarker, was down-regulated. Xenograft experiments in NSG mice bearing JEKO-1 GFP/luciferase+ tumors treated with BO-1055 (30mg/kg) 3x/week showed complete tumor remission after 2 weeks of treatment as monitored by luciferase image. Our results suggest that BO-1055 has potent activity against B-cell lymphoma and present a strong rationale for its further therapeutic development as an alkylating agent due to his low toxicity against normal tissue and high toxicity against hematopoietic tumors.

Disclosures
No relevant conflicts of interest to declare.
the -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Myeloid Leukemia Risk in Turkish Patients
Authors: Yalcin Serap , Mutlu Pelin , Cetin Turker , Sarper Meral , Ozgur Gokhan , Avcu Ferit 
Published: October 2019

Abstract
Interleukin-18 (IL-18) is a cytokine which belongs to the interleukin-1 superfamily and secreted by various immune and non-immune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between -137G/C (rs187238) IL-18 gene polymorphism and susceptibility to chronic myelogenous leukemia(CML) in Turkish patients. The frequencies of polymorphism -137G/C were studied in thirty chronic myelogenous and thirty healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. Significant associations were detected between the IL-18 rs187238 (G/C) polymorphism and CML patients. A higher prevalence of the C allele was found in CML cases with respect to controls (p<0.05). The GC heterozygote and CC homozygote genotypes are associated with the risk of CML when compared with controls (OR, 1.9023; 95% CI, 0.6171-5.8636 for GC genotype and OR, 10.3585; 95% CI, 0.5326-201.4622 for CC genotype). These results indicate that individuals that are either heterozygote (GC) or homozygote for CC genotype are associated with the development of chronic myelogenous leukemia in Turkish population. Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings.

Disclosures
No relevant conflicts of interest to declare.
Spectrum of BCR-ABL Kinase Domain Mutations; A Cohort Study from Saudi Arabia
Authors: Abalkhail Halah , Khalil Salem 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm (MPN) associated with a characteristic translocation between chromosome 9 and 22 to form Philadelphia chromosome (Ph). The introduction of tyrosine kinase inhibitors (TKIs) imatinib for CML marked a new era for targeted therapy. In general CML patients in chronic phase (CP) have a very good response to Imatinib with a ~85% projected overall rate of survival. However, a significant proportion harbor molecular residual disease and develop acquired resistance after initial response through a number of cellular and molecular mechanisms in which mutations in the Abl kinase domain are the best known cause of resistance. Mutations are detected in 35% of patients with resistance to TKI in Chronic Phase and up to 80% in patients with accelerated phase and blast phase.
Given the clinical importance of the mutation status, mutation analysis was established as a clinical service to aid in the clinical decision and identify the subset who would benefit from alternative therapies.
In this retrospective study, we assessed the ABL kinase domain mutation in 93 patients referred from our clinics at King Faisal Specialist Hospital and Research centre (General Organization) between 2011-2013 with Ph positive CML displaying either refractory to TKI or resistance displaying increase BCR-ABL1 levels by serial monitoring using Quantitative PCR. Mutation analysis was performed on RNA extracted from either blood or Bone marrows after amplification of the BCR/ABL1 transcript by nested PCR followed by Direct sequencing of the BCR-ABL1 Kinase domain including residues 243-487.
In total, 93 patients (46 Females and 47 males), Age between 10-71 years (median age: 38 years) of which 89 were adults and 4 pediatrics were analyzed. Among 93 patients, 20 (21.5%) were positive for 10 different mutations across the ABL1 Kinase domain mutations (7 patients had T315I, 3 patients had each of the following mutation: Y253H, F359I, 2 patients with E255K. Additionally, one patient with each of the following mutations: E355G, V299L, L248V, L298, Y326H and F317L). The duration from diagnosis to mutation detection ranged between 3-144 months with a median duration of 4 years.
Despite the retrospective nature and the relatively small sample size of a single center analysis, the mutation frequency is in line with similar studies reported from our region.
Further follow up is needed to identify the outcome of these patients acquiring ABL kinase mutations on targeted therapy.

Disclosures
No relevant conflicts of interest to declare.
Pharmacoeconomical Analysis of Chronic Myelogenous Leukemia Treatment Free Remission
Authors: Shuvaev Vasily , Abdulkadyrov Kudrat , Turkina Anna , Martynkevich Irina , Chelysheva Ekaterina , Fominykh Mikhail , Martchenko Valentin 
Published: October 2019

Abstract
Introduction. Implementation of target therapy in chronic myelogenous leukemia (CML) treatment allowed saving life for majority of CML patients. First and second generation tyrosine kinase inhibitors (TKI) usage experience showed that part of patients can achieve deep molecular responses. Clinical trials of treatment cessation in CML patients with deep molecular response demonstrated that substantial proportion of patients can be free from drug with predictable relapse risk and safe treatment re-initiation. This approach is interesting due to sustained increasing number of CML patients and avalanche like increment of budget burden because of continuous expensive TKI therapy.
The aim of our study was to assess potential budget impact of successful TKI cessation in CML patients with long-lasting deep molecular response.
Materials and methods. Pharmacoeconomical modelling of CML diagnostic and treatment process including treatment free remission (TFR). Markov chain approach was implemented to construct models for non-stop therapy and TFR in patients with sustained molecular response 4 logs (MR4.0) (Fig 1). Treatment re-initiation was considered in case of major molecular response loss. The total number of CML patients in Russia was 6500; annual rate of newly diagnosed CML cases was 800 (in accordance with Russian CML Registry data). The patient consent rate to TFR inclusion was assumed as 80%. Transition rates were chosen from clinical trials and own experience. Cost-utility analysis of first and second generation TKI apply was performed. Simulation of clinical and economical consequences was done on national level. Five-year (2015-2020) time horizon was used. To simplify presentation of our results we recalculated costs to US dollars.
Results. Our analysis showed that by year 2020 the estimated total CML patient number in Russia will be about 11000 patients with total direct yearly CML cost 109 mln $. TFR approach can decrease budget burden from 109 to 95 mln $ yearly and the total evaluated money saving during years 2015-2020 period in Russia will be 67 mln $ with complement cost-utility data (Fig 2).
Conclusion. Annual CML cost will increase due to increment of CML patients number. Nevertheless, TFR strategy in CML patients with long-lasting deep molecular response under continuous molecular monitoring can significantly decrease the healthcare budget burden. TFR approach has the advantage over sustained therapy on financial cost and efficacy of its use.

Disclosures
Turkina: Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.
Co-Administration of Hydroxyurea and a Specific AKT2 Inhibitor Has Beneficial Effects on Acute Vaso-Occlusive Events and Survival in Sickle Cell Disease Mice
Authors: Li Jing , Barazia Andrew , Kim Kyungho , Cho Jaehyung 
Published: October 2019

Abstract
We recently demonstrated that the basal levels of AKT phosphorylation were significantly increased in neutrophils and platelets isolated from sickle cell disease (SCD) patients compared with those cells from healthy donors and that specific inhibition of AKT2 impaired neutrophil-endothelial cell and neutrophil-platelet interactions in venules of Berkeley (SCD) mice (Li et al. J Clin Invest 2014). Although hydroxyurea (HU), an inducer of fetal hemoglobin, is the main therapy for treatment of SCD, it is unclear whether the short-term treatment with HU has immediate benefits on acute vaso-occlusive events in SCD. Using real-time fluorescence intravital microscopy, we demonstrated that co-administration of HU (100 microg/g body weight, iv injection) and Akti XII (3 microg/g body weight, iv injection), an AKT2 inhibitor, efficiently reduced neutrophil adhesion and platelet-neutrophil aggregation in cremaster muscle venules of TNF-α-challenged Berkeley mice. Importantly, compared with HU or Akti XII treatment alone, treatment with both agents significantly improved blood flow rates and survival in the mice. Further, similar results were obtained in Berkeley mice challenged with hypoxia (8% oxygen for 3 hours) and subsequent reoxygenation (room air for 3 hours). As determined by histochemistry of cremaster muscle sections following intravital microscopy of Berkeley mice, the expression of endothelial E-selectin and intercellular adhesion molecule 1 (ICAM-1) was significantly decreased by treatment with either HU or Akti XII. Leukocyte transmigration in the lung section of Berkeley mice was also inhibited by either agent, and the inhibitory effect was potentiated by co-administration of HU and Akti XII. Using the plasma and isolated cells of Berkeley mice, we found that the level of plasma nitric oxide species (NOx) was significantly elevated by treatment with HU but not Akti XII and that AKT2 phosphorylation levels in activated neutrophils and platelets were reduced by treatment with Akti XII but not HU. Taken together, these results suggest that short-term treatment of Berkeley mice with either HU or Akti XII inhibits inflammatory conditions: treatment with HU significantly increases plasma NOx levels, treatment with Akti XII decreases AKT2 phosphorylation in neutrophils and platelets without affecting plasma NOx levels, and administration of either agent reduces the surface expression of ICAM-1 and E-selectin on activated endothelial cells. Thus, our results provide evidence that co-administration of HU and a specific AKT2 inhibitor has immediate benefits on acute vaso-occlusive events and survival in SCD mice exceeding those seen for single therapy.

Disclosures
No relevant conflicts of interest to declare.