bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytogenetic Response Based On Revised IPSS Cytogenetic Risk Stratification and Minimal Residual Disease Monitoringby FISH In MDS Patients Treated By Low-Dose Decitabine
Authors: Li Xiao , Chang Chunkang , He Qi , Xu Feng , Zhang Qingxia , Wu Lingyun , Su Jiying , Zhang Xi , Zhou Liyu , Wu Dong , Zhang Zheng 
Published: October 2019

Abstract

Objective
To observe and analyze the response characteristics based on revised IPSS (IPSS-R) cytogenetic risk stratification in patients with myelodysplastic syndromes (MDS) who received low-dose decitabine treatment.

Patients and methods
Eighty-seven MDS patients received decitabine treatment (15-20mg/M2/d×5/per course) with a median of 4 courses (range, 1-10). The clinical and cytogenetic response after treatment were observed to evaluate whether the IPSS-R cytogenetic risk stratification could predict treatment response. For those patients with abnormal karyotypes who achieved clinical complete response (CR), percentage of clonal cells in bone marrow (BM) was calculated by G-banding together with fluorescence in situ hybridization (FISH) to determine the minimal residual disease (MRD). In addition, the effect of cytogenetic response on overall survival (OS) was also analyzed.

Results
Sixty of 87 patients (69.0%) achieved treatment response including 25 cases (28.7%) with CR. For the 44 patients with abnormal chromosome, 27 cases (61.3%) achieved cytogenetic response including 18 with complete cytogenetic response (cCR). The patients carrying poor or very poor karyotypes presented better clinical and cytogenetic response than those with intermediate or good karyotypes. Among the patients with poor or very poor karyotypes, the ones carrying chromosome 7 aberrance showed better response than the others. Among 18 patients with abnormal karyotypes who achieved clinical CR, 4 cases presented cytogenetic PR or NR through G-banding analysis. FISH analysis revealed an over 5 % of clonal cells in BM in two patients who presented G-banding defined cytogenetic CR. In addition, longer median OS (24 months) were observed for patients who achieved cytogenetic response than those who did not (12 months) (P=0.007)

Conclusion
IPSS-R cytogenetic risk stratification could be used to predict the clinical and cytogenetic response to decitabine treatment in MDS patients. The predicting effect may be related to the chromosome 7 involvement rather than the number of abnormal karyotypes. FISH together with G-banding analysis should be available in determining MRD in MDS patients after treatment.

Disclosures:
No relevant conflicts of interest to declare.
Azacitidine and Lenalidomide Combination In Higher-Risk Myelodysplastic Syndromes-Preliminary Results Of The Vilen-01 Protocol
Authors: Mittelman Moshe , Filanovsky Kalman , Rosenbaum Hanna , Raanani Pia , Braester Andrei , Goldschmidt Neta , Hellman Ilana , Kirgner Ilya , Perri Chava , Oster Howard S 
Published: October 2019

Abstract

Background
Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL).

Protocol
The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006].

Results
As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant).

Conclusions
These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease.

Disclosures:
No relevant conflicts of interest to declare.
Erlotinib Is Not Effective In Patients (Pts) With JAK-2 V617F Positive Polycythemia Vera
Authors: Cherry Mohamad , Khawandanah Mohamad , Zhao Zhizhuang Joe , Srour Samer A , Ozer Howard , Selby George , Ghabache Bassam , Al-Kali Aref 
Published: October 2019

Abstract

Introduction
Erlotinib is an epidermal growth factor receptor small-molecule inhibitor and is FDA approved for the treatment of lung and pancreatic cancers. In preclinical study, in vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppressed the growth and expansion of Polycythemia Vera (PV) hematopoietic progenitor cells while having little effect on normal cells. Several JAK inhibitors are being studied for the management of PV, one of which has been approved for the treatment of myelofibrosis (ruxolitinib).

Aim
To study the clinical effect of erlotinib in pts diagnosed with JAK2V617F + PV.

Methods
We conducted a single arm, prospective phase II study at the University of Oklahoma and the Oklahoma City VA hospitals in pts with WHO defined JAK-2 V617F positive PV from June 2010 to August 2012. Appropriate IRB approval was obtained in accordance with Hilsinki declaration. Pts had to be requiring phlebotomy. Toxicity was assessed by treating physicians using NCI version 4. Dose modification for erlotinib was done using label recommendations.

Results
Five Caucasian pts were enrolled (3 (60%) males, with median age at enrollment of 63 years, range 26-79). Pts had pretreatment median hemoglobin14.4 g/dL (10.4 -19.2 g/dL), median platelet count 511 x109 (424-681 x109), median white blood cell (WBC) 14.4 x109(7.8- 18.3 x109). Three pts had splenomegaly prior to treatment. Median number of prior pharmacologic treatments (hydroxyurea, anagralide or interferon) was 1, range 0-2. Pts were given erlotinib 150 mg orally daily for 16 weeks: responders (phlebotomy free or decrease in spleen size) were allowed to continue a total of 1 year of treatment, while non-responders were taken off the study. Three (60%) patients received therapy for 16 weeks and did not achieve hematological response or improvement in spleen size. Two (40%) pts were taken off the study after 2 doses secondary to severe toxicities (grade 3 colitis in 1 case, and grade 3 facial rash in 1case). No therapy continued beyond 16 weeks (due to toxicity or lack of response). All pts in the study developed rash (grade 1 – 3) and diarrhea (grade 1 – 2). Three pts developed mucositis (see Table 1). No death was observed during the study and follow up period (median follow up was 23 months, range 12-37 months). Study was closed due to lack of efficacy.

Conclusions
Despite in vitro efficacy of erlotinib as potent inhibitor of JAK-2 activity, erlotinib is not effective in pts with JAK-2 V617F positive PV with poor toxicity profile. Poor accrual was related to potential toxicity of erlotinib compared to alternative treatments in view of lack of clinical efficacy.

Disclosures:
No relevant conflicts of interest to declare.
Alterations Of The Chemokine Microenvironment In Chronic Lymphocytic Leukemia
Authors: SEILER TILL M , Aydin Roland , Herold Tobias , Holdenrieder Stefan , Hallek Michael , Hiddemann Wolfgang , Dreyling Martin , Bergmann Manuela A. 
Published: October 2019

Abstract

Background
In chronic lymphocytic leukemia (CLL), proliferation of the leukemic cell clone occurs in the bone marrow and lymphatic tissues rather than peripheral blood. In this microenvironment, CLL cells interact with accessory cells, such as T-cells and CD68+ nurselike cells (NLCs). In addition, cytokines and chemokines secreted by leukemic cells, stromal cells and T-cells are essential in forming the disease-specific microenvironment. However, the exact biological role of cytokines and chemokines needs to be defined.

Methods
In order to address this issue, we measured serum levels of 20 chemokines and cytokines in a prospective cohort of 159 previously untreated Binet stage A patients (pts) (GCLLSG CLL1 trial), 50 pts with advanced CLL in need of first line treatment (GCLLSG CLL8 trial) and 27 healthy individuals. For the study cohorts, serum samples had been centrally collected at study entry and stored at -80°C. Sera were analyzed on a Luminex-based multiplex platform, allowing simultaneous screening of multiple serum parameters.

Results
Serum levels of 13 chemokines (EGF, MCP-1, MIP-1alpha, MIP-1beta, sIl2Ralpha, VEGF, MCP-2, MCP-4, SDF-1, 6CKine, CTACK, TRAIL, SCF) differed significantly between healthy controls and CLL patients (p<0.05), indicating that the expression of these cytokines may potentially impact pathways common to CLL and the disease specific microenvironment. In addition, 7 chemokine serum levels were significantly higher in advanced stage CLL compared to patients at primary diagnosis, indicating a pronounced shift of the chemokine homeostasis upon disease progression. (Table)
We identified a strong correlation of inflammatory cytokines (TRAIL, TNFalpha; p=0.039), growth factors (EGF, VEGF, TPO, SCF; p<0.001) and chemokines involved in B- and T-cell migration and homing (MIP-1alpha, MIP-1beta, 6CKine, Il-16; p<0.05). These coordinately regulated cytokines may reflect pathways important to the pathobiology of CLL. Hierarchical cluster analyses revealed distinct chemokine expression patterns in healthy individuals, early CLL and advanced stage disease. Finally, sIl2Ralpha has been previously confirmed as an independent prognostic factor in early stage CLL

Conclusion
Due to the comparison of 27 healthy individuals and 209 CLL pts we were able to demonstrate that the chemokine homeostasis is significantly altered in CLL compared to healthy individuals. Chemokines involved in B- and T-cell migration and homing and recruitment, inflammation and growth factors are coordinately overexpressed, pointing towards pathways crucial to the formation of a disease specific microenvironment. These pathways might serve as potential targets for future therapeutic strategies.

Disclosures:
No relevant conflicts of interest to declare.
Aberrant Megakaryocytic/Erythroid Progenitors Contributes To Transformation Of Cbfb-SMMHC Induced Acute Myeloid Leukemia
Authors: Cai Qi , Jeannet Robin , Liu Hongjun , Kuo Ya-Huei 
Published: October 2019

Abstract
Inv(16)(p13q22) is a recurrent chromosomal rearrangement found in approximately 12% of human acute myeloid leukemia (AML) cases and creates a fusion gene between CBFb and MYH11. The fusion gene encodes a fusion protein CBFß-SMMHC which causes defects in lymphoid and myeloid differentiation. Previous studies also showed that primitive erythropoiesis is impaired by CBFß-SMMHC, however, CBFß-SMMHC knocked-in cells was able to contribute to adult erythropoiesis in chimeric mice. Expressing CBFß-SMMHC in the hematopoietic cells using a conditional knock-in mouse model (Cbfb56M/+/Mx1-Cre; 129SvEv strain) recapitulates inv(16)-associated AML. Previous studies in this model showed that CBFß-SMMHC expression leads to pre-leukemic hematopoietic alterations, and together with additional cooperative mutations, result in spontaneous myeloid leukemia in mice with a 3-6 month latency. We hypothesized that an expanded cell population at the pre-leukemic stage could be the target of additional mutations, and hence the cell of origin of leukemia initiating cells.
To further delineate the pre-leukemic progenitors and leukemia initiating cells, we backcrossed Cbfb56M/+/Mx1-Cre into C57BL/6 for more than 10 generations. Similar to previous studies in the129SvEv strain, expressing CBFß-SMMHC in adult C57BL/6 mice leads to cell number dependent development of AML. Analysis of pre-leukemic bone marrow as early as 2 weeks after induction revealed a 5.7-fold expansion of Pre-Meg/E cells (Pre-Megakaryocyte/Erythrocyte: Lin-cKit+Sca1-CD16-/loCD150+CD105-) compared to similarly treated control mice. While there was a significant increase in Pre-Meg/E population, we did not find significant increase in their proliferation but observed a 4.7 fold decrease of the erythroid progenitor (EP; Lin-cKit+Sca1-CD16-/loCD105hi) subset. Methylcellulose-based colony forming assay showed that pre-leukemic Pre-Meg/E had an impaired differentiation potential for erythroid lineage. In vitro erythroid differentiation assay also showed a partial block of differentiation from pre-leukemic Pre-Meg/E progenitors. These Pre-Meg/E like progenitors were able to induce leukemia in the presence of a known cooperative oncoprotein MPL when transplanted in lethally irradiated congenic recipient mice. In summary, our Results suggest that expression of CBFß-SMMHC impairs adult erythropoiesis at the transition of Pre-Meg/E to EPs, causing an expansion of Pre-Meg/E cells, which can be the target cell of additional mutations contributing to leukemia transformation.

Disclosures:
No relevant conflicts of interest to declare.
Decoding The BH3-Mimetic Pro-Apoptotic Activity Of Quercetin In Jurkat Cells
Authors: Primikyri Alexandra , Hatzimichael Eleftheria , Karali Evdoxia , Kostaras Eleftherios , Manztaris Michalis , Shin Jae-Sun , Chi Seung-Wook , Kolettas Evangelos , Gerothanassis Ioannis , Briasoulis Evangelos , Tzakos Andreas 
Published: October 2019

Abstract
Deregulation of apoptosis contributes largely to the pathogenesis of lymphoid neoplasms allowing the expansion of cell clones that develop resistance to drug-induced cell death. Therefore, subverting inherent resistance to apoptosis is a very challenging therapeutic issue and developing small molecules that can mimic the BH3 domain of the pro-apoptotic Bcl-2 family proteins appears to offer such potentials. Natural products, a rich source of compounds with BH3 mimetic activity, make a sound basis for such an approach. Quercetin, a natural polyphenol, has drawn much attention because it exerts anticancer cytotoxic effects, while sparing normal cells. Pro-apoptotic effects of quercetin have been shown in human lymphoma and leukemic cells and have been associated with Bcl-2 and Mcl-1 downregulation and Bax conformational activation. We undertook a multidisciplinary approach to elucidate the mode of action of quercetin, including cytotoxicity cell assays, biochemical approaches (pull down assays), NMR spectroscopy and docking calculations. We demonstrate that quercetin binds directly to the BH3 domain of the anti-apoptotic Bcl-2 and Bcl-xL proteins, exhibiting BH3-mimetic properties. Specifically, functional cytotoxicity assays of quercetin in Jurkat T-cell leukemic lines, Jurkat Bcl-2 and Jurkat Puro, indicated that quercetin binds to Bcl-2 protein. The direct binding of quercetin to Bcl-2 and to Bcl-xL was biochemically validated using pull down assays. NMR chemical shift perturbation experiments and docking calculations finally revealed that quercetin was bound to the pro-apoptotic BH3-binding site of the anti-apoptotic Bcl-2 family proteins (Figure 1). This property classifies quercetin as a natural flavonoid with BH3 mimetic activity, capable of driving leukemic cells to apoptosis. These results explain the cytotoxic effects of quercetin on Jurkat cells. These data can serve as a basis to consider studying BH3 mimetic natural products as adjuncts in the therapeutic approaches of lymphoid neoplasms in combination with chemotherapy, and can also provide a starting structure for developing novel potent analogues for the treatment of blood cancers.Figure 1Modeling (3D) the complex of quercetin with Bcl-2 (A) and Bcl-xl (B). Quercetin occupies the deep hydrophobic cleft in both proteins making an extended interaction network. The relevant residues are normally occupied by the pro-apoptotic Bak/Bad BH3 binding site in the complexFigure 1. Modeling (3D) the complex of quercetin with Bcl-2 (A) and Bcl-xl (B). Quercetin occupies the deep hydrophobic cleft in both proteins making an extended interaction network. The relevant residues are normally occupied by the pro-apoptotic Bak/Bad BH3 binding site in the complex

Disclosures:
No relevant conflicts of interest to declare.
The ASH Clinical Research Training Institute (CRTI) Positively Impacts The Success Of Early Career Hematologists In Patient-Oriented Clinical Research
Authors: Burns Linda J , Clayton Charles P , George James N. , Mitchell Beverly S. , Gitlin Scott D. 
Published: October 2019

Abstract
There is a recognized need to translate scientific discoveries to patient-oriented clinical research (POCR) in order to improve human health. To overcome obstacles that interfere with the recruitment and retention of physicians for POCR careers, in 2003 the American Society of Hematology (ASH) developed the Clinical Research Training Institute (CRTI), an enhanced and extensive mentored experience for early career POCR investigators. The ASH CRTI is limited to 20 trainees/year (senior fellows or junior faculty) with an equivalent number of faculty mentors. The year-long Institute includes a 1 week workshop with didactic sessions on a variety of POCR and career development topics, disease-specific small group sessions focusing on research protocol development with biostatistician participation, and one-on-one interactions with faculty and representatives with expertise in career-development awards from the U.S. National Institutes of Health. Trainees have additional interactions with their small groups and CRTI mentors throughout the ensuing year to promote career development and research collaborations. Communications between the trainees’ CRTI and home institution mentors are a vital component of the program. Evaluation of the POCR career development successes of the first 7 CRTI classes (140 trainees) was performed by reviewing trainees’ curriculum vitaes and their responses to an electronically distributed survey. Gender, racial and ethnic distributions were similar to that of U.S. Hematology/Oncology fellowship programs. The majority (66%) of trainees were senior fellows or graduates of adult hematology/oncology training programs, 31% of pediatric hematology/oncology programs and the remainder of other hematology-related programs. Eighty-six percent of trainees had self-described success establishing a POCR study and 85% considered themselves clinical investigators. Nearly half of trainees had positions that were primarily research focused. CRTI trainees received at least 144 external grant awards plus additional internal awards, and had published 1035 peer-reviewed manuscripts,173 chapters and 115 review articles. Over 95% of trainees were satisfied with their CRTI experience and testimonials supported their impression that CRTI had a significant impact on their career success. Enhancements introduced into the CRTI program, as a result of ongoing program evaluations, include broadening participant eligibility to include up to 5 international trainees per class to enhance global research collaborations and further enhancements to the trainee-mentor interactions. The outcomes of the ASH CRTI support the hypothesis that enhanced mentoring experiences contribute to the successful career development of physicians pursuing POCR careers.

Disclosures:
Clayton: American Society of Hematology: Employment.
Hematologic Recovery After Liver Transplantation
Authors: Seidler Christopher , Bozorgzadeh Adel , Ferrante-Hersperger Cheryl , Al-Mansour Zeina , George Mridula , Patel Bhavisha , Rawson Amanda 
Published: October 2019

Abstract

Introduction
Chronic liver disease is a national problem with over 3 million American suffering from end stage liver disease. The majority of patients with advanced liver disease have pancytopenia due to multiple factors. Hematology consults generated by the hematologic effects of end stage liver disease comprise 10-20% of consults. The majority of patients undergoing orthotopic liver transplantation achieve some degree of partial or complete hematologic recovery.

Methods
196 sequential records for patients undergoing orthotopic liver transplantation were analyzed. Complete data was available for 92 patients. Hematologic parameters were reviewed 1 month prior to transplantation, 1 month post, 1 year and 2 year post transplantation. A statistical analysis was performed using the two tailed t-test method.

Results
Rapid and sustained hematologic recovery occurred in the majority of patients and was significant except for WBC at 24 months.

Conclusions
Orthotopic liver transplantation results in rapid sustained hematologic response in the majority of patients. Rapid recovery of platelet counts was most significant and does not reflect Ssplenectomy. Co-morbidity and anti-rejection drugs also may lead to delayed marrow suppression. Further sub-set analysis and measure of additional factors will also be presented.

Disclosures:
No relevant conflicts of interest to declare.