bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deguelin Induces Cell Growth Arrest and Cell Death Via the Suppression of BCR-ABL and Survivin Expression in BCR-ABL-T315I Mutant Cells.
Authors: Oyake Tatsuo , Ito Shigeki , Kowata Shugo , Murai Kazunori , Ishida Yoji 
Published: October 2019

Abstract
Abstract 4255
Development of kinase domain mutation is a major drug-resistance mechanism for tyrosine kinase inhibitor (TKI) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) where TKI STI571 is ineffective against the BCR-ABL mutant, E255K or T315I. Therefore, new agents that effectively kill these cells with kinase domain mutation are absolutely necessary. Deguelin is a rotenoid from African plant Mundulea sericea, which has been recently shown to suppress the lung tumorigenesis via inhibiting the activation of PI3kinase-Akt signaling. More recently, deguelin has been shown to bind to ATP-binding pocket of heat shock protein (Hsp) 90 and inhibit functions of Hsp90 client proteins. However, the effects of deguelin on BCR-ABL mutant transformed cells are poorly understood. We investigated the effects of deguelin on the cell growth and cell death of BaF/3 pre-B-cells transformed with BCR-ABL-wild type (WT), BCR-ABL-E255K and BCR-ABL-T315I (kindly provided by Dr. Kimura, Saga University, Saga, Japan), by trypan-blue exclusion and Annexin V stain. Deguelin inhibited the proliferation of these transformed cells in a time-and a dose-dependent manner (IC50=1.0mM). In addition, flow cytometric analysis revealed a higher frequency of Annexin V(+) cells in deguelin-treated cells (mean ± SD : WT 80.1±15.3%, E255K 82.3±3.5%, T315I 94.0±0.4%, P< 0.05, respectively), compared to that in untreated cells (WT 11.5±1.6%, E255K 11.9±2.0%, T315I 15.3±4.8%, respectively). These results indicate that deguelin induces the cell-growth arrest and cell death in these cells. To better understand the mechanism of these effects, we examined the intracellular signaling and the expression of apoptosis associated proteins by immunoblot analysis. We found that deguelin suppressed BCR-ABL protein expression and prevented CrkL phosphorylation in these cells. In addition, the inhibitor of apoptosis protein, survivin expression was decreased at 24 hours after deguelin treatment. These results suggested that deguelin suppresses BCR-ABL and survivin expression, and inhibits CrkL phosphorylation in BCR-ABL mutant and WT cells. Since deguelin has been shown to inhibit the function of Hsp90 client proteins, deguelin may destabilize BCR-ABL and survivin by inhibiting Hsp90 function. Taken together, deguelin appears to induce cell growth arrest and apoptosis of BCR-ABL mutant and WT transformed cells via the suppression of BCR-ABL and survivin expression. Thus, deguelin merits further investigation as a potential therapeutic agent for CML with T315I ABL mutation.

Disclosures:
No relevant conflicts of interest to declare.
Effect of the Tyrosine Kinase Inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) On Blood Glucose Levels in Diabetic and Non-Diabetic Patients.
Authors: Agostino Nicole M. , Chinchilli Vernon M , Koszyk-Szewczyk Anita , Gingrich Rebecca , Sivik Jeff , Drabick Joseph 
Published: October 2019

Abstract
Abstract 4265

Background
Tyrosine kinase is a key enzyme utilized in many intracellular messaging pathways. Understanding of the role of particular tyrosine kinases in various malignancies has allowed for the design of compounds, the tyrosine kinase inhibitors (TKIs), which can specifically target these enzymes and hence, interfere with downstream signaling. TKIs have proven to be very successful in the treatment of a wide variety of malignant diseases including chronic myeloid leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia, renal cell carcinoma and gastrointenstinal stromal tumors. Given the widespread nature of tyrosine kinase as a target and the promiscuous nature of the various inhibitors, it would not be surprising that these drugs would have effects beyond the expected result of targeting merely the tyrosine kinase of interest. Scattered reports have suggested that these agents appear to affect blood glucose levels.

Results
We studied the blood glucose levels retrospectively in diabetic (19) and non-diabetic (82) patients treated with dasatinib (8), imatinib (39), sorafenib (23) and sunitinib (30). All 4 drugs resulted in statistically significant decreased blood glucose levels in both diabetic and non-diabetic patients that resolved with cessation of treatment. Mean decreases blood glucose values for both non-diabetic and diabetic patients for dasatinib were – 53 mg/dl, imatinib – 9 mg/dl, sorafenib – 12 mg/dl and sunitinib -14 mg/dl. While diabetic and non-diabetic patients had the same decreases in blood glucose, on average, blood glucose values overall were 40 mg/dl lower in non-diabetic patients than in diabetic patients on dasatanib and imatinib. Non-diabetics had an overall mean blood glucose value of 24 mg/dl lower than diabetic patients on sorafenib, and 15 mg/dl lower than diabetic patients on sunitinib. Diabetic patients required some modifications of their medications including cessation of insulin or other hypoglycemic agents. One diabetic patient developed symptomatic hypoglycemia on sunitinib.

Discussion
The mechanism for the hypoglycemic effect of these drugs is unclear, but of the 4 agents tested, c-kit is a common target. C-kit has been shown to play a role in pancreatic β-cell survival in mouse models, so it is unclear why an inhibitor of the c-kit tyrosine kinase would improve blood glucose levels. It is important for clinicians to keep the potentially hypoglycemic effects of these agents in mind in their patients since symptomatic hypoglycemia can occur and modification of hypoglycemic agents may be required. These results also suggest that inhibition of a tyrosine kinase, be it c-kit or some other undefined target, may improve diabetes mellitus and deserves further study as a potentially therapeutic option.

Disclosures:
No relevant conflicts of interest to declare.
Experience in Second Line TKI Treatment in 6 Million Region of Russia (St-Petersburg and Leningrad region).
Authors: Abdulkadirov Kudrat , Lomaia Elza , Abdulkadirova Alla , Shuvaev Vasiliy , Udalieva Vera , Usacheva Elena , Machulaitene Elena , Zotova Irina , Poznyak Ekaterina , Koryagina Elena , Ilina Natalia , Shneider Tatiana , Stepanova Svetlana , Romanova Ekaterina , Salamatova Eugenia , Goryunova Elena , Lazorko Natalija , Martinkevich Irina , Zaritskey Andrey 
Published: October 2019

Abstract
Abstract 4288
Resistance to imatinib could be overcome by new generations of TKIs. Data about the efficacy of second line TKI treatment may help to create a system for prognosing the duration of 2nd line TKI treatment and time of switching from second line TKI treatment to hematopoietic stem cell transplantation.
The aim of the study was to evaluate the results of 2nd line TKI treatment in patients resistant or intolerant to imatinib.

Patients and methods
44 resistant and 3 intolerant to imatinib pts were included. Cytogenetics with G-banding and PCR with sequencing were performed for evaluation the response and mutations. There were 39, 7 and 1 pts in CP, AP and BP respectively, Patients were treated by three different ATP-pocket inhibitors. The follow-up on 2nd line TKIs was 0.9-48mons (Median - 15.9 mons), median follow-up from diagnosis was 73,9 mons. In prognosis analysis (CHR, cytogenetics, Sokal) intolerant patients were not included.

Results
Probability of overall survival from diagnosis by 10 years was 85%. Probability of survival from the start of TKI2 by 4 y -90%. There were no differences in survival in pts with primary and secondary resistance, in CP and AP. Patients with low and intermediate Sokal risk did better than patients with high risk (p=0.014, Fig. 1.).
8 pts had T315I mutation when studied on second line TKI therapy.
Achievement of CCyR was 50% (58% when T3151 patients were excluded), it was higher in low+intermediate in comparison with high risk pts (60% vs 30%, p=0.091), in CP than in AP (56% vs 20%,p=0.07), in patients with CHR at switching than in those without CHR (72% vs 18%, p=0.014). We failed to find any differences in CCyR achievement in pts with different best cytogenetic response on imatinib (complete, major, minor, minimal responses, absence of cytogenetic response).
MCyR depended on the type of resistance - it was higher in secondary, than in primary resistant pts (80% vs 45%,p=0.06, Fig2). Probability of MCCyR loss was 20%, all of them appear during the first year of treatment. It was higher in AP than in CP (40% vs 12%,P=0.04).
Probability of 4 years PFS was high - 75%, also without differences in primary vs secondary resistance and even in AP vs CP.

Conclusion
Second line TKI treatment is very efficacious in imatinib resistant pts. The effect depended on the type of resistance and phase of the disease, CHR at the moment of switching to 2nd line treatment.

Disclosures:
No relevant conflicts of interest to declare.
Effects of Reduced Dose of Imatinib to Korean Chrionic Myeloid Leukemia in Chronic Phase.
Authors: Lee Se Ryeon , Park Yong , Seo Hee Yun , Sung Hwa Jung , Kim Seok Jin , Choi In keun , Choi Chul Won , Kim Byung Soo 
Published: October 2019

Abstract
Abstract 4290

Background
Some patients of CML in chronic phase receive reduced doses of imatinib due to some adverse effects. Recently, the efficacy of reduced dose of imatinib for the patients with small BSA was reported by our group and Japanese group, recently. This study was tried to verify the hypothesis of which BSA of CML patients might be an important factor to predict the effect of reduced dose imatinib.

Method
Fifty-six patients having record of BSA from the Korea University Medical Center who were treated with imatinib were retrospectively analyzed.

Result
All of the patients started the imatinib therapy with 400mg/day dose. 20 patients (35.7%) among them were reduced dose to 300mg and 4 of them were further reduced to 200mg/day. The main reasons for dose reduction were severe neutropenia or thrombocytopenia (grade 3 or 4) (89.4%). Following the dose reduction, the rate of toxicity was reduced and treatment was resumed and the dose was gradually increased until 9 patients tolerated a maintenance dose of 400mg/day and remainder had been taken the reduced dose. The cumulative CCR at 12 months was similar in both group (P = 0.89, 70.0% in reduced dose vs 72.7% in standard dose). The mean imatinib dose/BSA was significantly lower in patients receiving the reduced dose compared with those receiving the standard dose (P < 0.001)(183.4 ± 26.9 vs 230.5 ± 21.4), although the mean BSA didn't show the difference according to reduction of dose (P = 0.079)(1.62 ± 0.20 vs 1.75 ± 0.13). After median follow-up period of 37.3 months (6.0-76.1 months), 15 patients (75.0%) have sustained CCR in patients receiving reduced dose of imatinib.

Conclusion
From this study, we could find that the reduced dose of imatinib in CML patients might assure the relatively satisfactory response with low intolerable adverse effects. But we could not verify that BSA was the main factor to predict the effect of reduced dose of imatinib. So, further studies including though level of imatinib will be needed to clarify the effect of reduced dose of imatinib.

Disclosures:
No relevant conflicts of interest to declare.
Multicenter Retrospective Analysis of Second Allogeneic HSCT Outcomes for Hematologic Malignancies in Korea.
Authors: Ha Kim Kyoung , Kim Dong Hwan Dennis , Jang Jun Ho , Kim Kihyun , Jung Chul Won , Won Jong-Ho , Moon Joon Ho , Sohn Sang Kyun , Kim Yeo-Kyeoung , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung-Joon , Kim Jin Seok , Min Yoo Hong , Kim Dae-Young , Lee Je-Hwan , Lee Jung-Hee , Lee Kyoo-Hyung , Kim Inho , Yoon Sung-Soo , Park Seonyang , Lee Sang Min , Joo Young-Don 
Published: October 2019

Abstract
Abstract 4298

Background
Increasing number of autologous or allogeneic HSCT in Korea in this decade resulted in increasing requirement for second allogeneic hematopoietic stem cell transplantation (HSCT) as a result of the recurrence of primary disease or graft failure. Since Dec 2008, second HSCT has been approved by Korean government to be covered by national health insurance reimbursement system. However, there is no available data on the transplant outcomes following second allogeneic HSCT in Korea. Accordingly, the current study attempted to analyze the outcome of second allogeneic HSCT retrospectively.

Methods
Transplant data were collected retrospectively from 8 transplant centers in Korea. Inclusion criteria are as follows. 1) Age equal or over 15 years old, 2) Hematologic malignancies excluding aplastic anemia, PRCA, PNH or solid tumor, 3) Patients who underwent second alloHSCT receiving cord blood transplantation (CBT).

Results
Sixty four pts were included with following diagnoses: AML (n=28), ALL (n=5), CML (n=3), lymphoma (n=22), myeloma (n=5), and others (n=1). The median age was 37 (range 16-65). The first transplantation had been performed with autologous (59.4%) or allogeneic (40.6%) donors. The donors for second HSCT were HLA-identical sibling 32(47%), unrelated 28(49%), or haploidentical donor 2(4%). Conditioning regimen included TBI-based myeloablative 6(9%), non TBI myeloablative 19(30%), or reduced intensity regimen 38(60%). With median 16 months of follow up (range, 3 to 93 months), 40 pts died of transplant related toxicity (n=28; 70%), recurrence of primary disease (n=9; 22.5%) or other (n=3; 7.5%). After second HSCT, 56% were in complete remission, 38% in partial remission, and 6% were refractory. The 1- and 2- year overall survival rate was 42% and 29%, respectively.

Conclusion
The patients received non TBI conditioning regimens were shown longer survival.

Disclosures:
No relevant conflicts of interest to declare.
Dasatinib After Allogeneic Stem Cell Transplantation in Philadelphia-Positive Leukemias.
Authors: Scheid Christof , Chemnitz Jens , Holtick Udo , Krause Anke , Bergwelt-Baildon Michael , Hallek Michael 
Published: October 2019

Abstract
Abstract 4304
Dasatinib is a second generation tyrosine kinase inhibitor for the treatment of Ph+ chronic myeloid leukemia. However many patients recieving dasatinib are candidates for an allogeneic transplantation and will receive a transplant eventually. The use of dasatinib after an allogeneic transplant is very controversial: First the allogeneic antileukemic immune effect should theoretically obviate the need for further tyrosine kinase inhibition. Second the considerable hematological toxicity of dasatinib might impair the fragile donor hematopoiesis, at least given at full dosage. And third there is evidence that dasatinib inhibits both effector and regulatory T-cells which might hamper the graft-versus-leukemia effect and/or inrease the risk for Graft-versus-host disease.
We report our experience with dasatinib in 3 patients with relapsing or persisting Ph+ leukemias after allogeneic stem cell transplantation.
Pat. 1 is a 66yr old female patient with an imatinib-resistant lymphoid blast crisis who responded to dasatinib and was transplanted from an unrelated donor. After achieving a complete molecular remission she experienced a molecular relapse and was started on dasatinib 20 mg daily. 3 months later she reached a complete molecular remission without any major changes in blood counts and continued on dasatinib 20 mg.
Pat. 2 is a 42yr old male with Ph+ CML and a paraspinal extramedullary lesion who responded to dasatinib after being resistant to imatinib. After an allogeneic transplant from his HLA-compatible brother he was in complete hematologocial and major molecular remission but relapsed 3 months later. Ciclosporin A was stopped and dasatinib introduced at 70 mg once daily. 2 months later he achieved a complete hematological and molecular remission. No hematological toxicity was found.
Pat. 3 is a 41yr old female patient with a Ph+ c-ALL with a history of liver cancer and a partial liver transplantation. After achieving a complete remission with chemotherapy with imatinib she reveived an allogeneic stem cell transplantation from her brother who also had donated the liver graft. She lost her remission 9 months after transplant and was retransplanted with the same donor but without immunospuppression. Due to the lack of a complete molecular remission she started dasatinib at 50 mg/d and became bcr-abl negative 3 months later. Blood counts improved during treatment with dasatinib.
In summary all patients showed stable responses to dasatinib at low doses without any major hematological toxicity. With a follow up of 8-12 months we did not observe any GvHD during dasatinib treatment. In our hands low dose dasatinib is a feasible treatment option for relapse after allogeneic transplantation in Ph+ leukemias.

Disclosures:
No relevant conflicts of interest to declare.
The ANALYSIS of Chimerism IN ACTIVATED T Lymphocites CD25+ Improves the CAPACITY of the T Lymphocytes CD3+ Chimerism Dinamic to Predict COMPLICATIONS AFTER Allogenic STEM CELL TRANSPLANTATION.
Authors: Victor Noriega Concepcion , Jorge Gayoso , Serrano David , Gabriela Rodriguez Macias , Balsalobre Pascual , Borde Ismael Buno , Diez-Martin Jose L 
Published: October 2019

Abstract
Abstract 4307

Introduction
Complications after Allogenic Stem Cell Transplantation (Allo-SCT) are influenced by the immunological fenomena associated to the alloreactivity/allotolerance between donor and recepient. In this context, the usefulness of chimerism quantification in T lymphocytes for the prediction of complications after Allo-SCT is well known. However, to our knowledge, there is no information on the utility of chimerism analysis in activated lymphocytes (CD25+).

Objective
To stablish an asociation betwen the more common complications post Allo-Tph (aGVHD, cGVHD, relapse, reject), and the chimerism dynamics in CD25+ activated lymphocytes in the early period post-transplantation, trying to predict the patients with more risk of suffering from this complications.

Materials and Methods
The study included 38 Allo-SCT (17 NMA, 21 MA; 7 Haploidentical, 13 non-related donor, 18 identical donor; 7 UCB, 5 BM, 26 PB). Chimerism analysis was performed every 2 weeks until complete chimerism (CC) was achieved, and every 3 months thereafter. Follow up was censored when patients received DLI or 2nd Allo-SCT.Chimerism quantification was performed by microsatellite PCR (STR-PCR; AmpFlSTR SGM Plus; Applied Biosystems) on DNA obtained from peripheral blood and purified cell lineages (95% putity) by immunomagnetic technology (Miltenyi Biotec).

Results
Table 1 shows the results at day +30 for T and activated lymphocytes (CD3+ and CD25+) allocating patients in two groups depending on the relative percentage of recipient cells (% rec) in both cell lineages. 20 patients were in CC in CD25+, maintening this CC during the study. 18 patients were found in MC in CD25+ (18/38 MC). 1/18 was in CC in CD3+ TL, and 10/18 were in CC in whole blood. 17/18 were in MC both in CD3+ and CD25+ lymphocytes,
Although no statistical significance is achieved due to the reduced sample size, patients in the first group (% rec higher in activated that in T lymphocytes) tend to achieve CC later and to show higher risk of developing complications such as acute and chronic GVHD, relapse or rejection.

Conclusions
A higher incidence of complications post Allo-SCT (aGVHD, cGVHD, relapse, rejection) in patients with % of recipient in CD25+> % recipient in CD3 at day 30. Chimerism analysis in activated lymphocytes (CD25+) is of great utility after Allo-SCT since it allows beter prediction of complications than standard follow up of whole blood or T lymphocytes.

Disclosures:
No relevant conflicts of interest to declare.
Effect Analysis of Antithymocyte Globulin Versus Antilymphocyte Globulin for Graft Versus Host Disease Prophylaxis in 102 Cases of Allogeneic Hematopoitic Stem Cell.
Authors: Fu Chengcheng , Qu Shiqiang , Depei Wu , Sun Aining , Jin Zhengming , Qiu Huiying , Chang Weirong , Tang Xiaowen , Miao Miao , Ma Xiao , Wang Ying , Xue Shengli , Zhao Ye , Liu Yuejun , Hu Xiaohui , Wang Xiuli , Wu Xiaojin 
Published: October 2019

Abstract
Abstract 4325

Objective
Retrospective analysis the therapeutic and side effect of the rabbit antithymocyte (ATG) versus swine ALG within the preparative regimen of allogeneic hematopoietic transplantation (allo-HSCT) for graft versus host disease (GVHD) prophylaxis.

Methods
Totally 102 patients who had admitted to our hospital and been treated by allo-HSCT with the preparative regimen including ATG/ALG were followed up from June 2002 to June 2008. They were divided into ATG group and ALG group. The allergic reaction, effect of GVHD prophylaxis, transplantation related mortality (TRM), disease free survival (DFS) and relapse rate (RR) of these groups were retrospectively analyzed. Cumulative rate were analyzed by the Kaplan-Meier method and the factors associated with the III?‘‡W AGVHD were analyzed with the COX regression model.

Results
ALG group had more allergic reaction than ATG, but ATG group had more bacteremia and cytomegalovirus (CMV) antigenaemia. The haematopoiesis reconstitution was comparable in two groups. The III?‘‡W AGVHD, two-year TRM,DFS and RR were (40% vs 21%,p=0.028),(54% vs 29%,p=0.039),(41% vs 53%,p=0.174),(10% vs 24%,p=0.306),respectively in ATG/ALG groups. In multivariate analysis,10mg/kg ATG as a protective variable to III?‘‡W AGVHD occurrence(RR=0.53 ;95%CI, 0.38?‘0.71),The CD3+ cell counts of administration was associated with an increased risk for III?‘‡W GVHD(RR=4.43 ;95%CI, 3.87?‘4.95).

Conclusion
10mg/kg ATG significantly decreased the risks for III?‘‡W AGVHD and extensive chronic GVHD(ecGVHD); The lethal infections became the most important cause of death in the ATG group, but the increased risk for infection did not neutralize the reduction of TRM induced by the decrease of severe GVHD.

Disclosures:
No relevant conflicts of interest to declare.