bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Tyrosine Kinase Inhibitor (TKI) in Chronic Myeloid Leukemia (CML) Relapsing After T Cell Depleted Allogeneic Stem Cell Transplantation (SCT)
Authors: Ito Sawa , Battiwalla Minoo , Koklanaris Eleftheria K. , Superata Jeanine , Childs Richard , Barrett A. John 
Published: October 2019

Abstract
Abstract 2762
Although SCT is now uncommon treatment for CML, many patients transplanted for CML have become long term survivors and some continue to relapse late post transplant. It is therefore important to evaluate the management of relapse in CML transplant survivors in the era of TKI treatment. We studied 112 patients with Ph+ CML who underwent HLA identical sibling SCT between 1993 to 2008. The mean age was 36 years (range 13–69). Eighty (71%) were in chronic phase, 17 in accelerated phase, 5 in second chronic phase and 10 in blastic phase. Ninety-nine (88%) received myeloablative conditioning regimen with cyclophosphamide +/− fludarabine and total body irradiation and 13 received a non-myeloablative regimen. GVHD prophylaxis was with cyclosporine. Bone marrow or G-CSF mobilized peripheral blood stem cells from the donor were manipulated to achieve 4-log CD3+ cell reduction ex vivo. Peripheral blood BCR-ABL p210 product was regularly monitored by either double nested PCR (until 2003) or real time PCR (2003 to present). For molecular relapse, patients received donor lymphocyte infusions (DLI) with or without imatinib 400–600mg/day. Patients with hematological relapse received a variety of treatments including second SCT. At a median follow up of 6.2 years, 10 year-relapse free survival and overall survival were 34% and 57% respectively. Overall 49 (43.8%) patients relapsed, 28 with molecular and 22 with hematological relapse. Median time to relapse from HSCT was 379 days (range 16–3718 days). Overall survival was not significantly different between relapsed patients and non-relapsed patients. (10-year OS: 59 % vs 55%, P=0.385). Thirty-five relapsed patients (71.4%) were treated with TKI based therapy. Overall survival after relapse was significantly better after TKI based therapy compared to non-TKI based therapy. (5-year survival after relapse: 78% vs 36%, P=0.004 respectively). The benefit of TKI was greater in hematological relapse (median survival after hematological relapse 1182 days in TKI based vs 72 days in others P=0.025). At 7 years median follow up after relapse, 27 (96.4%) patients with molecular relapse are alive in major molecular remission and 20 (71%) no longer receive TKI. These results show that the outlook for relapse after SCT for CML is favorable in the TKI treatment era and that combination of TKI and DLI can achieve long-term disease free survival post relapse.Figure 1.Overall survival: relapse versus no relapseFigure 1. Overall survival: relapse versus no relapseFigure 2.Overall survival after relapse: TKI based therapy versus othersFigure 2. Overall survival after relapse: TKI based therapy versus others

Disclosures:
No relevant conflicts of interest to declare.
Reduced Response to Stromal Cell-Derived Factor-1(SDF-1) May Lead to Low Expression of p57kip2 in the Bone Marrow of Patients with De Novo Myelodysplastic Syndromes (MDS)
Authors: Zhao Youshan , Chang Chunkang , Guo Juan , Gu Shucheng 
Published: October 2019

Abstract
Abstract 2782

Purpose
To explore the expression of p57 in the bone marrow(BM) of patients with de novo myelodysplastic syndromes(MDS), and the role in MDS pathogenesis and prognosis, as well as the relationship between the expression of p57 and SDF-1/CXCR4 signal. Patients and Methods The expression of p57 and CXCR4 in bone marrow mononuclear cells (BMMCs) of 67 de novo MDS patients (including 46 low-risk, 21 high-risk according IPSS) were measured by real-time quantitative (RT)-PCR. BM CD34+ cell percentage was measured by flow cytometry. Besides, p57 expression was investigated when stromal cell-derived factor-1(SDF-1) was co-cultured with BMMCs from MDS cases and normal control respectively. Furthermore, comparison of p57 expression level before and after treatment in 25 MDS patients was studied. Results P57 expression was significantly decreased in MDS patients when compared to normal controls (p=0.003). Patients with abnormal karyotype showed lower expression of p57 compared to normal karyotype cases (P=0.028). A positive correlation between p57 and CXCR4 expression was investigated (r=0.609, P<0.001), and P57 expression was negatively correlated to BM CD34+ cell percentage (r=−0.393, P=0.008) in MDS patients. Additionally, P57 expression increased after treatment who received hematological response (P=0.016). P57 expression in BMMCs from normal control increased significantly when co-cultured with SDF-1 in vitro, which could be blocked by AMD3100, whereas SDF-1 induced a mild increase of p57 expression in MDS when compared to normal control (P<0.001). Conclusion Low expression of the p57 is common in MDS, which may play a role in pathogenesis and indicate poor prognosis. SDF-1 induced mild p57 expression increasing in MDS patients.

Disclosures:
No relevant conflicts of interest to declare.
Inhibitors of Mtor and PI3K Synergistically Block Plasmacytoma Cell Growth
Authors: Guenther Andreas , Burger Renate , Klapper Wolfram , Staudinger Matthias , Richter Kathrin , Ahrens Tanja , Gramatzki Martin 
Published: October 2019

Abstract
Abstract 2903

Introduction:
Both, the phosphoinositide-3-kinase (PI3K)-AKT pathway as well as its nutrient-dependent downstream target, the mToR (mammalian target of rapamycin) kinase, are essential for the growth and survival of malignant plasma cells. PI3K-AKT can be activated by the loss of the tumor suppressor phosphatase and tensin homolog (PTEN) or by stimulation with cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1). Inhibitors of the mToR pathway like sirolimus, everolimus and temsirolimus are approved for immunosuppression and treatment of renal cell cancer. In fact, they show activity in multiple myeloma patients. However, the clinical activity of mToR inhibitors may be limited by feedback loops in tumor cells that lead to activation of AKT upon inhibition of the rapamycin-sensitive Raptor complex. Selective PI3K inhibitors (Ly294002, NVP-BKM120) as well as dual PI3K-mToR inhibitors (NVP-BEZ235) are in clinical development. Here, the inhibitory effect of a panel of mToR and PI3K inhibitors, alone and in combination, was evaluated in malignant plasma cell lines and primary samples from myeloma patients.

Results:
In five human plasma cell lines, rapamycin, everolimus, Ly294002, NVP-BKM120 and NVP-BEZ235 (kindly provided by Novartis) induced a dose-dependent growth inhibition as measured by MTS assay. Despite the observed strong anti-myeloma activity of the mToR inhibitors rapamycin and everolimus with IC50 values in the nm range, the AKT pathway was activated as indicated by increased phosphorylation at Ser473. This observation was also made in explanted plasma cell tumors of INA-6 xenografted SCID mice that were treated with rapamycin, indicating that this feedback loop is also active in vivo. Therefore, combining mToR and PI3K inhibitors could be an effective strategy to overcome rapamycin-induced AKT activation. In fact, rapamycin in combination with the selective PI3K inhibitor Ly294002 or NVP-BKM120 led to synergistic growth inhibition in plasma cell lines, as calculated by the Calcusyn™ software (Biosoft). This abrogation of AKT activation was also seen in Western blot analysis. Combined treatment also enhanced the induction of apoptosis in cell lines as well as in plasmacytoma cells. Interestingly, the activity of the dual inhibitor NVP-BEZ235 could be even further enhanced by the addition of rapamycin.

Conclusion:
First clinical trials with mToR inhibitors showed anti-tumor activity and an acceptable safety profile in patients with multiple myeloma. The data presented here suggest that a combination of mToR inhibitors with PI3K targeting compounds or the use of dual inhibitors may have a favorable therapeutic potential.

Disclosures:
Guenther: Novartis, Celgene: Consultancy, Research Funding. Gramatzki:Novartis, Celgene: Consultancy, Research Funding.
Clofarabine Containing Conditioning Regimen for Allo-SCT in AML/ALL Patients: A Survey From the Acute Leukemia Working Party of EBMT
Authors: Chevallier Patrice , Labopin Myriam , Buchholz Stefanie , Ganser Arnold , Ciceri Fabio , Lioure Bruno , Faul Christoph , Guillerm Gaelle , Finke Juergen , Huynh Anne , Schubert Joerg , Kolb Hans Jochem , Polge Emmanuelle , Nagler Arnon , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 3004FN2
Clofarabine (CLO), a second generation purine analogue, has demonstrated an efficient anti-leukemia activity while showing a favorable toxicity profile. The aim of our study was to analyse the results of CLO as part of the conditioning regimen prior to allo-SCT for the treatment of patients with AML or ALL. This retrospective multicenter report assessed the outcome of 90 patients who received a clofarabine-containing conditioning regimen allogeneic stem cell transplantation (allo-SCT) for AML (n=69) or ALL (n=21) between November 2006 and September 2010 and reported on the EBMT registry. The median age was 42 years (range: 18–69) at transplant. The majority of patients presented with an active disease at transplant (CR1 n=8; CR2 n=16, active disease n=66). All patients had received a CLO-containing conditioning regimen (RIC n=88; MAC n=2) with the following combinations: CLO/TBI n=27; CLO/Busulfan n=10; CLO/Busulfan/ATG n=32; CLO/others drugs n=21. With a median follow-up of 14 months (range: 1–45), 2-years OS, LFS, relapse incidence, non-relapse mortality (NRM) and chronic GVHD were 28+-5%, 23+-5%, 41+-6%, 35+-5% and 38+-7%, respectively. When comparing AML and ALL patients, OS and LFS were significantly higher for AML patients (OS: 35+-6% vs 0%, p<0.0001); LFS: 30+-6% vs 0%, p<0.0001). Overall, engraftment was achieved in 84% of patients with no difference between AML and ALL patients. Patients achieving CR from an active disease were 66.5% in AML vs 40% in ALL (p=0.06). Also, 2-year chronic GVHD was 35% in AML vs 17% in ALL, p=0.32. In a Cox multivariate analysis, AML was the only factor associated with a better LFS (HR=0.37; 95%CI: 0.21–0.66, P=0.001). We conclude that the use of CLO-containing conditioning regimen for allo-SCT is an effective treatment for high-risk AML patients as CLO seems to provide higher anti-tumor and alloreactivity effects. In high-risk ALL patients, disappointing results are observed. Prospective studies are needed to evaluate the potential role of CLO as part of reduced toxicity conditioning regimens in acute leukemias.

Disclosures:
No relevant conflicts of interest to declare.
Quantitative Monitoring of EBV Viral Load in 222 Hematopoietic Stem Cell Transplant Patients: Risk Analysis and Development of EBV-Associated Post-Transplant Lymphoproliferative Diseases (PTLD)
Authors: Tang Jih-Luh , Yao Ming , Lu Meng-Yao , Ko Bor-Sheng , Huang Shang-Yi , Li Chi-Cheng , Lin Chien-Ting , Hou Hsin-An , Wu Shang-Ju , Chou Wen-Chien , Tsay Woei , Chen Yao-Chang , Tien Hwei-Fang , Jou Shiann-Tarng , Yang Yong-Li , Lin Dong-Tsamn , Lin Kai-Hsin 
Published: October 2019

Abstract
Abstract 3018
Background and Purposes Epstein-Barr virus (EBV)-associated PTLD is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Independent risk factors include use of ATG, acute GVHD, CMV antigenemia, T-depleted graft, and unrelated donor in our previous study. Quantitative real-time polymerase chain reaction (Q-PCR) was developed for early detection and intervention of EBV reactivation to prevent PTLD-related mortality.
Patients and Methods Between Apr 2004 and Oct 2010, EBV viral load in plasma was monitored by Q-PCR in 222 HSCT patients (total 2945 samples) in NTUH. EBV reactivation was defined as > 500 copies/mL in two consecutive assays or > 10-fold elevation than baseline level.
Results EBV reactivation occurred in 50 (22%) patients. The cumulated incidence of EBV reactivation was 28% at 1-year and 32% at 2-year. Median time to EBV reactivation was 40 days (ranges, 26–406) after SCT and median peak EBV-viral load, 10888 copies/ml (ranges, 948–3×107). The risk of EBV reactivation was significantly higher in patients receiving ATG (52% vs. 13%, p< 0.001), use of TBI (58% vs. 26%, p<0.001), mismatched donor (69% vs. 27%, p<0.001), CMV reactivation (44% vs. 19%, p<0.001) in univariate analysis. In multivariate analysis, independent risk factors include: ATG use (HR 5.44, p<0.001), TBI (HR 3.52, p<0.001), and Fludara-based conditioning (HR 3.16, P=0.01). PTLD developed in 8 patients (5%) who didn't monitor EBV viral load regularly, and two were dead.
Conclusions Monitoring of EBV viral load is a sensitive and useful tool in the surveillance of EBV-reactivation. Frequent monitoring in high-risk patients is important to prevent occurrence of EBV-PTLD.

Disclosures:
No relevant conflicts of interest to declare.
Attempting to Classify Prolonged Graft-Versus-Host-Disease According to Monocyte Activation Status in Addition to T-Cell
Authors: Kuroda Rie , Maeba Hideaki , Mase Shintaro , Araki Raita , Fujiki Toshihiro , Koizumi Shoichi , Yachie Akihiro , Nishimura Ryosei 
Published: October 2019

Abstract
Abstract 3045
We have reported that measuring the activation markers and homing molecules on T-cells obtained from human peripheral blood (PB) samples provides useful information for predicting acute graft-versus-host disease (GVHD) severity in affected organs. Although T-cells are major player for developing GVHD, rodent GVHD studies have demonstrated that other immune cells such as monocytes/macrophages, B-cells, and mast cells involved in the pathogenesis of acute and chronic GVHD. We, therefore, evaluated activation markers and homing molecules regularly not only on T-cells but also on monocytes in PB obtained from 31 childhood patients (more than 600 samples at various time points) receiving hematopoietic stem cell transplantation (HSCT) by multicolor flow cytometry. The following markers were used: CD69, CD25, and HLA-DR for T cell activation, CCR4, CCR5, CXCR3, CCR9, and CLA for homing markers. Inflammatory monocytes were defined as CD14dimCD16+ cells or CD14+CD163+ cells. In addition we combined the data of cytokine profiles secreted mainly by T cells such as soluble interleukin 2 receptor, or monocytes such as neopterin, or both such as tumor necrosis factor-α (TNF-α), soluble TNF-αRI, and soluble TNF-αRII. In all cases showing acute GVHD, both T-cell and monocyte activation markers were elevated. Only either T-cell or monocyte activation was not observed in acute GVHD cases. However, we have some interesting results classified according to the status of T-cells and monocytes after day 100: 1) In the cases both T-cells and monocytes were highly activated as shown in Figure 1A, tapering of immunosuppressants led to exacerbation of GVHD, and prolonged administration of the drugs including steroids were needed. However steroid response itself was relatively good. 2) In the cases only T-cells, much less monocytes, were activated as shown in Figure 1B, calcineurin inhibitors were quite effective in improving GVHD. 3) In the cases of sustained chronic GVHD, neither T-cells nor mononytes were activated as shown in Figure 1C. Response to immunosuppressants was quite low. 4) When CD4 T-cell repertoire, not CD8, became normal, tapering of drugs was successful. In all cases successfully tapered immunosuppressive drugs, elevated activation markers of T-cells and monocytes completely returned to same levels of normal volunteers. In conclusion, evaluating the activation markers and homing molecules not only on T-cells but also on monocytes, combined with cytokine profiling, might provide useful information for management of patients with prolonged GVHD.

Disclosures:
No relevant conflicts of interest to declare.
LACK of ASSOCIATION BETWEEN Race and Probability of TRANSPLANT AMONG PATIENTS Referred for Hematopoietic CELL TRANSPLANTATION (HCT) for MULTIPLE Myeloma
Authors: Sharma Manish , Bromberg Michael , Klumpp Thomas R. , Kropf Patricia , Martin Mary Ellen , Emmons Robert V. , Mangan Kenneth F. 
Published: October 2019

Abstract
Abstract 3129

Background:
As documented in recently published large database reviews, race appears to be a barrier to the access to HCT. Hypotheses as to why this may be the case include (but are not limited to): 1. patient preference; 2. delayed time to referral from community physicians to transplant centers; 3. delays in transplant once evaluated by a transplant center; 4. Possible increased prevalence of comorbidities among racial minorities referred for transplant. We attempt to address some of these issues by reviewing our 20-year experience with transplantation for multiple myeloma.

Methods:
We queried our core clinical database for potential associations between race and the following parameters: 1. Median interval between date of diagnosis and date of referral; 2. Median interval between date of initial visit and date of transplant 3. Probability of actually receiving a transplant following formal evaluation by a transplant physician by race; 4. Type of transplant recommended 5. Reasons for not receiving a transplant.

Results:
Between January 1990 and June 2011, 441 patients with multiple myeloma were referred to our center for consideration of HCT, of whom 293 (66%) were Caucasian, 94 (21%) were African American (AA), 27 (6%) were of unknown race, and 27 (6%) were of other races. The median interval from diagnosis to referral for transplant for AA patients was 145 days, versus 137 days for Caucasian patients (p=0.32). Fifty-three of the 94 AA patients (56%), versus 157 of the 293 Caucasian patients (54%) have received at least one transplant to date (p=0.72). The median interval between the date of the initial visit to our transplant center and the occurrence of an initial transplant was 120 days for AA, versus 150 days for Caucasians (p=0.39). The probability of being transplanted on an allogeneic or hybrid (auto-allo) initial transplant protocol was 0% for AA making it to transplant vs 6% for Caucasions making it to transplant (p=0.07). Reasons for not receiving a transplant are indicated in Table 1 (global p-value = 0.94).

Conclusions:
African American and Caucasian patients with myeloma have similar intervals from diagnosis to referral, similar intervals from referral to transplant, and are equally likely to actually receive a transplant once referral to the transplant center took place. Therefore, the reported barrier to transplantation for myeloma patients appears to be prior to referral to the transplant center.

Disclosures:
No relevant conflicts of interest to declare.
An Approach for Tailoring Diverse Therapeutic Inducers of Fetal Globin to Genetic Modifier Profiles,
Authors: Perrine Susan P , Chui David H.K. , Sangerman Jose I , Boosalis Michael S , Faller Douglas V 
Published: October 2019

Abstract
Abstract 3188
The clinical severity of the beta thalassemia syndromes and hemoglobinopathies can be dramatically modified by up-regulation of basal fetal globin expression through co-inheritance of 3 influential genetic modifiers, or by fetal globin-inducing therapeutics. One approved therapeutic, Hydroxyurea (HU), benefits some patients, but does not reduce anemia enough to achieve transfusion-independence in many thalassemia patients, and additional HbF-enhancing therapies are needed which can be applied in combination regimens without added toxicity. A challenge to successful application of HbF-inducing therapies is the broad genetic heterogeneity, which produces variable baseline HbF levels, and, to date, unpredictable responsiveness to therapeutics among individual patients. Therapies tailored to genetic modifiers (QTL) which modulate baseline HbF levels would allow rational treatment selection for specific subsets of patients. GWAS screening of 1000 patients in diverse populations, and analyses of patients enrolled on two recent clinical trials in sickle cell disease and beta thalassemia, demonstrated that modifiers in the 3 most influential QTLs which increase HbF or F-cells occur commonly, in 30–50% of patients, with BCL11A polymorphisms occurring in 20–30%. Using molecular modeling and high-throughput screening of chemical libraries, we recently discovered 8 therapeutics (6 clinical-stage or approved) which enhance HbF expression through different mechanisms, including displacement of a repressor complex containing HDAC-3 (RB7) or suppression of BCL11A mRNA (MS-275). Two pan-HDAC inhibitors (Butyrate and MS-275) profoundly decrease the 3 BCL11A isoforms by 80–100% in normal erythroid progenitors, while other HDAC inhibitors (LBH389, SAHA) have no effect or even increase BCL11A expression. Decreases in BCL11A provide a favorable effect, similar to the BCL11A QTL, increasing both baseline HbF levels and responsiveness to HbF-inducing drugs. Other inducers (DLT, Benserazide, NSC95397, RB16, ST20) induce the gamma-globin promoter without epigenetic effects. MS-275, DLT, and RB7 increase the promoter activity by 5–6 fold in normal progenitors, while prior generation short chain fatty acid agents induced by 2-fold. This small but diverse therapeutic pipeline, encompassing different mechanisms of action, now allows: 1) epigenetic and/or non-epigenetic gamma-globin induction; 2) significantly higher induction than prior generation inducers; and 3) potential drug combinations which may benefit those patients who do not have favorable QTL polymorphisms. Individual therapeutics can now be investigated in genotyped subjects to provide a basis for tailoring specific inducer combinations to QTL profiles, offering potential for higher therapeutic benefit.

Disclosures:
No relevant conflicts of interest to declare.