bluuebunny/crossref_metadata_2025 huggingface dataset:
Elimination of Established Risk-Factors in Primary Central Nervous System Lymphoma - Impact of High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantaion - a Multicenter Retrospective Analysis
Authors: Schorb Elisabeth , Kasenda Benjamin , Atta Johannes , von Bubnoff Nikolas , Elter Thomas , Hess Georg , Krause Stefan W. , Morgner Anke , Stephan Kaun , Fritsch Kristina , Finke Jürgen , Illerhaus Gerald
Published: October 2019

Abstract 3089

Introduction:

High-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) demonstrated high efficacy in the treatment of newly-diagnosed primary CNS lymphoma (PCNSL) in eligible patients (pts). Prognosis of PCNSL is associated with several clinical and histopathological risk factors (RF). Early complete response (CR) during chemotherapy (CHT) was recently reported to be an additional independent prognostic factor in pts undergoing polychemotherapy without HDT+ASCT. In this analysis, we examined the extent to which known RF determined survival in pts who were treated with HDT-ASCT. We additionally investigated the impact of HDT-ASCT specific factors (e.g. conditioning regimen) on survival.

Pts. and Methods:

Retrospective multicenter (N=10) analysis of 100 pts with untreated PCNSL who underwent HCT-ASCT with or without whole brain radiotherapy (WBRT). We used univariate and multivariate Cox regression analysis to investigate the prognostic impact of the following factors on overall survival (OS): early CR, age, performance status, involvement of deep brain structures, and LDH serum level and thiotepa dose. Until now data of 82 pts have been analyzed.

Results:

Median age at diagnosis was 53 years (range 23–69), the majority was male (67%). After a median follow-up of 58 months median OS was reached after 121 mo (range 3–149 mo). Before HDT+ASCT, 48/82 pts (58%) did not achieve CR (35 PR, 3 SD, 10 PD). After HDT+ASCT, 54/82 pts (66%) were in CR and altogether 39% of the pts were irradiated after HDT+ASCT. Of note, of those pts with PD before HDT+ASCT, 5/10 achieved CR after HDT+ASCT without WBRT. Overall, at the time of last follow-up, 24 pts have died. Of the surviving pts, 50 were in CR (86%), 2 in PR (3%), 2 in SD, and 2 developed progression /relapse. None of the established RF (age, performance status, involvement of deep brain structures, and LDH serum level) significantly distinguished outcome with regard to OS in uni and multivariate analysis. Additionally, neither CR before HDT-ASCT, nor sex nor the dose of thiotepa (10mg versu 20mg/m2) was associated with decreased OS.

Conclusion:

We conclude that HCT+ASCT is able to neutralize established RF in PCNSL. HDT+ASCT is a high-efficient treatment option independently of remission rate before entering HDT. New prognostic factors for pts eligible for HCT-ASCT have to be identified to guide therapy and care for PCNSL pts and to define stratification criteria for future trials. Most recent follow up will be presented.

Disclosures:

No relevant conflicts of interest to declare.
Autologous Stem Cell Transplantation (ASCT) for Enteropathy-Associated T-Cell Lymphoma (EATCL): A Retrospective Study of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Jantunen Esa , Boumendil Ariane , Rambaldi Alessandro , Schapira Marc , Luan Jian Jian , Gramatzki Martin , Lenhoff Stig , Oberg Gunnar J. , Dreger Peter , Sureda Anna ,   on behalf of the Lymphoma WP of the EBMT
Published: October 2019

Abstract 3115

Background:

EATCL is a rare subtype of peripheral T-cell lymphoma frequently observed in patients with a history of celiac disease. EATCL is characterized by poor prognosis when treated with conventional chemotherapy with only 10–20 % of long-term survivors. Limited data are available on feasibility and efficacy of stem cell transplantation in this lymphoma entity.

Patients and methods: The database of the EBMT was used to identify patients with EATCL who had received autologous and/or allogeneic stem cell transplantation in 2000–2007. All centres reporting these patients were contacted to receive confirmation to histopathology report/pathology review and to obtain information in regard to treatment prior to stem cell transplantation and more recent follow-up data.

Results:

Altogether 85 patients with EATCL were identified. Seventy-three patients had received ASCT and 12 patients allogeneic SCT. Histological report/review with additional follow-up data was available from 22 ASCT treated patients which are reported here. There were 14 females (64 %) and eight males with a median age of 55 years at the time of transplant. Half of the patients had a history of coeliac disease. The median number of treatment lines before ASCT was 1 and 50 % of the patients were in the first remission at the time of ASCT. BEAM was the most commonly used high-dose regimen (17 pts, 77 %) and all patents received blood stem cell grafts. The median time from the diagnosis to ASCT was 6 months. The median follow-up time for living patients was 45 months from ASCT. During the follow-up relapse has been observed in 13 patients (59 %), the median time was only four months from ASCT. The median disease-free survival and overall survival were nine months and 15 months, respectively. Two-year overall survival, disease-free survival, cumulative incidence of relapse and non-relase mortality (NRM) was 45%, 40%, 55% and 4%, respectively.

Conclusions:

ASCT is feasible in selected patients with EATCL with a low NRM. Of transplanted patients 40 % remained disease-free beyond 2 years. This seems to be superior when compared to historical experiences although selection factors should be taken into account. ASCT is a treatment option in transplant eligible EATCL patients who respond to initial therapy.

Disclosures:

No relevant conflicts of interest to declare.
Is There a Difference in Treatment Patterns Among Follicular Lymphoma Patients Receiving Care in the Outpatient Hospital Versus the Community Clinic Setting?
Authors: Satram-Hoang Sacha , Reyes Carolina
Published: October 2019

Abstract 3134

Introduction:

No studies have addressed whether the site of care involved in the treatment of patients with follicular lymphoma (FL) affects the delivery of appropriate treatment for this condition. We investigated the differences in treatment patterns between two sites of care: the outpatient hospital (OH) and the community clinic (CC) setting.

Methods:

Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort analysis of 4225 FL patients diagnosed between January 1, 1998 to December 31, 2007, >66 years, enrolled in Medicare Part A and B, and received initial treatment with rituximab (R), chemotherapy (CT), or R+CT. Chi-square test for categorical variables and ANOVA or t-test for continuous variables were used to assess differences in patient and disease related characteristics by site of care. Kaplan-Meier curves and corresponding log-rank test were used to compare time to initial treatment by site of care.

Results:

There were 3149 CC patients and 541 OH patients. The mean age was 75 years, 55% were female, and 92% were white. In general, the demographic and clinical characteristics were balanced between both sites of care, with the exception of disease stage at diagnosis where patients treated in the OH setting were more likely to be diagnosed with stage IV disease (39% vs. 34%; p<.05). Overall, 29% of patients received CT, 25% received R and 45% received R+CT. The mean time to treatment initiation was generally shorter in the CC (10 months versus 11 months) across all treatment categories (log rank p=0.1961). In the CC, the mean time to treatment initiation was 10 months for CT, 14 months for R, and 8 months for R+CT. In the OH, the mean time to treatment initiation was 12 months for CT, 16 months for R and 9 months for R+CT. Duration of treatment was similar in the CC and OH for CT and R+CT, but R had a slightly longer duration in the CC (median = 66 days) compared to the OH (median =59 days). There were more treatment cycles delivered in the CC compared to the OH. In the CC, 61% of patients received <6 cycles, 21% received 6–8 cycles and 18% received >8 cycles. In the OH, 77% received <6 cycles, 12% received 6–8 cycles and 11% received >8 cycles. Compliance with the R+CT dosing schedule (once every 3 weeks for up to 8 cycles) was higher in the CC (54%) compared to the OH (34%) cohorts (p<.0001).

Conclusions:

This observational study showed that patients treated in the OH setting tend to have longer time to treatment initiation, less cycles across all regimens, and were less likely to receive a compliant R+CT dosing schedule for FL compared to patients in the CC. These results suggest an opportunity to improve delivery of treatment to optimize outcomes in different treatment settings.

Disclosures:

Satram-Hoang: Genentech, Inc: Consultancy. Reyes:Genentech, Inc: Employment.
Anemia of Chronic Kidney Disease – Hepcidin Is a Predictor,
Authors: Gopal Srila , Madhumathi Rao , Ashby Damien R
Published: October 2019

Abstract 3182

Methods:

We carried out a prospective study of 167 patients with CKD stages 1 to 4 followed over a two year period. Using a competitive radioimmunoassay, we measured plasma hepcidin at baseline and studied its association to baseline clinical parameters, as well as the development of anemia and need for ESA over a two year follow up period. Exclusion criteria included any erythropoietin stimulating agent (ESA) therapy at baseline. Variables were log transformed to satisfy normality assumptions.

Results:

Median (P5-P95) Glomerular filtration rate (GFR) was 42 (20–109) ml/min and 45% were anemic at the time of enrollment by KDOQI criteria, 11 % (18/167) having severe anemia. In patients with CKD, Hepcidin was positively correlated with serum iron (Spearmans rho,p:serum iron,0.22,0.005) and negatively correlated to EPO levels (Spearmans rho,p:-0.23,0.003 vss.-0.55,0.002). Hepcidin levels at baseline were not significantly associated with GFR, hemoglobin or CRP, and did not differ according to diabetes or ethnicity. Though Hepcidin levels did not differ by the presence of anemia at baseline, they were significantly higher among patients who developed severe anemia (n=23) at the end of the first year (40 ng/mL vs. 25 ng/mL, p<0.01). A total of 13 patients initiated ESA during follow up; a 2-fold higher hepcidin was associated with a hazard ratio of 2.25 (95% CI 0.89 to 5.62) for the need to initiate ESA therapy (Fig 1), adjusted for GFR.

Conclusion:

High hepcidin, unrelated to inflammation, is a predictor for the development of anemia and the need for initiation of ESA therapy in CKD patients. The role of Hepcidin as a therapeutic target in the anemia of CKD needs further study.

Disclosures:

No relevant conflicts of interest to declare.
Transplantation of Peripheral Blood Cells As Compared with Bone Marrow From HLA-Identical Related Donors Is Associated with Superior Long-Term Outcomes
Authors: Mielcarek Marco , Storer Barry , Martin Paul J. , Negrin Robert S , Forman Stephen J. , Flowers Mary E.D. , Inamoto Yoshihiro , Chauncey Thomas , Storb Rainer , Appelbaum Frederick R. , Bensinger William I
Published: October 2019

Abstract 319

Between 1996 and 1999, 172 patients (median age, 42; range, 12–55 years) with hematologic malignancies were randomly assigned to receive either bone marrow (BM) or G-CSF-mobilized peripheral blood stem cells (PBSC) from HLA-identical siblings after myeloablative conditioning. Early results of this 3-institution study (Bensinger et al., NEJM; Vol. 344, No .3, 2001) showed that the use of PBSC, compared with BM, was associated with significantly superior rates of 2-year overall and disease-free survival. To assess the long-term impact of evolving chronic graft-versus-host disease (GVHD) on outcomes, we analyzed follow-up data from all participating patients.

Our follow-up analysis showed sustained protection against recurrent malignancy associated with the use of PBSC compared with BM (Figure 1). The estimated 10-year probability of relapse was 20% with PBSC and 32% with BM (adjusted hazard ratio [HR] for BM versus PBSC, 2.22; 95% confidence interval [CI], 1.2–4.1; p=0.01). In contrast to the earlier analysis, the hazard of overall mortality for all patients was not significantly different between the two groups. However, there was a trend toward superior overall survival associated with use of PBSC, which was attributable to increased mortality with use of BM in the subgroup of patients with high-risk cancers (n=80; HR, 1.42; 95% CI, 0.8–2.5; p=0.21). The 2-year cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment was 48% with PBSC and 37% with BM (HR, 0.86; 95% CI, 0.5–1.4; p=0.55). We found no evidence that the use of PBSC prolonged the duration of systemic immunosuppressive treatment among patients with chronic GVHD (HR, 1.21; 95% CI, 0.6–2.6; p=0.64). In conclusion, among patients who had hematologic malignancies treated with myeloablative conditioning and hematopoietic cell transplantation from HLA-identical sibling donors, the use of PBSC conferred greater long-term protection against recurrent malignancy than BM without causing excess chronic GVHD-related mortality.

Disclosures:

No relevant conflicts of interest to declare.
Different Patterns of Myocardial Iron Overload by T2* Cardiovascular MR As Markers of Risk for Cardiac Complication in Thalassemia Major,
Authors: Meloni Antonella , Pepe Pasquale , Keilberg Petra , Favilli Brunella , Positano Vincenzo , Capra Marcello , Caruso Vincenzo , Cianciulli Paolo , Filosa Aldo , Zuccarelli Angelo , De Franceschi Lucia , Lombardi Massimo , Pepe Alessia
Published: October 2019

Abstract 3190

Introduction:

Cardiac complications mainly related to myocardial iron overload (MIO) remain the main cause of morbidity and mortality in thalassemia major (TM). Thalassemia cardiomyopathy is treatable and partly reversible if appropriate chelation therapy is instituted in time. The validated multislice multiecho T2* Cardiovascular Magnetic Resonance (CMR) technique has permitted to quantify segmental and global myocardial iron burden detecting different patterns of iron overload. The aim of this study was to verify the risk of cardiac complications related to different patterns of MIO in a large cohort of TM patients.

Methods:

We considered 812 TM patients for who CMR and cardiac data were collected in a central data base. Three short-axis views (basal, medium, apical) of the left ventricle were acquired using a multislice multiecho T2* sequence. Using a previously validated software the 16 segmental T2* values and the mean global heart T2* value were provided. A conservative cut off of 20 ms was considered the limit of normal for the segmental and global T2* values.

Results:

We identified 4 groups of patients: group I (17%) with homogeneous MIO (all segments with T2*<20 ms), group II (12%) with heterogeneous MIO (some segments with T2*<20 ms and others with T2*≥20 ms) and global heart T2*<20 ms; group III (29%) with heterogeneous MIO and global heart T2*≥20 ms; group IV (42%) with no MIO (all segments with T2*≥20 ms). The clinically relevant findings in the 4 groups are summarized in Table 1. The percentage of patients with cardiac complications was significantly different in the 4 groups (P<0.0001). In particular, the percentage of patients with heart failure was significantly different in the 4 groups (P<0.0001). No significant differences were found among groups in the percentage of arrhythmias and pulmonary hypertension. Odds Ratio for cardiac complications was 1.7 (1.0–2.7 OR 95% CI; P=0.041) for patients with homogeneous MIO versus patients with no MIO. Odds Ratio for heart failure was 2.3 (1.3–4.2 OR 95% CI; P=0.004) for patients with homogeneous MIO versus patients with no MIO and 2.2 (1.1–4.2 OR 95% CI; P=0.020) for patients with heterogeneous MIO and global heart T2*<20 ms versus patients with no MIO.

Conclusions:

Homogeneous MIO predicts a significantly higher risk to develop cardiac complications, especially heart failure, suggesting an intensive chelation therapy in this group of patients.

Disclosures:

No relevant conflicts of interest to declare.
Correlation of NT-ProBNP Levels and Cardiac Iron Concentration in Patients with Transfusion-Dependent Thalassemia Major,
Authors: Kattamis Antonios , Apostolakou Filia , Delaporta Polyxeni , Papassotiriou Ioannis
Published: October 2019

Abstract 3192

Background:

Iron-induced cardiotoxicity remains the leading cause of morbidity and mortality in patients with transfusion-dependent thalassemia major (TM). Heart failure in these patients, which may be reversible but has a poor prognosis, is characterized by myocardial iron deposition-related early diastolic dysfunction. N-terminal-proBNP (amino-terminal) (NT-proBNP) is a sensitive biomarker for the detection of asymptomatic left ventricular (LV) dysfunction.

Patients and Methods: In this study, we prospectively evaluated plasma NT-proBNP levels determined on the Roche cobas e411immunoassay analyzer using electrochemiluminescence technique in 187 adult patients aged 19–54 years with TM. Possible correlations with the proposed recently cardiac iron concentration [Fe] based on an equation derived from heart T2* assessment by MRI: [Fe] = 45.0 × [T2*]−1.22 with [Fe] in milligrams per gram dry weight and T2* in milliseconds (Carpenter et al Circulation 2011;123;1519–1528) were explored.

Results:

143 patients had low cardiac hemosiderosis, defined as [Fe] < 1.1 mg/g dry weight, corresponding to T2*>20 milliseconds and 44 patients with high cardiac hemosiderosis, defined as [Fe] >1.2 mg/g dry weight. The main results of the study showed that: a) NT-proBNP levels were markedly increased in thalassemic patients (152.2 26.4 pg/mL, ranged from 6.0 – 1336.0 pg/mL compared to normal control levels 40.1 19.7 pg/mL, p<0.001, b) NT-proBNP levels were significantly higher in high cardiac hemosiderosis patients compared to low cardiac hemosiderosis patients (185.1 78.2 vs 128.9 20.2 pg/mL, p<0.05), c) NT-proBNP levels correlated with [Fe] values (r= 0.387, p<0.001). This correlation was significant in patients with high cardiac hemosiderosis (r= 0.520, p<0.001), but not in patients with low cardiac hemosiderosis (p>0.1), and d) no significant correlation was found between NT-proBNP levels and left ventricular ejection fraction (LVEF) values, (p>0.3).

Conclusions:

Our study demonstrate for first time the significant association of NT-proBNP levels and cardiac iron concentration in patients with TM linking blood chemistry and imaging techniques. Multicenter studies of these parameters during iron chelation therapies are needed to validate their association and further exploit its clinical use.

Disclosures:

Kattamis: Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: Wording to add.
The Timing of Acute Renal Failure Strongly Affects Survival of Immunoglobulin Light Chain (AL) Amyloidosis Patients Undergoing Autologous Stem Cell Transplantation,
Authors: Leung Nelson , Kumar Shaji , Dispenzieri Angela , Lacy Martha Q , Buadi Francis K , Hayman Suzanne R , Dingli David , Hogan William J , Gastineau Dennis A. , Glavey Siobhan V , Gertz Morie A
Published: October 2019

Abstract 4120

Introduction:

Autologous stem cell transplantation (ASCT) remains an effective treatment for immunoglobulin light chain (AL) amyloidosis but its high treatment related mortality is a concern. The development of acute renal failure can strongly affect the survival of these patients. This study looks at the impact of the timing of dialysis initiation on the overall survival (OS). Methods: AL patients who underwent ASCT from 3/96 to 1/10 were selected. Patients were placed into 4 groups: I - never dialyzed, II - initiated dialysis prior to ASCT, III - dialysis began within 30 days of ASCT and IV - dialysis was started after 30 days of ASCT. Results: Four hundred and ten patients were selected for study and 75 (18.3%) received dialysis. Baseline characteristics are listed in Table 1. In univariate analysis, serum creatinine (Scr) and b-2 microglobulin (b2m) were associated with dialysis post-ASCT. Both became non-significant in the multivariate model suggesting they are co-dependent. Dialysis had a strong influence on survival, p < 0.001 (Fig 1). This was most evident when dialysis was started after ASCT (group III (p = 0.003) and IV (p = 0.004)), but not before (II, p = 0.19).To explore the interactions of dialysis with cardiac biomarkers in their relationship with OS, cardiac troponins T (cTnT) and N terminal-pro-brain natriuretic peptide (NT-pro-BNP) were analyzed with timing of dialysis in a proportional hazard model. Timing of dialysis (p < 0.001), cTnT (p = 0.03) and NT-pro-BNP (p = 0.03) all were associated with OS. Using Receiver Operator Characteristic (ROC) curves, best cut points were chosen for cTnT (0.01 ng/ml) and NT-pro-BNP (1350 pg/ml) for survival. When treated as categorical variables, the proportional hazard model found that only NT-pro-BNP (p = 0.002) and timing of dialysis (p < 0.001) were independent predictors of OS but cTnT had loss its significance (p = 0.07). Using Kaplan Meier method, dialysis was a significant risk factor in patients with low cTnT and both high and low NT-pro-BNP (p < 0.001) but not in patients with elevated cTnT (p = 0.25). Discussion: The timing of acute renal failure strongly affects the OS of AL patients undergoing ASCT. In our study, patients who started dialysis prior to ASCT did not have an inferior OS compared to patients who never needed dialysis. On the other hand, starting dialysis after ASCT significantly shortened OS. The timing of dialysis was an independent predictor of OS even when combined with cardiac biomarkers. NT-pro-BNP appears to be the stronger marker when timing of dialysis is considered in the multivariate analysis.

Disclosures:

No relevant conflicts of interest to declare.
Allogeneic Cytokine-Induced Killer Cells Kill Dendritic Cells Efficiently Resulting in Less Graft-Versus-Host Disease
Authors: Mase Shintaro , Maeba Hideaki , Kuroda Rie , Araki Raita , Fujiki Toshihiro , Yagita Hideo , Yachie Akihiro , Koizumi Shoichi , Nishimura Ryosei
Published: October 2019

Abstract 4308

Cytokine-induced killer (CIK) cells are ex vivo–expanded T lymphocytes expressing both natural killer (NK)– and T-cell markers. We have reported that adoptive transfer of allogeneic CIK cells in a murine model caused minimal graft-versus-host disease (GVHD) with retention of antitumor activity mediated by NKG2D, which is an activating receptor expressed on NK cells. The mechanism of suppression of GVHD after allogeneic bone marrow transplantation is, in part, due to the abundant production of IFN-gamma from the CIK cells, which has protective effect against GVHD. We have also demonstrated that allogeneic CIK cells displayed a significant lower acquisition of homing molecules, required for the entry of inflamed and GVHD target organs (a4b7, CCR9, E-selectin, CXCR3, and CCR5) and a higher susceptibility to apoptosis compared to allogeneic splenocytes. There also might be some causes other than we mentioned above. Host residual dendritic cells (DCs) have a crucial role for initiating GVHD reaction, because they present recipient alloantigens to donor T cells, which finally attack on recipient tissues. Murine alloreactive NK cells, even when infused in large numbers, do not cause GVHD in the mouse by killing recipient DCs. Similarly, it remains a possibility that the reduced GVHD in CIK cells receiving mice was due to the elimination of residual host DCs by CIK cells. To test this, DCs generated from bone marrow cells with the addition of GM-CSF were used for 51Cr release cytotoxicity assays as target cells. Although autologous CIK cells (Balb/c) had relatively strong killing activity against DCs (Balb/c), allogeneic CIK cells (B6) had much more killing activity even from at a 5:1 effector-target ratio as shown below. Allogeneic CD8+ cells did not show any killing activity against DCs. In addition, killing activity against DCs did not changed with/without adding NKG2D blocking antibody, suggesting that other mechanisms to undergo cell lysis should exist in CIK cells in addition to NKG2D/NKG2D ligand system, which are mainly involved in tumor eradication. To further evaluate whether allogeneic CIK cells kill host DCs in vivo, lethally irradiated Balb/c recipients were given BM (B6) with CIK cells or splenocytes to compare the percent of residual host-typed DCs in the spleen five days after bone marrow transplantation. Percent of host-typed DCs tended to be lower in the mice receiving alllogeneic CIK cells compared with those receiving fresh splenocytes or BM alone. In conclusion, allogeneic CIK cells caused less GVHD due in part to elimination of host DCs.

Disclosures:

No relevant conflicts of interest to declare.
Successful Unrelated Bone Marrow Transplantation for Three patients with Amegakaryocytic Thrombocytopenia with Radio-Ulnar Synostosis (CTRUS) in Japan
Authors: Ohtsuka Yoshitoshi
Published: October 2019

Abstract 4510

Objectives:

Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (CTRUS) is a rare inherited bone marrow failure syndrome that has the potential to progress to pancytopenia that behaves like TAR.The diagnosis of CTRUS is made later when pronation-supination of the forearm is discovered to be restricted. Hox 11a was reported to be abnormal in the initial cases but at least 1 other case did not have this abnormality. Hematopoietic stem-cell transplantation (HSCT) is presently the only curative treatment approach. We used a reduced intensity transplantation regimen in CTRUS patient with aplastic anemia.We reported two cases of CTRUS who underwent successful unrelated bone marrow transplantation.

Methods:

Conditioning regimen consisted of Flu, ATG, CY, and TLI (300cGy). For GVHD prophylaxis, all received FK506 and short course MTX. The number of transplanted nucleated cells were 6.35, 6.8, 5.8 ×108/kg. All patients underwent an alternative donor SCT. The each age at transplant for patients were 8, 18,11 months.

Results:

The patients had rapid and durable engraftment at day +13, +16, +23 with minimal complications.No regimen related toxicity were observed, and no viral re-activation (CMV, EBV, VZV) were seen. Each patients developed acute GVHD involving skin only (grade I - II).One of three patients developed chronic GVHD (skin only limited type). All patients are alive and transfusion independent with each follow-up time of 61, 56, 33 months.

Conclusions:

Allo-BMT from an unrelated donor is a curative and suitable approach for patients with amegakaryocytic thrombocytopenia with radio-ulnar synostosis (CTRUS), reduced intensity conditioning might be a feasible approach to stem-cell transplantation in patients who do not have a sibling donor. In our three cases, the mutation in exon 2 of HOXA11 gene was not found, which may suggest that these cases are possibly a subtype of this syndrome.Careful clinical course watching is required if another complications or the disease relapse will occur again.

Disclosures:

No relevant conflicts of interest to declare.
Reversal of Multidrug Resistance by Magnetic Fe3O4 Nanoparticle Loading Daunorubicin and Bromotetrandrine in Nude Mice Bearing Leukemia Tumor Xenografts
Authors: Ren Yan-Yan , Chen Bao-An , Cai Xiao-hui , Liu Ran , Wu Wei-wei
Published: October 2019

Abstract 5013

PURPOSE:

This paper was to study the reverse effect of magnetic Fe3O4 nanoparticle loading daunorubicin and bromotetrandrine(Fe3O4-MNPs/DNR/BrTet) with the conduction of alternating magnetic field in nude mice bearing K562/A02 xenografts, and to provide theoretic evidence for the clinical application of malignancies as a new treatment.

METHODS:

20 BALB/c nude mice with equivalent different gender, which were age-matched (four weeks of age) and weight-matched (16-22g), were randomly divided to 5 groups. The subclone of K562/A02 cells was inoculated subcutaneously into the oxter of all athymic nude mice. Group 1 each mouse was given 0.9% normal saline 0.2ml/once; Group 2, DNR 1mg/kg and BrTet 1mg/kg; Group 3, DNR 1mg/ml and BrTet 10mg/kg; Group 4, Fe3O4-MNPs 10.5mg/kg; Group 5, Fe3O4-MNPs/DNR/BrTet 12.5mg/kg(DNR: BrTet: Fe3O4-MNPs=1:1:10.5). After being delivered in an alternating magnetic field for 40minutes, the incidence of growth characteristics of mice, and volume of tumor were observed for 14 days. At the 14th day, the mice were sacrificed by cervical dislocation to detect all tumors by weight measuring, Hematoxylin and eosin staining, Western-blot and so on.

RESULTS:

The average tumors' weight and volume was much less in Group 4 and 5 than others, there were significantly different (P<0.05). The results of hematoxylin and eosin staining showed that obvious necrosis area was observed in Group 4 and Group 5, and there was less necrosis in the Group 3 compared with the other groups. The Western-blot showed the expression of caspase-3 and bax in Group 4 and 5 increased two times than other groups, while the expression of bcl-2 decreased to half of others.

CONCLUSION:

Fe3O4-MNPs/DNR/BrTet can reverse multidrug resistance efficiently in vivo through inducing apoptosis, which may be related to the upregulating of bax and downregulating of bcl-2. Moreover, our synthesized magnetic Fe3O4 nanoparticle may be as a high efficiency and security medicine carriers to treat malignancies.

Disclosures:

No relevant conflicts of interest to declare.
Changes in Gene Expression Profiles in Patients with 5q- Syndrome Caused by Lenalidomide Treatment
Authors: Belickova Monika , Cermak Jaroslav , Vesela Jitka , Cechova Eliska , Zemanova Zuzana , Michalova Kyra , Dostalova Merkerova Michaela , Jonasova Anna
Published: October 2019

Abstract 5023

A direct effects of lenalidomide on gene expression in 5q- patients was studied using HumanRef-8 v2 Expression BeadChips (Illumina). Expression profiles of 6 patients (before treatment and at the time of the first erytroid response) and 6 healthy controls were investigated from CD14+ monocytes of peripheral blood. Differentially expressed genes were identified by Significance Analysis of Microarrays (SAM). Simultaneously, selected genes (TNF, JUN, IL1) were monitored in the course of treatment using Real-Time PCR with Taqman Gene Expression Assays.

A comparison of gene expression levels before and during lenalidomide treatment revealed 97 differentially expressed genes (FC >2; p<0.05) related to following biological processes: immune response (16 genes), inflammatory response (11 genes), response to bacteria (8 genes), anti-apoptosis (7 genes), regulation of MAP kinase activity (5 genes), oxygen transport (4 genes), and regulation of cell proliferation (11 genes). An overexpression of a number of cytokines (e.g. TNF, IL8, IL1B, CCL3L, CXCL2, and TNFAIP3) was detected in patients before treatment, after lenalidomide administration expression of the majority of the up-regulated cytokine genes decreased to the control baseline level. Detected overproduction of the cytokines in 5q- syndrome may lead to an increased apoptosis of hematopoietic progenitor cells and together with excessive oxidative stress may contribute to the damage the hematopoietic niche. In the same manner, untreated patients showed suppressed expression of two genes (CXCR4, CRTAP) which play an important role in the stem cell niche. After treatment, we detected increased expression of these genes. Both the observations might explain favorable effects of lenalidomide on the bone marrow stroma defect seen in 5q- syndrome. On the other hand, a substantial increase of the ARPC1B gene (an activator and a substrate of Aurora A) expression was detected after lenalidomide treatment. Since overexpression of Aurora A leads to polyploidy and chromosomal instability, ARPC1B might play a role in the disease progression observed in some patients treated with lenalidomide.

To conclude, described changes in genes expression may contribute to identification of the pathways affected by lenalidomide and to the explanation of some effects of this drug that have not been fully understood yet.

Supported by grants NS/9634 MZCR, UHKT2005 00023736, MSM0021620808 and COST EUGESMA

Disclosures:

No relevant conflicts of interest to declare.
The Clinical and Biologic Significance of Thrombocytosis in Myeloid Disorders
Authors: Zikria Jennifer , Galili Naomi , Tsai Wei Yann , Raza Azra
Published: October 2019

Abstract 5031

Purpose

Myelodysplastic syndromes (MDS) are typically characterized by peripheral blood cytopenias. However, some MDS is associated with thrombocytosis rather than thrombocytopenia. The prognostic significance of thrombocytosis is unknown. The purpose of this study was to compare the overall survival (OS) of MDS patient based on their platelet count.

Methods

We reviewed a prospective cohort of patients with myeloid disorders from 1994 to present. Out of the 1,654 unique patients, 102 had platelets > 450,000 (5.7%) throughout their disease; 88 had stable platelet counts, 6 had varying platelet counts, and 12 were excluded because of missing information.

OS of patients with thrombocytosis (>450,000 platelet count) was compared to FAB/WHO case matched patients with normal (100–450 platelet counts) and low platelet counts (<100 platelet count). OS was evaluated using unadjusted and adjusted Cox proportional hazard regression modeling with all-cause mortality as the dependent variable and demographic and clinical characteristics as independent variable; adjusted for IPSS risk group at first sample collection and age-adjusted mortality. The OS curves were constructed using Kaplan-Meier methods.

Results

The worst OS occurred in patients with unstable platelet counts, followed by thrombocytopenia, and then thrombocytosis. Thrombocytopenia was associated with a poorer prognosis than thrombocytosis, although not significantly worse. Patients with normal platelet counts had the best prognosis. Thrombocytosis significantly reduced OS compared to patients with normal platelet counts (HR 1.44, p= 0.04) using adjusted Cox analysis. Thrombocytopenia had significantly reduced OS compared to patient with normal platelet counts (HR 1.8, p=0.0002) using unadjusted Cox regression. Patients who had unstable platelet counts had significantly the worst OS (HR 5.7, p= 0.0009). Both older age at diagnosis and IPSS independently and significantly affected OS.

Conclusion

MDS patients with both thrombocytopenia and thrombocytosis have significantly decreased OS compared to normal platelet counts.{abspict}

Disclosures:

No relevant conflicts of interest to declare.
Low Expression of RPS14 Accompanied with p53-Independent Over-Apoptosis in Myelodysplastic Syndromes Patients with 5q- Aberration
Authors: Wu Lingyun , Zhang Yin , He Qi , Zhang Qingxia , Chang Chunkang , Li Xiao
Published: October 2019

Abstract 5046

Purpose

In this study, we focused on evaluating ribosomal protein S14 (RPS14) and p53 expression and their correlation analysis with the purpose of investigating the role of RPS14-MDM2-p53 pathway in hematopoietic cell apoptosis of myelodysplatic syndrome (MDS) patients with 5q- aberration.

Patients and Methods:

Real time quantitative PCR was used to detect the expression levels of RPS14, MDM2 and p53 in 18 MDS patients, among which 7 with isolated del (5q) and 11 del (5q) with other chromosomal abnormalities were included. Besides, alkaline phosphatase-anti-alkaline phosphatase (APAAP) and terminal deoxynucleotidyI transferase dUTP nick end labeling (TUNEL) techniques were carried out simultaneously for each sample to respectively examine the expression of p53 and the apoptosis level of bone marrow (BM) mononuclear cells (MNCs). 10 healthy controls were included in the study.

Results:

under-expression of RPS14 gene was seen in 15/18 patients' (83.3%), of which 6/7 were isolated 5q- and 9/11 were 5q- with other chromosomal abnormalities. RPS14 expression was negatively correlated with the proportion of 5q- clonal cell in BM while it showed a positive correlation with both of the expression of MDM2 and p53. The expression of p53 was not correlated to the high apoptosis level of BM in patients with del (5q). Furthermore, APAAP and TUNEL results demonstrated apoptotic cells in patients BM were p53-negative (see Fig 1). Conclusions: RPS14 gene was under-expressed in MDS patients with 5q- aberration, which did not result in a p53-dependent apoptosis. A p53-independent pathway may contribute to the over apoptosis of 5q- MDS patients.

Disclosures:

No relevant conflicts of interest to declare.
MyD88 Could Promote Multiple Myeloma Cells Growth and Survival
Authors: Xu Yang , Depei Wu , Tian Hong , Wang Rongxian , Yang Zhen
Published: October 2019

Abstract 5086

Toll like receptors (TLRs) are the major agents for innate immunity, which recognize invading microbial products. In previous study, we proved that activated TLR4 and TLR9 could promote MM cells growth and activated NF-κB signaling played a crucial role for ligands of TLR4 and TLR9 via increasing IL-6 autocrine. It was reported that MyD88 could play the key role in TLR signaling pathway and TLR4 and TLR9 shared the same MyD88-dependent pathway. In this study, we observed that expression of MyD88 mRNA in primary MM cells was higher than normal plasma cells and most of MM cell lines had a high MyD88 transcripts. Futher experiments demonstrated that transient over-expression of MyD88 could promote MM primary cells and MM cell lines growth and production of IL-6, IL-1, TNF-α, IFN-γ, VEGF and TGF-β. Moreover, down-regulation of MyD88 by sepecific virus based siRNA plamids in MM cell lines preliminarily resulted in reduced MM cells proliferation and increased MM cells apoptosis. These results highly suggested that MyD88 played a crucial role for TLR ligands to promote MM cells growth and survival, which make it possible to develop TLR system and MyD88 gene as the MM therapy target in the future.

Disclosures:

No relevant conflicts of interest to declare.
Level of Scientific Evidence Underlying Recommendations Arising From the National Comprehensive Cancer Network Clinical Practice Guidelines for Hematologic Malignancies
Authors: Kusuma Benny , Go Ronald S.
Published: October 2019

Abstract 509

Purpose:

The level of scientific evidence on which the National Comprehensive Cancer Network (NCCN) guidelines are based has not been systematically investigated. We describe the distribution of categories of evidence and consensus (EC) among the 10 most common hematologic malignancies with regard to recommendations for staging, initial and salvage therapy, and surveillance.

Methods:

NCCN uses a system of guideline development distinct from other major professional organizations. The NCCN definitions for EC are as follows: category I, high level of evidence with uniform consensus; category IIA, lower level of evidence with uniform consensus; category IIB, lower level of evidence without a uniform consensus but with no major disagreement; and category III, any level of evidence but with major disagreement.

Results:

Of the 1160 recommendations found in the 10 guidelines, the proportions of category I, IIA, IIB, and III EC were 3%, 93%, 4%, and 0%, respectively. Recommendations with category I were found in acute myeloid leukemia (4%), multiple myeloma (7%), Hodgkin's lymphoma (1%), diffuse large B-cell lymphoma (4%), follicular lymphoma (11%). Chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal zone lymphoma, AIDS-related B-cell lymphoma, and Burkitt lymphoma did not have any category I recommendations. Three percent of all therapeutic recommendations were category I. Guideline with the highest proportion of category I therapeutic recommendations was for diffuse large B-cell lymphoma (46%). No category I recommendations were found on staging or surveillance.

Conclusion:

Recommendations issued in the NCCN guidelines are largely developed from lower levels of evidence but with uniform expert opinion. This underscores the urgent need and available opportunities to expand evidence base in oncology.

Disclosures:

No relevant conflicts of interest to declare.
Potentiation of bortezomib's Anti-Myeloma Effects in Combination with Anti-DR5 Agonistic Antibody: The Role of ER Stress in DR5 Editing and DR-Mediated Apoptotic Signaling
Authors: Miki Hirokazu , Abe Masahiro , Kagawa Kumiko , Oda Asuka , Amou Hiroe , Ikegame Akishige , Watanabe Keiichiro , Hiasa Masahiro , Harada Takeshi , Fujii Shiro , Nakamura Shingen , Nakano Ayako , Takeuchi Kyoko , Ozaki Shuji , Shiotsu Yukimasa , Ri Masaki , Iida Shinsuke , Matsumoto Toshio
Published: October 2019

Abstract 5104

Bortezomib (BTZ) is widely used in the treatment of myeloma (MM) with marked response rates in both relapsed/refractory as well as newly diagnosed MM. However, significant numbers of patients still remain outside benefit of the BTZ treatment; and various combinatory treatments with BTZ have been implemented to improve BTZ's anti-MM effects. On the other hand, immunotherapies seem attractive for yet incurable malignancies by chemotherapeutic agents such as MM and their clinical application has been studied. One such approach is a TNF-related apoptosis-inducing ligand (TRAIL)-mediated immunotherapy. In the present study, we therefore explored the role of BTZ on TRAIL receptor editing and its downstream signaling with special reference to endoplasmic reticulum (ER) stress and the cytotoxic effects of BTZ and anti-TRAIL receptor agonistic antibody in combination on MM cells. Most MM cells expressed DR4 but weakly DR5, while normal peripheral blood mononuclear cells expressed neither DR4 nor DR5. BTZ at 10 nM markedly up-regulated the surface levels of DR5 and its mRNA expression but not those of DR4 in MM cell lines and primary MM cells. Furthermore, BTZ decreased the levels of c-FLIP, an inhibitor of DISC, along with activation of caspase-8 and caspase-3, suggesting potentiation of the DR-mediated extrinsic apoptotic pathway. Consistently, BTZ and anti-DR5 agonistic antibody cooperatively enhanced the cytotoxicity against MM cells. BTZ induced phosphorylation of eIF2alpha, ATF4 and CHOP, along with disappearance of anti-apoptotic proteins including Mcl-1 in MM cells, suggesting the enhancement of ER stress and subsequent suppression of protein translation by BTZ. However, such induction of ER stress by BTZ was not observed in BTZ-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, with a point mutation in BTZ-binding proteasome beta5 subunit (Ri et al. Leukemia 2010). In KMS-11/BTZ and OPM-2/BTZ, surface protein as well as mRNA levels of DR5 were not up-regulated by BTZ, suggesting a critical role of ER stress in up-regulation of DR5 expression by BTZ. Because DR5 expression has been shown to be transcriptionally up-regulated by CHOP, the up-regulation of DR5 mRNA and protein in MM cells by BTZ is suggested to be at least in part due to CHOP induced by BTZ-mediated ER stress. Although BTZ exerts its anti-MM effects through induction of ER stress, the present study demonstrates that induction of ER stress by BTZ is also able to sensitize MM cells to TRAIL-mediated immunotherapy. Therefore, the combination of BTZ and TRAIL-mediated immunotherapy is warranted for further study.

Disclosures:

No relevant conflicts of interest to declare.
Here Is the Sub-Title:Apoptosis on Multiple Myeloma U266 Cell by Phosphorylation c-Jun of Brucine
Authors: Ma Yanping , Li Zhihua , Wang Yihua , Feng Jing
Published: October 2019

Abstract 5112

Objective:

To investigate the Mechanism of the apoptotic effect of brucine on human multiple myeloma.

Method:

U266 cells (5×104) were plated in the presence or absence of the brucine (0, 0.05, 0.1, 0.2, 0.4 mg/ml) in 96 well culture plates for 24–72 h. The anti-proliferative response of brucine was assessed by MTT assay. The analysis of cell cycle of U266 cell with or without brucine was mesured by flow cytometry. The expression change of c-Jun after joining brucine, brucine and JNK specific inhibitor SP600125 was detected using RT-PCR.

Results

The apoptotic effect of brucine show a dose and time dependent manner. Cell cycle analysis using flow cytometry revealed accumulation of cells at sub-G0/G1 phase. The apoptosis rate separately were (4.137±0.01)%, (10.55±0.03)%, (12.31±0.04)%, (27.67±0.08)%, (29.67±0.09)% (p<0.01). Detecting c-Jun gene expression respectively after joining brucine, brucine and JNK specific inhibitor SP600125 by RT-PCR. The gray scale values were (0.7961±0.007),(0.4683±0.003).

Conclusions

Within the 0.4mg/ml concentration of brucine can induce apoptosis in U266 cells. Brucine by JNK signaling pathway through phosphorylation of c-Jun induced apoptosis in U266 cells.

Disclosures:

No relevant conflicts of interest to declare.
Role of NKG2D in Cytokine-Induced Killer (CIK) Cells Against Multiple Myeloma Cells
Authors: Lu Xu-zhang , Chen Bao-An , Ma Lin-di , Cai Xiao-hui , Zhou Min
Published: October 2019

Abstract 5119

Cytokine-induced killer (CIK) cells are T lymphocytes enriched in CD3+CD56+ cells, which can be easily and rapidly expanded in vitro from human peripheral blood, bone marrow or cord blood mononuclear cells with the sequential addition of interferon (IFN)-{gamma}, OKT-3 and high doses of interleukin (IL)-2. The cytokine-induced killer (CIK) cells have been reported to have potent cytotoxicity against a variety of tumor cells including multiple myleoma (MM) cells. The mechanism of CIK cell recognizing MM cells remains unknow. Recent studies indicated that ligation of NKG2D on immunological cells directiy induce cytotoxicity. We suspect whether NKG2D receptor induction on CIK cells by cytokines is responsible for the killing of MM cells by CIK. We expended CIK cells from healthy controlswith interferon (IFN)-γ, CD3 monoclonal antibodies (mAb) and IL-2, and checked expression of NK cell receptors on CIK cells by flow cytometry. We found higher expression of NKG2D receptor and lower other NK receptors, such as CD158a,CD158b and NCRs on expanded CIK. These CIK cells showed higer cytotoxicity to multiple myleoma cell line U266 expressing NKG2D ligands. Interestingly, when cocultured with U266 cells, only NKG2D expressing CIK cells released IFN-γ detected by flow cytometry. We next analyzed NKG2D ligands expression on primary plasma cells in 22 MM patients by flow cytometry, the primary plasma cells in 16/22 (72.7%) MM patients expressed different levels of ULBPs or MICA/B on the cell surface. CIK cells showed higher cytotoxicity (12.5%) to NKG2D ligands expressing primary plasma cells compared to those did not express NKG2D ligands. The killing of CIK against MM cells were partially blocked by treatment of CIK with anti-NKG2D antibody. We conclude that NKG2D-NKG2D ligangd interaction may be one of the mechanisms by which CIK cells kill MM cells.

Disclosures:

No relevant conflicts of interest to declare.