bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes and Treatments of Relapsed AL Amyloidosis Following Stem Cell Transplant
Authors: Warsame Rahma , Bang Soo-Mee , Kumar Shaji K. , Lacy Martha Q , Buadi Francis K , Dingli David , Hayman Suzanne R , Lust John A , Russell Stephen , Witzig Thomas E. , Kyle Robert A. , Leung Nelson , Zeldenrust Steven R , Rajkumar S. Vincent , Gertz Morie A , Dispenzieri Angela 
Published: October 2019

Abstract
Abstract 1858
Systemic light chain amyloidosis (AL amyloidosis) is a condition where clonal plasma cells produce misfolded insoluble immunoglobulin light chains that deposit in various organs causing progressive organ dysfunction. Chemotherapy and autologous stem cell transplant (ASCT) when eligible is the standard treatment options for patients with AL amyloidosis. There are several studies who report long term outcomes of patient post ASCT. However, there is a paucity of literature describing the outcomes of patients who have received ASCT but have relapsed. We performed a retrospective study to assess the outcomes and treatment regimens employed following relapse after ASCT. Between 1996 and 2009, 410 patients received ASCT at the Mayo Clinic as first line therapy. Of those 410 patients 42 patients died within 3 months of transplant, 64 patients died without documented relapse, 158 patients were alive without documented progression, and 146 patients had documented progression. Those 146 patients are the subject of our study. The median time to hematologic relapse was 2 years (range: 0.2–15.5 years). At relapse, 59 patients were treated with IMiD based therapy, 36 with alkylator based therapy, 24 with bortezomib, 15 with steroids, and 5 with second ASCT. The respective hematologic response rates were 58%, 33%, 50%, 53%, and 60%. The remaining six patients were not evaluable for response for one other following reasons: organ transplants; no further therapy; inevaluable disease. With a median post relapse follow up of 3.6 years, the median overall survival (OS) from the first post ASCT relapse was 4.6 years. The median post transplant follow up was 6.1 years, the median OS for these patients was 7.3 years from the time of transplant. These data provide novel information about outcomes after SCT relapse, which should be useful not only for patients and doctors but also for investigators designing studies for salvage therapies post-transplant.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy of 5% Albumin and Fresh Frozen Plasma (AFFP) Versus Fresh Frozen Plasma (FFP) only as Replacement fluid in Plasma Exchange for Thrombotic Thrombocytopenic Purpura (TTP)
Authors: Louie James , Boctor Fouad , Chiang Jason , Anwar Zeeshan , Wittenberg Amanda , Gogas Elena 
Published: October 2019

Abstract
Abstract 272
The treatment of Thrombotic Thrombocytopenic Purpura (TTP) with therapeutic plasma exchange (TPE) with Fresh Frozen Plasma (FFP) and/or Cryopoor Plasma (CPP) replacement is well established. This process adds plasma ADAMTS-13 activity and removes plasma ADAMTS-13 inhibitor. Limited data has indicated combination of 5% albumin in the first half of the procedure followed by FFP in the second half of the procedure is effective in treating TTP. Theoretical calculation of addition of exogenous ADAMTS-13 is still substantial because ADAMTS-13 infused initially is removed as the plasma exchange procedure progresses. A 50% reduction of FFP would decrease the number of donor exposures and transfusion reactions associated with human plasma. Further, plasma of limited supply, such as AB plasma, can be more effectively used.
We report a retrospective comparison of TPE for TTP using all FFP versus 5% Albumin/FFP (AFFP) replacement fluid. One health system with two closely connected tertiary campuses with common Hematology/Oncology services and Transfusion Medicine services treated 17 idiopathic TTP patients (March/2009 – June/2012) with documented very low ADAMTS-13 levels (<10) and high inhibitor levels (≥0.4). All other thrombotic microangiopathies were excluded from this comparison. One campus treated 10 patients with FFP and the other campus treated 7 patients with AFFP. Daily one plasma volume TPE was performed until target platelet count was achieved and the patient was then tapered off TPE. For AFFP replacement, 50% of the replacement fluid was 5% albumin given in the first half of the procedure followed by FFP for the second half. Additional medical therapy was managed by the same Hematology/Oncology service.
Table 1 shows that the FFP versus the AFFP groups at presentations are comparable. Table 2 indicated FFP versus AFFP treatment is comparable. For the FFP and AFFP groups respectively, mean number of total procedures: 16 vs. 14, length of time from first TPE to last TPE 19 vs. 22 days, Relapses 2 vs. 2, and deaths 1 vs. 0.

Conclusion:
The use of AFFP as replacement fluid for idiopathic TTP does not appear to be inferior to 100% FFP replacement. Length of treatment, rate of recovery, and relapse rate are comparable. There were more deaths in the FFP cohort but the low number of observations limits the significance. AFFP fluid replacement should be considered for TPE in idiopathic TTP.

Disclosures:
No relevant conflicts of interest to declare.
Subanalysis of the StiL NHL 1–2003 Study: Achievement of Complete Response with Bendamustine-Rituximab (B-R) and CHOP-R in the First-Line Treatment of Indolent and Mantle Cell Lymphomas Results in Superior Survival Compared to Partial Response.
Authors: Rummel Mathias J. , Niederle Norbert , Maschmeyer Georg , Banat G.-Andre , von Grünhagen Ulrich , Losem Chrisoph , Kofahl-Krause Dorothea , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Duerk Heinz A. , Ballo Harald , Stauch Martina Beate , Roller Fritz , Barth Juergen , Hinke Axel , Burchardt Alexander C. , Brugger Wolfram 
Published: October 2019

Abstract
Abstract 2724

Background:
The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome.

Methods:
514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles.

Results:
The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS.
Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002).
We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866).

Conclusions:
Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome.

Disclosures:
No relevant conflicts of interest to declare.
L-Asparaginase Monotherapy in Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal Type: Results of A Phase II Study.
Authors: Guo Ye , Ma Xuejun , Xia Zuguang , Xue Kai , Zhang Qunling , Hong Xiaonan 
Published: October 2019

Abstract
Abstract 2730

Introduction:
Recently, L-asparaginase-based combination chemotherapy was found to be effective in salvage treatment in patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type. To explore the single-agent activity of L-asparaginase, we conducted a single-institute, prospective phase II study.

Methods:
Patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type were eligible for enrollment regardless of prior treatment. L-asparaginase monotherapy (6000 U/m2 on days 1 to 7) was administered as the protocol treatment and repeated every 3 weeks for at most 8 cycles. For responding patients, the decision to proceed with hematopoietic stem-cell transplantation was made at the discretion of treating physicians. The primary endpoint was the best objective response after L-asparaginase.

Results:
A total of 40 patients were enrolled and treated with L-asparaginase for a median of 5 cycles (range, 1 – 8). The patient characteristics were shown in Table 1. Half of the patients had stage IV disease at enrollment and the vast majority (18 patients) presented with disseminated cutaneous and soft-tissue involvement. Thirty-seven patients (92.5%) had prior exposure to systemic chemotherapy and 14 of them (37.8%) received more than 1 line. The overall response rate was 82.5%. The complete response (CR) and partial response (PR) rates were 40% and 42.5%, respectively. The incidence of adverse events was shown in Table 2. In short, anemia, neutropenia, hypoalbuminemia, nausea and liver-related disorders were common toxicities, which were usually mild and manageable. No grade 4 adverse events and treatment-related mortality were observed. Five patients (12.5%) developed allergic reaction to L-asparaginase and 3 of them had to withdraw from the study since L-asparaginase re-challenge with prophylactic antiallergic agents was unsuccessful. After a median follow-up time of 31.6 months (range, 21.9 – 41.3), the median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached. Response status (CR, PR or no response) after L-asparaginase had a significant impact on either PFS (Figure 1) or OS (Figure 2). Moreover, its prognostic value was confirmed in the multivariate analysis.

Conclusions:
L-asparaginase demonstrated a high single-agent activity in salvage setting for patients with extranodal NK/T-cell lymphoma, nasal type. The first-line L-asparaginase-containing chemotherapy regimen warrants urgent investigation.

Disclosures:
Off Label Use: L-asparaginase, which was used in our study for NK/T-cell lymphoma, is approved to treat acute lymphocytic leukemia by US and Chinese FDA.
Impact of Rituximab On the Treatment of Waldenström's Macroglobulinemia (WM).
Authors: Thomas Sheeba K. , Delasalle Kay B , Shah Jatin J. , Wang Luhua , Orlowski Robert Z. , Weber Donna M. 
Published: October 2019

Abstract
Abstract 2734

Background:
Rituximab was first approved by the FDA for use in relapsed and/or refractory low grade or follicular B cell non-Hodgkin's lymphoma in 11/1997. Since that time it has been widely used in WM, and is the backbone of drug combinations developed for treatment of this disease.

Methods:
To evaluate the impact of rituximab on overall survival (OS), we retrospectively evaluated patients (pts) treated at our center who received primary therapy for symptomatic WM with combinations of either alkylating agents (AA), nucleoside analogs (NA) +/− AA, or bortezomib (B), each with or without rituximab (R). The effect of primary therapy on OS was compared between patients receiving primary therapy before and after rituximab use for WM began at our center (11/11/1998). OS was calculated from the date of initial treatment until date of death or last follow-up. Due to small patient numbers, those who received vincristine-doxorubicin-dexamethasone (2 pts), single agent rituximab (3 pts), or rituximab-alkylating agent combinations (11 pts) as primary therapy, were excluded from the analysis.

Results:
Among 315 patients with previously untreated symptomatic WM treated since 3/1966, 118 received AA alone; 137 received NA +/− AA alone (85 pts) or with R (52 pts), and 44 received B + R. Median age, hemoglobin, platelet count and β2 microglobulin were comparable between all treatment groups (AA alone, NA +/− AA alone, NA +/− AA + R, B + R). Only median albumin differed significantly, with levels of 3.7 g/dL (AA alone), 4.1 g/dL (NA+/− AA alone), 4.3 g/dL (NA+/− AA + R) and 4.4 g/dL (B + R), respectively (p < 0.01). The median OS of pts treated with AA was 4.5 years, and 6.5 years with NA +/− AA, while the median OS of pts treated with NA+/− AA + R (median follow-up: 8 years) and B + R (median follow-up: 2.6 years) has not been reached. Comparing all patients treated with vs. without R, median OS is >13 years vs. 5.6 years (p<0.01).

Conclusions:
While pts with WM have most certainly benefitted from improvements in supportive care and the greater availability of salvage therapy options in the modern era, the addition of rituximab to available therapies appears to have significantly improved the OS of patients with WM compared with AA or NA +/− AA alone. Our data supports the role of rituximab as an indispensable component of modern therapy for this disease.

Disclosures:
No relevant conflicts of interest to declare.
Overexpression of Eukaryotic Initiation Factor 4E Induces Critical Transcription Factors Such As c-Myc in Multiple Myeloma Resulting in Enhanced Clonogenic Tumor Growth in Vitro and in Vivo.
Authors: Li Shirong , Fu Jing , Schecter Jordan M. , Lu Caisheng , Mapara Markus , Lentzsch Suzanne 
Published: October 2019

Abstract
Abstract 2908

Introduction:
The eukaryotic initiation factor 4E (eIF4E) is a critical regulator in protein synthesis. It has been shown that overexpression and/or activation of eIF4E is critical for oncogenic protein synthesis. The precise role of protein translation in multiple myeloma (MM) is less clear. Recently it has been shown that eIF4E protein levels are higher in primary CD138+ MM cells than in normal plasma cells (Li, Jin et al. 2011) and that mutations in genes related to mRNA translation are involved in the pathogenesis of multiple (Chapman, Lawrence et al. 2011). Therefore, understanding the mechanisms that control protein synthesis is an emerging new research area in MM with significant potential for developing innovative therapies. In this study, we analyzed the effects of introduction of ectopic eIF4E in MM cell lines compared with their parent cells in vitro and in vivo.

Results:
To examine the effect of overexpressed eIF4E in MM, we transduced MM cell lines with lentiviral particles encoding human eIF4E with GFP as selection marker. Introduction of ectopic eIF4E significantly increased critical factors for myeloma cell growth such as myc, cyclin D1, C/EBP beta and IRF4 as detected by western blotting. Overexpression of eIF4E resulted in a significant (p<0.001) increase of DNA synthesis compared to empty vector control (EV) cells. Cell cycle analysis revealed a decreasing number of cells in G0/G1 phase (62% vs 49%) and cells arresting in the G2/M phase (14% vs 23%), not affecting cell apoptosis. Overexpression of eIF4E further led to the significant increase (p=0.004) of clonogenic tumor growth with expansion of clonogenic colony numbers (22.3 ± 2.5 vs 40.3 ± 2.1) and size. To determine whether overexpressed eIF4E also affects MM tumor growth in vivo, we generated subcutaneous MM xenografts in severe combined immunodeficient x beige (SCID/bg) mice using the EV and eIF4E-OE-U266 cells. In contrast to EV-U266 tumors, animals bearing eIF4E-OE-U266 xenografts showed a significant increase (p<0.001) of tumor growth by 180% after 13 days.

Conclusion:
Here we show that eIF4E, a key player in translational machinery, promotes multiple myeloma cell growth both in vitro and in vivo. When eIF4E is overexpressed, it enhances protein expression of a subset of transcripts encoding regulators of the cell cycle and proliferation.

Disclosures:
Lentzsch: Celgene: Consultancy, Research Funding.
Organotypic Epigenetic Signature Predicts Bone and Marrow Niche Forming Capacity of Stromal Progenitors in a Novel Mouse Model in Vivo.
Authors: Reinisch Andreas , Etchart Nathalie , Hofmann Nicole A , Frühwirth Margareta , Ortner Anna , Thaler Daniela , Feilhauer Birgit , Hartwig Udo F , Beham-Schmid Christine , Trajanosky Slave , Wagner Wolfgang , Alves Frauke , Schallmoser Katharina , Andreeff Michael , Strunk Dirk 
Published: October 2019

Abstract
Abstract 2987
Mesenchymal stem/progenitor cells (MSPCs) from numerous tissues are currently tested in clinical trials despite a limited understanding of their in vivo behavior. In this study we used MSPCs from adult and fetal tissues to select the appropriate source for clinical application. We asked whether MSPCs derived from human bone marrow (BM), white adipose tissue (WAT) and umbilical cord (UC), compared to skin fibroblasts, bear an equivalent bone and marrow niche formation potential with of in vivo. Furthermore we evaluated attraction and engraftment of murine as well as human hematopoietic stem/progenitor cells (HSPCs) into newly formed MSPC-derived niches. To elucidate potential mechanisms responsible for a tissue-specific MSPC potential after transplantation gene expression profiling and DNA methylation analysis on a novel high resolution 450K-CpG methylation array were employed.
MSPCs were transplanted subcutaneously to test for their spontaneous bone and marrow niche formation potential in immune-deficient NSG mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ). BM-derived MSPC transplantation reproducibly led to the development of mature bone (17/17 donors) through an endochondral ossification process leading to subsequent marrow niche formation. Additionally, these newly formed hematopoietic microenvironments attracted complete mouse hematopoiesis including immature lineage negative, Sca-1 positive, c-kit positive (LSK) HSPCs. Non-BM derived MSPCs completely lacked bone and marrow niche-forming potential and did not attract hematopoietic cells (0/9 donors). Induction of human hematopoietic chimerism through transplantation of umbilical cord blood (UCB)-derived human CD34+ HSPCs in advance of subcutaneous ectopic bone and marrow development resulted in immigration of re-transplantable human hematopoiesis into extra-medullary ossicles. Comparative 450K-CpG methylation array profiling of MSPCs revealed a tissue-specific epigenetic signature virtually corresponding to the in vivo differentiation. MSPCs from BM but neither fibroblasts nor MSPCs from WAT or UC showed epigenetically imprinted human bone and marrow niche (HuNiche) formation capacity favoring BM-MSPCs for skeletal regeneration. This novel HuNiche model should be ideally suited for studying normal and malignant hematopoiesis regulation in an ectopic human marrow with subsequent human hematopoietic engraftment that mimics clinical BM transplantation reality.

Disclosures:
No relevant conflicts of interest to declare.
Identification of a Human Endogenous Retrovirus Type-E (HERV-E) Envelope with Selective Expression in Clear Cell Kidney Cancer That Is Immunogenic in Vitro.
Authors: Cherkasova Elena , Weisman Quinn , Kajigaya Sachiko , Takahashi Yoshiyuki , Reger Robert N , Harashima Nanae 
Published: October 2019

Abstract
Abstract 3015
Recently, we isolated and expanded a CD8+ T-cell clone from the blood of a patient with regressing renal cell carcinoma following an allogeneic hematopoietic stem cell transplant (HSCT) that killed patient tumor cells in vitro. This CTL clone was found to have tumor specific cytotoxicity, recognizing an HLA-A11-restricted 10-mer peptide named CT-RCC-1. The transcripts encoding this antigen, CT-RCC-8 and CT-RCC-9 were found to be derived from a novel human endogenous retrovirus type E (named CT-RCC HERV-E) located on chromosome 6q. Both transcripts present splice variants that share a common sequence region encoded in the retroviral 5'LTR that is spliced to non-shared regions derived from the protease and polymerase genes, respectively. Remarkably, these transcripts were found to be selectively expressed in the clear cell variant of renal cell carcinoma (ccRCC) with no expression observed in normal tissues or any other type of tumor cell. We have now discovered transcripts encoding the entire envelope gene (env) of the CT-RCC HERV-E provirus are also expressed in ccRCC. Expression of these unique HERV-E env transcripts was detected in kidney cancer cells by RT-PCR, Northern blot, and sequence analysis. The proviral env was found to be expressed concurrent with the previously identified CT-RCC-8 and -9 transcripts, and was only observed in ccRCC cells with no expression observed in any other tumors or normal tissues. We generated 2 peptides derived from the env surface region and 2 peptides derived from the env transmembrane region that were predicted to have a high binding affinity for HLA-A2. Dendritic cells generated from the PBMC of healthy HLA A2+ donors were pulsed with one of these 4 env peptides then were used to stimulate autologous T-cells in vitro. After three stimulations, 3 of these peptides were found to expand CD8+ T-cells that secreted IFN-γ when co-cultured with a HERV-E Env expressing ccRCC tumor cell line transfected to express HLA A2+ but did not secrete IFN-γ against the wild type tumor that was HLA A2 negative.
Conclusion: The envelope of the CT-RCC HERV-E provirus is expressed selectively in ccRCC and encodes highly immunogenic antigens that can be targeted by cytotoxic T-cells. Our data suggests antigens derived from this newly discovered HERV-E envelope could represent excellent targets for T-cell based immunotherapy for kidney cancer.

Disclosures:
No relevant conflicts of interest to declare.