bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patterns Of Care and Outcomes Of Anthracyclines In Grade 3 Follicular Lymphoma (FL)
Authors: Nastoupil Loretta J. , Rai Ashish , Lipscomb Joseph , Williams Jessica N , Ward Kevin , Howard David H , Flowers Christopher R. 
Published: October 2019

Abstract

Background
The role of anthracyclines in the management of Grade 3 (G3) FL is unclear. Furthermore, the patterns of care and outcomes of first-line treatment strategies for G3 FL in older adults are not clearly established. We describe the patterns of use, determinants of treatment, and survival outcomes of first-line management strategies for G3 FL with emphasis on four common first-line regimens: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), rituximab (R) plus CHOP (R-CHOP), cyclophosphamide, vincristine, and prednisone (CVP), and R plus CVP (R-CVP).

Methods
We used the linked Surveillance, Epidemiology, and End Results -Medicare database to identify 1,308 G3 FL patients (pts) diagnosed between 1995 and 2009 and focused on pts diagnosed between 1999 and 2009 when claims with R appear. We ascertained first-line management strategies from Medicare claims made within 90 days of diagnosis. We used multiple variable logistic regression models to evaluate the relationship between pt characteristics and the use of first-line R-CHOP. We used Kaplan-Meier estimators stratified by FL stage to evaluate survival functions for first-line management strategies and performed multiple variable Cox proportional hazards regressions adjusted for pt demographics, comorbidity index, disease characteristics, and year of diagnosis to compare the impact of first-line management strategies on survival.

Results
Of the 1,308 G3 FL pts, 59% were female, 91% were Caucasian, 3% were African American, 44% had stage III/IV disease, 6% had B-symptoms, and 36% had extranodal involvement. The median age at diagnosis was 75 (interquartile range 70-80). Common first-line management strategies were: observation (obs), 29%; R-CHOP, 26%; CHOP, 9%; radiotherapy alone (XRT), 8%; R alone, 8%; R-CVP, 7%; and CVP, 5%. The use of R-CVP and R-CHOP increased over time (Figure 1).
In the cohort of pts diagnosed between 1999 and 2009 the use of R-CHOP was less commonly associated with age >80 years (ref. age 66-70 years; OR 0.19; 95% CI 0.11-0.31), comorbidity index ≥ 2 (ref. index =0; OR 0.54; 95% CI 0.31-0.92), and more commonly associated with stage III/IV FL (OR 1.46; 95% CI 1.05-2.02), and year of diagnosis (ref. years 1999-2001; OR for 2002 3.68; 95% CI 1.77-7.64; steady increase thereafter).
The table displays median survival and hazard ratios (HRs) for first-line management strategies. The most favorable outcomes were associated with first-line R-chemotherapy (R-Chemo). Among first-line R-chemo regimens, R-CHOP was associated with the most favorable outcomes (Figure 2).

Conclusion
R-CHOP is the most commonly used first-line regimen in the United States for older adult pts with FL G3. Even after controlling for disease characteristics and comorbidity, R-CHOP was associated with the most favorable survival outcome.

Disclosures:
No relevant conflicts of interest to declare.
Early Ofatumumab Treatment For High-Risk, Treatment-Naive Patients With Chronic Lymphocytic Leukemia
Authors: Jain Nitin , Keating Michael J. , Ferrajoli Alessandra , Konopleva Marina , Thomas Deborah A. , Pemmaraju Naveen , DiNardo Courtney D. , O'Brien Susan , Wierda William G. 
Published: October 2019

Background
Ofatumumab is a human IgG1-kappa monoclonal antibody that binds to CD20 on normal B cells and on B chronic lymphocytic leukemia cells, resulting in B cell lysis. Ofatumumab has single-agent activity in patients (pts) with refractory CLL (Wierda, JCO 2010). Pts with CLL who have early stage disease (Rai 0-II) but have high-risk prognostic markers such as deletion 17p or deletion 11q have an increased risk of disease progression. Currently, these pts are offered watch-and-wait approach. The objective of this Phase II study is to evaluate the efficacy of ofatumumab in treating these pts with the goal to delay time to first chemoimmunotherapy treatment.

Methods
Pts with CLL/SLL were eligible provided they had high-risk for progression based on the presence of at least one of the following features: Rai stage II, serum beta-2 microglobulin (β2M) ≥3 mg/L, absolute lymphocyte count ≥25,000/µL, unmutated (≤2%) IGHV gene or mutated IGHV3-21, ZAP70 positive, CD38 positive (≥ 30%), or 11q or 17p deletion by FISH. Pts having a 2008 IWCLL/NCI-WG indication for CLL treatment were not eligible. Pts with Rai stage III-IV CLL were not eligible. Ofatumumab 300 mg dose 1, then 1000 mg weekly for 7 additional weeks (8 doses) was administered. Response assessment, including bone marrow evaluation, was done at least 2 months after last dose of ofatumumab and pts were followed for progression-free survival and time to first chemoimmunotherapy.

Results
Twenty-five pts (9 women, 16 men) were enrolled so far. The median age was 59 yrs (range, 40-81). The baseline characteristics are listed in the Table. Fifty percent of pts had unmutated IGHV gene. Thirty-four percent of pts had high-risk cytogenetic by FISH analysis. The median follow-up on the study is 4.7 months (range, 0.5-26). Grade 3-4 adverse events included infusion reaction in 6 pts. Autoimmune hepatitis with grade 4 ALT, grade 4 AST, and grade 4 alkaline phosphatase elevations was seen in 1 pt. Other grade 3-4 toxicities included rash (1 pt), shingles (1 pt), and tumor lysis (1 pt). Tumor lysis was seen in the pt with the WBC count of 207 K/µL. Eighteen pts (7 too early) are evaluable for response. Responses are as follows: 6 CR, 3 nPR, 3 PR, and 6 with stable disease. Three pts have progressed at 18.8, 14.1 and 3.2 months after starting the study treatment; 2 pts had unmutated IGHV gene (FISH negative) and one pt had trisomy 12 (IGHV mutation status unknown). None of the pts with deletion 17p or deletion 11q have progressed. All pts are alive at this time. The median overall follow up time is 7.6 months (range, 1-28).

Conclusions
Ofatumumab is well tolerated in pts with early stage CLL and may delay time to first chemoimmunotherapy.

Disclosures:
Ferrajoli: GlaxoSmithKline: Research Funding.
Multiple Myeloma Profile In Latin America: Clinical and Epidemiological Observational Study
Authors: Hungria Vania T M , Maiolino Angelo , Martinez Gracia Aparecida , De Souza Carmino A , Bittencourt Rosane , Bruggemann Peters Lygia Goretti , Colleoni Gisele W. B. , Oliveira de Oliveira Luciana Correa , Sousa Lais , Coelho Erika , Pasquini Ricardo , Magalhaes Silvia M. M. , Nunes Renata , Pinto Neto Jorge Vaz , Delboni Faria Rosa Malena , de Souza Mair Pedro , Hamerschlak Nelson , Fantl Dorotea Beatriz , Navarro Juan Ramon , Conte Guillermo , Almaguer David Gomez , Ruiz-Arguelles Guillermo , Durie Brian G M 
Published: October 2019

Abstract

Introduction
Little is known about the incidence and clinical features of Multiple Myeloma (MM) in Latin America. A clinical registry of Latin American (LA) patients with MM represents an opportunity to gain insight into the prevalence of the disease in this region, the patterns of care and the current treatment status in different LA countries.

Objective
To characterize the demographic and clinical features of patients with multiple myeloma from five LA countries (Brazil, Argentina, Chile, Mexico and Peru) and to create a LA database on MM; in addition to investigating the patterns of care for MM patients in Latin America.

Patients and Methods
This is an observational, non-intervention study, with a prospective evaluation of data. Eligible patients were diagnosed with multiple myeloma, between January 1, 2005, and December 31, 2007, at any one of the participating centers, regardless of disease stage or treatment modality. The follow-up period extended to at least 5 years for each patient (December 31, 2012).

Results
Eight hundred and seventy six patients were included. The median age was 60 years old (25-97), 53.4% male and 46.6% female. The median follow-up was 31.4 months, and the median overall survival was 57 months. The median overall survival to patients who received high-dose chemotherapy was 77 months and for patients who received conventional chemotherapy was 48 months (p<0.001). The multivariate prognostic model included patient baseline variables that were associated with mortality in the Kaplan-Meier univariate analyses. Only hypercalcemia, DSS II and III, ISS stage III andnon- high-dose chemotherapy were independent predictors of mortality.

Conclusion
This current study, which is the largest case series of MM patients in Latin America, recognizes the feasibility of large, collaborative, observational studies among various tertiary-care hematology centers in Latin America.

Note
We will present more details related to the demographic and most frequently used treatments in Latin America for newly diagnosed and relapsed patients in these LA countries.

Disclosures:
No relevant conflicts of interest to declare.
Vitro Culture and Regulation Of Osteoblasts and Cellular Immunity Function In Multiple Myeloma patients
Authors: Fu Rong , Gao Shan , Shao Zonghong 
Published: October 2019

Abstract

Objective
To investigate the biological characteristics of osteoblasts（OBs) cultured in vitro from bone marrow（BM) of multiple myeloma(MM) patients and to explore their generation and osteogenic potential. Then the affects by some factors such as bortezomib and MM patient serum on the OBs were observed. To explore the cellular immunity changes and the relationship between OBs and the immunity in MM.

Methods
OBs from BM of MM patients were cultured in vitro. The generation and osteogenic potential of OBs from MM patients and normal subjects were compared. The changes of their osteogenic potential and biological characteristics were observed. The antigens (CD34、CD138、CD45) on OBs and the quantities of T cell subsets，Dendritic cells(DC)，effective T cells、regulatory T cells and helper T cells (Th）were examined with flow cytometry assay. And then correlation was analyzed between OBs and the immunity. The levels of IL-7 were measured with ELISA. The BMP2 mRNAs were measured by RT-PCR.

Results
OBs from BM of MM patients could be cultured in vitro. The quantity of OBs from MM patients was less than normal subjects. There were calcium depositions in both groups after cultured for 4weeks culture. But the depositions of MM patients was less than that of normal controls. The OBs cultured with MM patient serum were less than those without patient serum. Bortezomib increased those from MM patients. CD138, CD45, CD34 were not detected on the cultured cells. The ratio of CD4+/CD8+、DC1/DC2、CD8+CD25+/CD3+T were reduced, that of helper T cell (Th1/Th2) was significantly decreased; the percentages of CD4+CD25+/ CD3+T and CD4+CD25+CD127low/CD4+T were significantly higher. Some of them were correlated with the quantity of OBs. The level of IL-7 in serum of MM patients was higher than that of normal controls. The expression of BMP2 mRNA was seen in the normal OBs and MM patients’ OBs culured with bortezomib, but not be seen in those without bortezomib.

Conclusions
OBs could be cultured in vitro from BM of MM patients. The proliferation and osteogenic potential of OBs from MM patients were decreased. Bortezomib was a positive regulatory of OBs and MM patient serum was a negative one. They both could affect the proliferation and osteogenic potential of OBs. There were down-regulations of quantity and function of T cell subgroup, DC cell, helper T cell, effector T cell while the regulatory T cells relatively raised. Predominantly of them were correlated with the quantity of OBs.

Disclosures:
No relevant conflicts of interest to declare.
Selective Inhibition Of The PI3K-Alpha Isoform Blocks Myeloma Cell Growth and Survival
Authors: Guenther Andreas , Burger Renate , Klapper Wolfram , Staudinger Matthias , Gramatzki Martin 
Published: October 2019

Abstract

Introduction
Both, the phosphoinositide-3kinase (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 exists in four isotypes (α - δ), the role of each of these isotypes in multiple myeloma (MM), however, is not defined. Therefore, we evaluated systematically the in vitroanti-myeloma activity of NVP-BYL719 (Novartis), a newly developed inhibitor highly selective for the PI3K α isoform, and compared it with the activity of other inhibitors targeting the PI3K/AKT/mToR signaling network at different sites. Since inhibition of mToRC1 may lead to PI3K activation by a feedback loop, we looked also at combinations of NVP-BYL719 and rapalogs.

Materials and Methods
An MTS based growth assay was used to measure growth inhibition of NVP-BYL719 in comparison to different inhibitors (the pan-PI3K inhibitors Ly294002 and NVP-BKM120, the dual PI3K/mToR inhibitor NVP-BEZ235, and the allosteric mToR inhibitors rapamycin and everolimus) on six human malignant plasma cell lines and two non-myeloma cell lines, K562 and Raji. Western blot analysis was used to confirm inhibitor activity and specificity. In addition, combinations of PI3K and mToR inhibitors were tested and antagonistic/synergistic activity was calculated with the CalcuSynTM (Biosoft) software.

Results
The selective PI3K alpha inhibitor NVP-BYL719 inhibited myeloma cell growth at a dose level (IC50 < 10 µM in 5/6 cell lines), where non-MM cell lines were not affected. Only cell line U266 was showed moderate sensitivity. The levels of the PI3K isoforms αwere comparable in all tested MM cell , as shown by Western blot. NVP-BYL719 blocked phosphorylation of AKT and of protein S6, an mToR downstream target. Of note, whenever rapamycin was combined with a PI3K inhibitor including NVP-BYL719, synergistic growth inhibition was seen, even in combination with the dual PI3K/mToR inhibitor NVP-BEZ235.

Conclusions
Here, the PI3Kα isoform is reported as being essential for the growth of myeloma cells. This provides the rationale for the therapeutic exploration of such isoform specific PI3K inhibitors in MM allowing dose intensification with less toxicity. Allosteric mToR inhibitors, already active in early clinical trials in MM patients may provide interesting combination partners for these PI3K-inhibitors.

Disclosures:
Guenther: Novartis: Consultancy. Gramatzki:Novartis: Consultancy.
LICs Of APL-Like Leukemia Lead a Step-Wise and Divergent Differentiation Course
Authors: Liu Xiang-Zhen , Dai Jian-Min , Ding Fei , Ding Jing , Chen Juan , Guo Ning , Zhang Wu , Li Jun-ming , Chen Sai-juan , Chen Zhu , Wang Zhen-Yi , Zhu Jiang 
Published: October 2019

Abstract
The differentiation of leukemia-initiating cells (LICs) is generally regarded as a one-way alterative process to self-renewal. However, how differentiation impacts the leukemic stemness is largely unexplored. Here we show that a top tier of undifferentiated (UD), and a medium tier of partially differentiated (PD) LICs coexist within a PML/RARa-expressing mouse leukemia model. PD-LICs not only self-renew or even de-differentiate, but also mature into terminally differentiated (TD) monocytic or granulocytic non-LICs. Notably, PD-LICs but not UD-LICs were partially refractory to the differentiation-inducing effect of ATRA, a cognate ligand of PML/RARa. Nevertheless, the upregulation of monocytic transcriptional factor Irf8, albeit being dampened by RA signaling, relieves the differentiation arrest of most PD-LICs. Thus, our study reveals a sequential and divergent differentiation course of PML/RARa-expressing LICs under the regulation of discrete stage- and lineage- specific mechanisms.

Disclosures:
No relevant conflicts of interest to declare.
Quality Controls Of Immune Regulatory Properties Of Ex-Vivo, GMP-Grade Expanded Mesenchymal Stromal Cells For Clinical Use
Authors: Menard Cedric , Pacelli Luciano , Bassi Giulio , Dulong Joelle , Bezier Isabelle , Zanoncello Jasmina , Bifari Francesco , Ricciardi Mario , Schrezenmeier Hubert , Sensebé Luc , Tarte Karin , Krampera Mauro 
Published: October 2019

Abstract
Aim of CASCADE is to standardize GMP-grade production and clinical use of Mesenchymal Stromal Cells (MSC). Immunological Unit is aimed at setting up and validating a standardized panel of functional assays to fully characterize the immunomodulatory properties of MSC obtained from bone marrow and adipose tissue through different GMP-grade expansion protocols (platelet lysate- vs. fetal calf serum).
Immune cells were isolated using indirect immunomagnetic depletion (purity >96%). MSC were expanded in the same medium used for production and harvested at 70% confluence. Primed MSC (pMSC) were obtained after 48h-treatment with rh-IFNγ and rh-TNFα. MSC or pMSC were cocultured with T, B, NK cells for 4 or 6 days, and proliferation was evaluated by CFDA-SE dilution. T cells were stimulated with αCD3 + αCD28 antibodies; B cells were activated with CD40L, its enhancer, IL-2, CpG 2006, and anti-IgM/IgA/IgG; NK cells were activated with 100 U/ml rhIL-2. Cocultures were performed also with specific molecule inhibitors: L-1MT (IDO), snPP (HO-1), NS-398 (COX2), L-NMMA (iNOS) and anti-IFNγ antibody. For MSC immunogenicity assay, allogeneic T cell proliferation was evaluated at day 5 of culture; in addition, NK cells were activated for 2 days with rh-IL2, and MSC and pMSC were used as target cells.
Inflammatory milieu significantly upregulated MHC class I and II, CD54, CD106, CD40, CD274, CD112, CD155 expression, and downregulated NKG2D ligands and mesenchymal markers (CD73, CD90, CD105). AT-derived MSC expressed less MHC class II, CD200 and CD106 molecules than BM-MSC. MSC coculture inhibited T and NK cell proliferation without inducing apoptosis, and this effect was greater in presence of primed MSC. Only primed MSC were capable of suppressing B cell proliferation. MSC inhibited apoptosis of resting T, B, and NK cells, while inflammatory priming increased their pro-survival activity. Activation of IDO and HO-1 was the main mechanism involved in MSC immune modulation. MSC never promoted allogeneic T cell proliferation; by contrast, IL-2-activated NK cells could efficiently recognize and kill allogenic unprimed MSC, while primed MSC became insensitive to NK cells. Some differences were observed depending on the origin and culture conditions of clinical-grade MSC.
All the experimental protocols to assess MSC inhibitory effects on immune effector cells have been standardized and will be applied for the release of GMP-grade MSC produced inside the CASCADE Consortium.

Disclosures:
No relevant conflicts of interest to declare.
BB02 Improves Therapeutical Effectiveness Of Extracorporeal Photopheresis With 8-MOP In a Murine Model Of Graft-Versus-Host Disease
Authors: Garcia-Bernal David , Blanquer Miguel , del Rio Jose Antonio , Correal Enrique , del Carmen Algueró Maria , Majado Maria Juliana , Moraleda Jose María 
Published: October 2019

Abstract

Introduction
Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy involving the separation of peripheral blood autologous mononuclear cells followed by ex-vivo administration of 8-methoxypsoralen (8-MOP) and UVA radiation before reinfusion. ECP is efficient for the treatment of multiple diseases mediated by unregulated T cell populations, such as cutaneous T cell lymphoma, autoinmune diseases or graft-versus-host disease (GVHD), the major complication after allogeneic bone marrow transplantation. Our aim in the present work was to compare the therapeutic effectiveness of 8-MOP with other two new compounds (BB01 and BB02) in a experimental murine model of GVHD.

Methods
Murine GVHD was induced after transplanting bone marrow cells and splenocytes from donor Balb/c mice into C57Bl6J recipients previously conditioned with a lethal dose of 10 Gy split into two doses of 5 Gy spaced 24 hours apart. To investigate the therapeutic effectiveness of ECP with either 8-MOP, BB01 or BB02, splenocytes from separate cohorts of C57Bl6J with GVHD were isolated 12 days after transplantation, incubated with the different compounds, irradiated with UVA light and injected intravenously once a week for four weeks. Survival after transplantation was monitored daily and clinical GVHD was graded using a previously described score analyzing weight loss, posture (hunching), activity, skin integrity and fur texture (Cooke et al, 1996). Mice of each group were evaluated and graded from 0 to 2 for each criterion, obtaining a clinical index by summation of the five criteria scores (maximum index=10).

Results
Mice treated weekly with BB02 showed a significant higher survival than those treated with 8-MOP (p=0,038), while BB01 had a similar effect to that of 8-MOP. Mice treated with either compound improved their clinical GVHD score compared to untreated mice group, being significantly lower with BB02 than with BB01 and 8-MOP (p=0,023).

Conclusions
BB02 was more efficient than 8-MOP in the reversal of murine GVHD, while BB01 showed the same therapeutic effectiveness than 8-MOP.

Acknowledgments
Work financed by the Spanish Ministry of Science and Innovation (Ref: BFU2010-19599) and the Spanish Net of Cell Therapy (TerCel) from Institute of Health Carlos III.

Disclosures:
No relevant conflicts of interest to declare.