bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fludarabine and Mitoxantrone Followed by Yttrium-90 Ibritumumab Tiuxetan in Untreated Patients with Follicular Lymphoma. Long Term Efficacy and Toxicity Results of the FLUMIZ Trial.
Authors: Zinzani Pier Luigi , Derenzini Enrico , Pellegrini Cinzia , Rigacci Luigi , Fabbri Alberto , Quirini Federica , Stefoni Vittorio , Gandolfi Letizia , Argnani Lisa , Casadei Beatrice , Broccoli Alessandro , Pulsoni Alessandro , Gobbi Marco , Perrotti Alessio , Zaccaria Alfonso , Voso Maria Teresa , Cabras Maria Giuseppina , Renzo Amalia De , Baccarani Michele 
Published: October 2019

Abstract
Abstract 1604
We previously reported the results of a multicenter non-randomized phase II trial of fludarabine and mitoxantrone plus radioimmunotherapy (RIT) [FLUMIZ (Fludarabine, Mitoxantrone, Zevalin) trial], demonstrating that this combination was safe and very effective in untreated patients with follicular non-Hodgkin lymphoma. We are now providing long term efficacy and toxicity results of this combination strategy.
Sixty-one patients with stage III and IV untreated follicular lymphoma were enrolled between June 2004 and April 2006, at 13 Italian institutions. Briefly, treatment schedule was the following: oral fludarabine 40 mg/m2 on days 1–3, intravenous mitoxantrone 10 mg/m2 on day 1 every 28 days for six cycles, followed by one course of yttrium-90 (90Y)-labelled ibritumumab tiuxetan (Zevalin), which consisted in two weekly infusions of Rituximab 250 mg/m2 followed by a weight based dose of 90Y-ibritumumab tiuxetan. Primary endpoints at the time of the first analysis were complete response and hematological toxic effects, secondary endpoints were overall survival (OS) and progression free survival (PFS). Fifty-seven patients were treated with RIT after the completion of six courses of fludarabine and mitoxantrone (FN) regimen. Four patients were excluded because of disease progression (n=1) and bone marrow infiltration > 25% (n=3) at the end of the FN regimen. Median follow up at the time of the last analysis was 52 months (range 24–75). Five-year PFS was estimated to be 68%, 5-year OS was estimated to be 93.0%. Noteworthy, late hematological side effects such as myelodisplastic syndromes or acute myeloid leukemias have not been observed so far. All patients had a complete hematological recovery after the completion of the sequential treatment. 16 patients relapsed during the follow-up period and 4 patients died due to disease progression. 22 patients (38%) are in first complete remission after more than 4 years of follow-up. All relapsed patients underwent second line chemotherapy and high dose chemotherapy with stem cell rescue was performed in 4 patients.
These results confirm the long term efficacy and safety of 6 cycles of fludarabine and mitoxantrone followed by consolidation with 90Y-ibritumumab tiuxetan: the 5-year PFS and OS compare favourably with the results of chemoimmunotherapy alone in untreated follicular lymphoma, with no increased incidence of secondary hematologic malignancie

Disclosures:
No relevant conflicts of interest to declare.
Inflammatory and Thrombotic Mediators in Small Cell Lung Carcinoma: Potential Role in Thromboembolic Complications
Authors: Hoppensteadt Debra , Khan Hussein , Thethi Indermohan , Demir Muzaffer , Adiguzel Cafer , Rahman Saud , Fareed Jawed 
Published: October 2019

Abstract
Abstract 2294

Introduction:
Small Cell Lung Carcinoma (SCLC) patients exhibit a higher prevalence of thromboembolic complications. We hypothesized that in this malignancy, procoagulant and inflammatory mediators contribute to the pathogenesis of such complications and warfarin treatment may down regulate these levels. Methods: In a prospective, randomized, controlled study, patients with inoperable lung cancer (n=100) were randomized to receive chemotherapy and radiation with and without warfarin (INR 1.5 – 2.5). Blood samples were drawn prior to and after the 2nd treatment cycle with warfarin or control and retrospectively analyzed for microparticles and thrombin generation markers such as fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT) and prothrombin fragment F1.2 (F1.2). In addition, biochip array for C-reactive protein (CRP), D Dimer, neuron specific enolase (NSE), neutrophil gelatinase associated lipocalin (NGAL), tumor necrosis factor receptor 1 (TNFR1), and thrombomodulin (TM) were measured. The results were compared with a normal population (N=50).Results: The results are shown in the following table.
The microparticles were markedly increased in the SCLC patients (3 fold increase) at baseline. Similarly, the thrombin generation markers showed variable increase (1.5–3.2 fold increase). In the biochip array analysis, variable increase was noted. CRP (2.4 fold), D DIMER (11.6 fold), NSE (1.8 fold), NGAL (1.7 fold), TNFR1 (2 fold) and TM (1.3 fold) were all increased as compared to normal controls. All of the markers exhibited a decrease after warfarin treatment with a most pronounced decrease in the D Dimer and TNFR1.

Conclusions:
These results validate the hypothesis that SCLC patients exhibit a hypercoagulable state that is associated with simultaneous upregulation of inflammatory mediators. Warfarin treatment results in a down regulation of these mediators. Our results provide a rationale for prophylactic anticoagulant therapy in this group of patients with conventional and newer oral anticoagulant drugs.

Disclosures:
No relevant conflicts of interest to declare.
A Novel Role of Histone Deacetylase 11 (HDAC11) in Regulation of Myeloid-Derived Suppressor Cell (MDSC) Expansion
Authors: Sahakian Eva , Powers John , Rock-Klotz Jennifer , Adriani Marsilio , Woan Karrune V. , Merino Oscar , Gill Ajaypal S. , Deng Susan , Cheng Fengdong , Villagra Alejandro , Luetteke Noreen , Seto Edward , Sotomayor Eduardo M. , Borrello Ivan M. , Pinilla-Ibarz Javier 
Published: October 2019

Abstract
Abstract 2439
HDAC11 is the newest member of the HDAC family. The physiological role of this HDAC was largely unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in myeloid cells in-vitro1. To better elucidate the role of HDAC11 in these cells, we have utilized an HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression /transcriptional activity in immune cells in vivo.
Immature myeloid cells (IMCs) differentiate into dendritic cells, macrophages, and neutrophils and are also considered to be precursors of MDSCs in tumor-bearing hosts. Here, we show for the first time that HDAC11 plays an important role in this process. First, IMCs from the bone marrow and spleen of TgHDAC11-eGFP mice display high expression of eGFP indicative of HDAC11 transcriptional activation in these cells in the steady state. Subcutaneous injection of PANCO2 tumor cells into these mice resulted in expansion of MDSCs (identified by the expression of CD11b+/GR1+ [Ly6G and Ly6C] with variable expression of CD49d and CD115) in their lymphoid organs which was similar in magnitude to the expansion observed in tumor-bearing wild type (WT) mice. Of note, flow cytometric analysis revealed that expression of eGFP was significantly decreased in the myeloid compartment of tumor bearing TgHDAC11-eGFP mice, suggesting that the transition of IMC into MDSCs might require a decrease in HDAC11 expression. Reminiscent of our findings in the eGFP mice, studies in non-transgenic mice also demonstrated that tumor derived CD11b+ Ly6G+ MDSCs display less HDAC11 mRNA expression. Additional support for the regulatory role of HDAC11 in MDSC expansion/function has been recently provided by our studies in HDAC11KO mice, demonstrating the acquisition of a suppressive cell phenotype, by myeloid cells identical to MDSCs, in the steady state and in the absence of tumor challenge.
Taken together, HDAC11 might function as a negative regulator of MDSC expansion/function in vivo. A better understanding of this previously unknown role of HDAC11 in MDSC biology might lead to targeted epigenetic therapies to influence the suppressive abilities of these cells and augment the efficacy of immunotherapeutic approaches against hematologic malignancies.
1. Villagra A, et al. Nat Immunol. 2009 Jan;10(1):92-100

Disclosures:
No relevant conflicts of interest to declare.
Expression and Immunomodulatory Function of RANKL in Leukemia
Authors: Schmiedel Benjamin J , Baessler Tina , Azuma Miyuki , Kanz Lothar , Salih Helmut R. 
Published: October 2019

Abstract
Abstract 245
The TNF family member RANKL and its receptors RANK and osteoprotegerin (OPG) are key regulators of bone remodelling, but have also been shown to influence progression of malignancies like breast cancer (Tan et al., Nature 2011), myeloma (Sordillo et al., Cancer 2003) and CLL (Secchiero et al. J Cell Physiol. 2006). NK cells are cytotoxic lymphocytes that play an important role in tumor immune surveillance especially of hematopoietic malignancies. Their reactivity is influenced by a variety of activating and inhibitory molecules expressed by their target cells including several members of the TNF family. Recently, we reported that RANK, upon interaction with RANKL which can be expressed by malignant hematopoietic cells, mediates signals that impair NK reactivity (Schmiedel et al., Blood 2010 116,21:893–893). Here we extended these analyses and comprehensively studied the expression and immunomodulatory function of RANKL in leukemia. Analysis of primary leukemia cells revealed substantial RANKL surface expression in a high proportion of the investigated cases (AML, 47 of 65 (72%); ALL, 16 of 21 (76%); CML, 6 of 10 (60%); CLL, all 54 (100%)). Signaling via surface-expressed RANKL into the malignant cells mediated the release of cytokines like TNF, IL-6, IL-8 and IL-10 which have been shown to act as autocrine and paracrine growth and survival factors in leukemia. Moreover, the factors released upon RANKL signaling upregulated RANK expression on NK cells. In line, NK cells from leukemia patients (n=75) displayed significantly (p<0.001, Mann-Whitney U-test) higher RANK expression compared to healthy controls (n=30) confirming our notion that RANK-RANKL interaction may contribute to leukemia pathophysiology. We further found that RANK-RANKL interaction, beyond directly inhibiting NK cell function via RANK, may contribute to evasion of leukemia cells from NK immunosurveillance by creating an NK inhibitory cytokine milieu. This was revealed by impaired cytotoxicity and degranulation in response to leukemia targets following exposure of the NK cells to the factors released upon RANKL signaling by leukemia cells. Notably, the RANKL-mediated cytokine release of leukemia cells could be disrupted by the clinically approved RANKL antibody Denosumab/AMG162. Thus, RANKL signaling may trigger a “vicious cycle” comprising of release of immunosuppressive cytokines and also upregulation of RANK on NK cells. The latter both directly inhibits NK reactivity and may result in augmented RANKL signaling into leukemia cells. Our data suggest that therapeutic modulation of the RANK/RANKL system e.g. with Denosumab/AMG162, which is approved for treatment of osteolysis, may be a promising strategy to reinforce NK reactivity against hematopoietic malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Result of FDG PET Imaging After Chemotherapy +/− Immunotherapy Is a Significant and Independent Prognostic Indicator of Outcome for Patients with Follicular Lymphoma: Survey From a Single Institution
Authors: Magagnoli Massimo , Mazza Rita , Gandolfi Sara , Rodari Marcello , Giordano Laura , Anastasia Antonella , Lopci Egesta , Chiti Arturo , Santoro Armando , Balzarotti Monica 
Published: October 2019

Abstract
Abstract 2674

Aim
FDG positron emission tomography (PET) is the mainstay of response evaluation in some lymphoma subgroups such as DLBCL or HL according to Cheson criteria 2007. Due to its indolent behaviour, PET restaging has been poorly explored in Follicular Lymphoma (FL)

Methods:
The analysis was retrospectively conducted in pts with FL who underwent whole-body 18F-FDG-PET as part of response evaluation at the end of first line or savage treatment program at our institution from August 2001 to June 2010.

Results:
Seventy five patients were identified. Main clinical characteristics: median age 58 (range 26– 78); male 37 pts; B symptoms 6 pts; bulky disease 5 pts; stage IV 42 pts; bone marrow involvement 32 pts. Fifty-five pts were evaluated after first line treatment program, while 20 pts after salvage therapy program. Main chemotherapy regimen: CHOP or CHOP-like 38, CVP 11, polichemotherapy containing high-dose cytosine-arabinoside 11, fludarabine containing regimens 4. Furthermore, 19 pts underwent autologous peripheral stem-cell transplantation after either first line or salvage therapy. Eleven pts also received consolidation radiotherapy. Forty-two pts received Rituximab during chemotherapy. At the end of treatment, 54 pts reached complete remission as confirmed by PET. With a median follow-up of 53 months, a significantly lower actuarial 4yr PFS was observed in post-treatment PET+ versus. PET- patients: 35.1% vs. 74.8% (log rank p<0.01). Among all other prognostic factors analyzed (B-symptoms, bulky disease, chemotherapy regimens, chemotherapy vs chemoimmunotherapy, first line therapy vs salvage chemotherapy), only stage IV showed a correlation with PFS.
In a multivariate Cox model including all patients, post-treatment PET+ (HR 2.20; C.I. 95%: 1.02–4.76 p<0.04) and Stage IV (HR 3.08; C.I. 95%: 1.23–7.73 p<0.01) were unfavorable predictors for PFS.

Conclusion:
This retrospective study demonstrates that post-treatment negative PET is a powerful predictor for PFS. Patients who are PET- can expect a prolonged PFS either in first line or successive lines of treatment. Future clinical trials are needed to evaluate a PET oriented approach focused on improving outcomes according to PET response.

Disclosures:
No relevant conflicts of interest to declare.
B Cell Lymphoma, Unclassifiable: Survival Advantage for Aggressive Therapy
Authors: Cobain Erin , Ahmadi Tahamtan , Hoffmann Marc , Loren Alison W. , Frey Noelle V. , Svoboda Jakub , Luger Selina , Stadtmauer Edward A. , Nasta Sunita D. 
Published: October 2019

Abstract
Abstract 2689

Background:
Burkitt lymphoma (BL) and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BLL) are mature B-cell non-Hodgkin lymphomas with an aggressive clinical course. Whereas the advent of short, intensive, multi-agent chemoimmunotherapy regimens has significantly improved the outcomes for BL patients (pts), questions remain regarding the optimal therapy for BLL.
Patients and Methods: We analyzed 25 patients (pts), aged 20 to 73 (median: 51 years), treated at the University of Pennsylvania for either BL or BLL from 2005 to 2010. All pts had c- myc+ lymphoma, with a Ki-67>98% and a negative HIV test. In order to be classified as BLL, expression of bcl-6 was required. Bcl-2 expression was noticed in 7/14 (50%) of BLL cases. All patients had Stage III/IV disease. All but two pts had high-risk disease by IPI. All 10 pts with BL were treated with the R-HyperCVAD regimen. Of the 14 pts with BLL, 7 where treated with R-HyperCVAD and 7 with R-CHOP (+ intrathecal prophylaxis in five out of seven pts). No differences in IPI, PS or co-morbidities were noted between the three groups. Notably, patients treated with R-CHOP were slightly younger with median of 52 years vs. median age of 62 years for those with BLL, treated with R-HyperCVAD.

Results:
Overall response rate (ORR) to R-HyperCVAD in BL was 70%, with two treatment-related deaths. At median follow up of 24 months, progression-free survival (PFS) was 72% (95% CI: 36–90%). ORR in BLL treated with R-HyperCVAD was 86% with one treatment-related death vs.57% when treated with R-CHOP, with two treatment-related deaths. At median follow up of 9 months for both groups, PFS for BLL treated with R-HyperCVAD was 54% (95% CI: 14–83%), whereas only one pt treated with R-CHOP was free of disease after 9 months with a median PFS of 8 months and median overall survival (OS) of 9 months. Within our data set, only one of the six pts with primary refractory disease and one of four relapses responded to salvage therapy. None of the BL/BLL pts treated with R-HyperCVAD, who achieved a CR, relapsed. Four of the seven relapses after R-CHOP presented with CNS involvement.

Conclusion:
Our data suggest that R-HyperCVAD allows for long-term disease control in both BL and BLL, with a somewhat lower PFS in BLL. In contrast, R-CHOP appears to be inferior with no long-term disease control in BLL.

Disclosures:
No relevant conflicts of interest to declare.
Gemcitabine, Dexamethasone and Cisplatin (GDP regimen) As First Salvage Treatment of Patients with Refractory or Relapsed Diffuse large B Cell Non Hodgkin Lymphoma (DLBCL)
Authors: Hamid Thoraya Mohamed Abdel , Ramadan Mona fawzy , Bahnassy Abeer , Taleb Fouad Abu- , Saber Magdy 
Published: October 2019

Abstract
Abstract 2696

Background:
Many chemotherapy regimens have been used for patients with refractory or relapsed DLBCL. No regimen has demonstrated superiority to another in this setting. Specific markers could predict the response to certain agents. Aim: to evaluate the response of GDP regimen in relapsed and refractory DLBCL patients and to assess ribonucleotide reductase subunit M1 (RRM1) as a possible predictor marker to Gemcitabine response. Patients and method: Patients with Relapsed or refractory DLBCL after one previous anthracycline-containing chemotherapy regimen were treated with the GDP regimen. RRM1 was assessed by immunohistochemistry in 55 cases and its expression was correlated to treatment outcome. Patients who could not proceed to stem cell transplantation (SCT) were followed for chemotherapy response and their results are presented. Results: The study included 70 patients with a median age of 40 years (range 18–73). At start of GDP, 19 patients (27.1%) were refractory and 51 (72.9%) were relapsed. After 4 cycles of treatment, 42 patients achieved CR, with a CR rate of 60% (95% CI: 53–68%). The median DFS was 6 months (95% CI: 5 to7 months), this DFS didn't include patients who underwent auto SCT. After a median follow-up of 20 months (range 6 to 30 months), the median OS of the patients who achieved CR was not reached, while those who didn't achieve CR had a median OS of 27.4 months (p= 0.01). Correlation between response and the pretreatment prognostic factors including IPI score or any of its elements, previous line of chemotherapy, time to relapse and status at time of salvage were studied with only significant difference in response to GDP between patients with refractory and those with relapsed disease (CR= 21.1% versus 60% respectively, p < 0.001). There was significant correlation between RRMI study results and response to GDP, 30/31 cases with low RRM1 expression achieved CR (96.8%), while only 7/24 cases with high expression achieved CR (29.2%), (p=0.001). No significant relation could be found between RRM1 expression and DFS. Conclusion: GDP regimen is active for patients with refractory or relapsed DLBCL however, the duration of response is short and high-dose therapy with SCT support is the reference postremission treatment. RRM1expression can predict response to Gemcitabine-based chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.
Lenalidomide, Bendamustine, and Rituximab As First-Line Therapy for Patients > 65 Years with Mantle Cell Lymphoma: Results From the Phase I Portion of the Nordic Lymphoma Group MCL4 (LENA-BERIT) Trial
Authors: Jerkeman Mats , Kolstad Arne , Laurell Anna , Räty Riikka , Grønbæk Kirsten , Pedersen Lone Bredo , Geisler Christian H. 
Published: October 2019

Abstract
Abstract 2700

Background:
Mantle cell lymphoma is a disease of the elderly, with a median age of 70 years. Younger patients may be treated with potentially curative treatment including high dose chemotherapy. For elderly patients, however, no standard therapy has been defined. In a randomized comparison between R-CHOP and R-bendamustine (R-B) by the German StiL Group, R-B was associated with less toxicity and improved outcomes, making R-B a preferable first-line treatment option. Lenalidomide (LEN) is another active agent in MCL, with a response rate of 53% as a single agent in relapsed/refractory MCL. In the current trial, we investigate if the addition of lenalidomide to R-B may enhance efficacy, with manageable toxicity, for the older population of MCL patients.

Methods:
In phase I, the MTD of LEN was to be determined, starting with 5 mg/day increasing up to 25 mg/day in a sequential dose escalation using a 3+3 design. LEN, bendamustine and rituximab are given in 6 cycles/28 days. LEN D1-21, B 90 mg/m2 D1-2 and R 375 mg/m2 D1. The maintenance phase consists of LEN 25 mg/day, D1-21, for 7 cycles. Eligibility criteria are age > 65 years or ≤ 65 years, unable to tolerate high dose chemotherapy, with stage II-IV untreated mantle cell lymphoma.

Results:
The trial was commenced in October 2009.The phase I portion initially recruited 12 pts according to the original protocol design in 3 cohorts with LEN dose from 5–15 mg d 1–21. Median age was 72.5 years, range 66–85. MIPI high risk n=8, intermediate risk n=4. Response after 6 cycles: CR/CRu n=9/10, PR n=1/10 (ORR 100%). Molecular remission in BM: 5/9 pts. Toxicity was more profound than expected, mostly during cycle 1 (SAE n=9, AE Grade III/IV n=14). Notable was a high incidence of cutaneous and allergic AE. No patients could receive more than 10 cycles, median 6.5. A dose limiting toxicity (DLT) was noted at the dose of 15 mg. This led to a modification of the phase I protocol: Cohort A: No LEN in cycle 1, cycles 2–6: 10 mg LEN days 1–14. During maintenance, cycles 7–8: LEN 10 mg days 1–21, cycles 9–13: LEN 15 mg days 1–21. Cohort B: Same as Cohort A, but reducing B to 70 mg/m2 in cycles 2–6. Cohort C: as Cohort B, but reducing LEN to 5 mg days 1–14 cycles 2–6. In Cohort A, 2 of 6 patients experienced a DLT. Evaluation of Cohort B (6 pts) is ongoing.

Conclusions:
The addition of LEN to the R-B regimen leads to increased toxicity in elderly patients with MCL. Early data indicate a high response rate.

Disclosures:
No relevant conflicts of interest to declare.