bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modified-CHOP with Reduced Dose of Non-Pegylated Liposomal Doxorubicin ± Rituximab in First Line Treatment for Elderly Patients with Aggressive Lymphoma Non Suitables for Standard Chemotherapy.
Authors: Gimeno Eva , Sánchez Blanca , Alvarez Alberto , Pedro Carme , Abella Eugenia , Gomez Miquel , Saumell Silvia , Comin Josep , Besses Carles , Salar Antonio 
Published: October 2019

Abstract
Abstract 4752

BACKGROUND
CHOP ± Rituximab ( R) is the standard regimen for elderly patients (pts) with aggressive lymphoma but many of them are not suitable for it due to severe associated comorbidities. The aim was to evaluate retrospectively the efficacy and safety of a modified-CHOP (with reduced dose non-pegylated liposomal doxorubicin (NPLD) ± R in elderly pts with clinically aggressive lymphoma not tributary to standard anthracycline-containing chemotherapy.

PATIENTS AND METHODS
Retrospective analysis of 30 pts (16M/14W). Median age 76 years (60-88). Stage III-IV: 19 pts (58%). IPI 3-5: 16 pts (49%). Median baseline left ventricular ejection fraction (LVEF): 63% (33-80). Median NT-proBNP determination: 1431 ng/L (60-9120), 14 patients had NT-proBNP>900. All patients had one or more severe comorbidities. Schedule: NPLD 30mg/m2 (d1), cyclophosphamide 750mg/m2 (d1), vincristine 1.4mg/m2 (d1), prednisone 100mg/d (d1-5) ± R 375mg/m2 (d1) + Pegfilgrastim (d2) every 21 days.

RESULTS
Median follow-up time was 18 months. Median number of cycles was 4 (range 1-6). Complete response (CR/uCR): 24 pts (73%), Partial response: 4 pts (12%). Two pts progressed during chemotherapy and 10 pts relapsed during follow-up (5 of them dying with active disease). Overall Survival (OS) at 12 and 24 months was 76% (95%CI 61-91) and 70% (95%CI 49-91), respectively. Progression-free survival (PFS) at 12 and 24 months was 65% (95%CI 49-81) and 55% (95%CI 32-78), respectively. A total of 154 cycles were administered. 52% of patients showed grade III-IV neutropenia and 33% of them required hospital admission for febrile neutropenia. LVEF neither NT-proBNP value was significantly different before and after treatment with one patient showing an important improvement in his LVEF. Multivariate analysis recognized NT-proBNP determination >900ng/L as the most negative important factor in OS and PFD.

CONCLUSION

Disclosures:
No relevant conflicts of interest to declare.
Non Hodgkin Lymphoma: Experience of a Referral Hospital.
Authors: Castellanos-Sinco Humberto , Rivas-Vera Silvia , Argote Victoria E. Ferrer , Martínez-Murillo Carlos , Peñafiel Christian Omar Ramos 
Published: October 2019

Abstract
Abstract 4774

Introduction
Non-Hodgkin lymphomas corresponds a heterogeneous group of neoplasms deriving of lymphocytes, in development countries represents a great cause of morbility and mortality. The General Hospital of Mexico is a referral centre localized in Mexico City, whose first cause of primary hematology attention in NHL.

Material and methods
Is an observational, descriptive and retrospective study, based on medical records of patients treated between 1992-2009.

Objectives
Determine the response, overall survival (OS) and event free survival (EFS) (progression, death or last visit) associated with treatment by CHOP as first line treatment without rituximab and four cycles of DEP as a second line treatment (dexamethasone 40 mg/m2 IV daily, days 1-4, VP-16 300 mg/m2 IV daily, days 1-2 and cysplatin 100 mg/m2 IV day 1), in cycles of 21 days each one.

Results
In a period of 17 years, 303 of 632 patients were eligible. The average age was 52 years, with male:female relation 1:1.1. Thirty four percent of the sample were older 60 years. The most frequent NHL was diffuse large B cell lymphoma (DLBCL) (N=146 treated), 60% were IPI low plus intermediate low; the most frequent indolent NHL were follicular lymphoma (N=20 treated), 71% were FLIPI low plus intermediate. The resting 94 cases were treated with CHOP, too.

Conclusion
The global trend is the addition of rituximab to all of CHOP-based regimens. In our country, because the economics limitations, the use of rituximab is low. The CHOP regimen remains the first line treatment; and the second line treatments are based on the experience of the institutional protocols. DEP is the institutional protocol for second line treatment and their response, OS and EFS are comparable to more expensive protocols (ESHAP, DHAP). Concluding that DEP is a low toxic and cheaper second line regimen and this could be an alternative for development countries.

Disclosures:
No relevant conflicts of interest to declare.
Response of Patients with Aggressive Non Hodgkin's Gastro Intestinal Tract Lymphoma to Upfront Rituximab Based Chemotherapy: A Single Institution Experience.
Authors: Ciobanu Bety , Sreenivasappa Shylendra B , Shah Mousami , Yim Barbara , Catchatourian Rosalind 
Published: October 2019

Abstract
Abstract 4791

Background
Response and factors affecting response in patients with aggressive Non Hodgkin's Gastro Intestinal (GI) tract lymphoma to upfront Rituximab based chemotherapy is not well characterized.

Methods
41 consecutive pts diagnosed and treated with GI tract lymphoma in 2002 to 2009 were studied as a retrospective cohort for clinical presentation, prognostic characteristics and long term survival. Prognostic characteristics and survival was analyzed using logistic regression and Cox Proportional Hazards model. Multiple imputation methods were used for missing data.

Results
41 pts, median age at presentation was 58 yr (28-80). 10 (24.4%) were African Americans, 22 (51.2%) were Hispanics and 10 (24.4%) were Caucasians. 35 (85.4%) had gastric lymphoma and 6 (14.6%) had intestinal lymphoma. 33 pts had aggressive NHL. 31 had Diffuse large B cell lymphoma, 2 Mantel cell lymphoma and 1 Burkitt's lymphoma. 6 (17.6%) presented with stage IE, 4 (11.8) stage II1, 6(17.6%) Stage II2, 7(20.6%) Stage IIE, and 10 (29.4%) Stage IV. 28(82.3%) pts were diagnosed by endoscope. 5 (14.7%) pts underwent surgery as they presented with obstruction or bleeding, none underwent curative resection. All pts received Rituximab based chemotherapy upfront. 29 received CHOPR, 2 CVPR and 2 Hyper CVAD R. Mean follow up was 23.7 months.
22 (64.8%) pts had a complete response, 6 (17.6%) partial response and 6 (17.6%) had progressive disease. 11 pts relapsed. The median disease free survival (DFS) was 13 months (1-105). Age was the sole significant prognostic factor that influenced DFS OR 1.047 CI 1.003-1.094). Age (OR 1.164 CI 1.045-1.296), stage (OR 1.743 CI 1.053-2.888) and performance status (OR 2.703 CI 1.030-7.097) were factors which significantly affect survival.
Survival function was 100%, 55.6% and 58.3% for low, intermediate and high risk group of stage modified IPI for gastric lymphoma. 100%, 70% 58.3% for low intermediate and high risk group as per the revised IPI but survival functions are not significant.
12 (35.3%) of pts tolerated chemotherapy with no grade 3 or 4 adverse events. 13 (38%) had g 3or 4 hematological toxicity. 5 (15%) had surgery post chemotherapy. 2 (6%) has GI perforation and 3 (9%) developed GI bleeding post chemotherapy. Surgical complications occurred after the 1st cycle of chemotherapy.

Conclusion
Aggressive Non Hodgkins GI lymphoma can be effectively treated with Rituximab based chemotherapy as upfront therapy with a response rate of 83%. Age, stage and performance status significantly effect survival. R IPI may need to be revised to predict survival in gastric lymphoma. 15% treated with chemotherapy upfront may need surgery for complications. Perforation rate was about 3% and most surgical complications occur after 1st cycle of chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.
Efficacy and Safety of Yttrium-90 Ibritumomab Tiuxetan in Older Patients with Indolent Non-Hodgkin Lymphoma.
Authors: Capalbo Silvana , Palumbo Gaetano , Dell'Olio Matteo , Franzese Maria Grazia , Guarini Attilio , Di Renzo Nicola , Spinosa Giuseppina , Lapietra Angela , V Elsa Pennese , Cascavilla Nicola 
Published: October 2019

Abstract
Abstract 4795

Introduction
Radioimmunotherapy (RIT) has emerged as an important treatment options for patients with non-Hodgkin lymphoma (NHL). Yttrium-90 ibritumomab tiuxetan (Zevalin®) consist of ibritumomab, a murine monoclonal antibody to CD20, conjugated to the metal chelator tiuxetan for retention of the beta emitter Yttrium-90. Clinical trials with this agent have demonstrated significant activity in indolent NHL with mild toxicity. The median age of NHL patients included in these trials is mainly < 65 years. Our aim was to evaluate the effectiveness of Zevalin as treatment option for patient > 65 years old with indolent NHL.

Patients and Methods
Between November 2005 to June 2009 fifteen patients, five males and ten females, median age 76 years (range 67-82), with indolent NHL (13 follicular and 2 small lymphocytic) were treated with Zevalin. Six patients had stage IV disease, five stage III and four stage II. All patients received an initial infusion of rituximab at a dose of 250 mg/m(e)2 on day 1 and a second infusion at same dose on day 8 followed by a weight-based dose of Zevalin (median dose 1006 MBq; range 668-1260). Eight patients perfomed Zevalin as consolidation after first line therapy with Rituximab plus chemotherapy (6 R-CHOP, 1 R-FN, 1 R-COMP): of these three were in complete remission (CR) and five in partial remission (PR). Seven patients perfomed Zevalin in relapse (four in first and three in second relapse).

Results
After RIT 13 of 15 patients were evaluable. Overall response rate was 92% (10 CR, 2 PR); in particular all patients in first line of treatment achieved CR. One patient had stable disease. At a median follow-up of 15 months (range 2-34), all patients are alive in persistent CR or PR. One of two patients in PR achieved CR after successive therapy. Treatment was well tolerated; transient thrombocytopenia (grade 3-4) was seen in 9 patients and transient neutropenia (grade 3-4 ) in 6 patients. Only one patient developed herpex-zoster virus infection.

Conclusion
In our experience, Zevalin produces high response rate (up to 90%) and durable remission without severe toxicity in older patients with indolent NHL. Notably, in first-line treatment, RIT resulted in PR-to-CR conversion in all five patients in PR after the R-chemotherapy. The favourable safety profile of this regimen makes it an effective consolidation treatment for older patients who, because of age and comorbidity, are not eligible for intensive treatment as high-dose therapy and stem cell transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Abbreviated, Dose Dense Fludarabine and Rituximab for Elderly Patients with Indolent B Cell Malignancies.
Authors: Ballester Gabriela , Frazer Lisa , Tirona Maria , Ballester Oscar F 
Published: October 2019

Abstract
Abstract 4796

Introduction
Therapy for indolent B cell malignancies is primarily palliative. Therefore limiting toxicities by reducing drug exposure is desirable, particularly in elderly individuals. The combination of fludarabine and rituximab has been extensively used in patients with these disorders. We sought to decrease the number of fludarabine cycles, attempting to maintain the high response rates of this combination by increasing the doses of rituximab and the dose density.

Patients and Methods
We designed an abbreviated, but dose dense regimen (addFR) consisting of fludarabine 25 mg/m2/d for 5 days on weeks 1, 6 and 11 plus rituximab at 375mg/m2 on weeks 2-5 and 7-10. Maintenance was offered to responding patients with rituximab for 4 weekly doses every 6 months (for 2 years). This schema represents a 50% decrease in the dosage on fludarabine with a 33% increase in the dosage of rituximab compared to the standard regimen. Twelve patients with a median age of 70 years, (range 43 to 85, 9 of the 12 patient are older than 65 years of age) have been treated. Nine patients had chronic lymphocytic leukemia (CLL, n= 5) or small lymphocytic lymphoma (SLL, n= 4). Three patients had marginal zone lymphoma (MZL). Three patients had received prior therapy. Responses were assessed by standard criteria 4 weeks after completion of the planned 11 weeks of therapy.

Results
Two patients are still completing their 11 weeks of therapy. Ten patients have completed the 11 weeks of addFR. They are evaluable for toxicity and responses. Hematological toxicities included neutropenia Grade >III in 2 patients with a single episode of neutropenic fevers requiring hospitalization. One patient with refractory disease was shown to have histological transformation from SLL to a diffuse large B cell lymphoma. All of the remaining 9 patients achieved a complete clinical remission, including 8 patients with CLL/SLL and 1 patient with MZL. With a median follow up of 13 months (range 10 to 23 months); these 9 patients have remained free of disease progression.

Conclusions
addFR seems to be well tolerated and effective even in patients older than 65 years of age. Experience with a larger number of patients and longer follow up is needed.

Disclosures:
No relevant conflicts of interest to declare.
Improved Immune Reconstitution After Bortezomib-Based Acute Graft-Versus-Host Disease Prophylaxis for HLA-Mismatched Unrelated Donor Reduced-Intensity Conditioning Allogeneic Transplantation.
Authors: Koreth John , Stevenson Kristen E. , Kim Haesook T. , McDonough Sean , Herrera Maria I. , Reynolds Carol G. , Murga Gorka , Ho Vincent T. , Cutler Corey , Armand Philippe , Soiffer Robert J. , Antin Joseph H. , Alyea Edwin P. , Ritz Jerome 
Published: October 2019

Abstract
Abstract 48

We recently reported on the use of the proteasome-inhibitor bortezomib as a novel strategy to control acute graft-versus-host-disease (GVHD). We evaluated bortezomib, tacrolimus and mini-methotrexate for GVHD prophylaxis after reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) with unrelated donors mismatched at 1-2 HLA loci (-A, -B, -C, -DRB1). The regimen was safe, with zero non-relapse mortality. There was a 13% incidence of grade II-IV acute GVHD.
We analyzed immune reconstitution in the bortezomib cohort (n=24) [Bort] vs. i) 8/8 matched-related donor (-A, -B, -C, -DRB1) RIC HSCT cohort (n=96) [MRD]; ii) 8/8 matched-unrelated donor RIC HSCT cohort (n=139) [MUD]; and iii) 1-2 HLA mismatched-unrelated donor RIC HSCT cohort (n=24) [MMUD]. Comparator groups received sirolimus, tacrolimus and mini-methotrexate GVHD prophylaxis. All received fludarabine/busulfan conditioning and G-CSF mobilized adult-donor peripheral blood stem cells.
All groups had rapid hematopoietic engraftment and >90% median donor-chimerism by day +45 post-HSCT. They were not different with regards to age (p=0.53), sex (p=0.39) and acute grade II-IV GVHD (p=0.63). There was a difference in the proportion of good-risk disease: [Bort] (46%), [MRD] (21%), [MUD] (14%) and [MMUD] (21%) (p=0.005). Chronic GVHD was also different: [Bort] (41%), [MRD] (39%), [MUD] (53%) and [MMUD] (67%) (p=0.03).
Peripheral blood cells incubated with directly conjugated monoclonal antibodies defining distinct lymphocyte populations were analyzed by flow cytometry. Lymphocyte subsets included T (CD3+, CD4+, CD8+) B (CD19+, CD20+) NK (CD56+CD16+) NK-T (CD56+CD3+) and regulatory-T (Treg; CD4+CD25+) cells.
Unadjusted analyses revealed no significant differences in B, NK, NK-T or Treg recovery. In contrast, CD3+, CD4+ and CD8+ T-cell reconstitution was significantly higher in the bortezomib group, especially at 3 months post-HSCT.
T-cell immune reconstitution parameters are improved after HLA-mismatched RIC HSCT and bortezomib-based GVHD prophylaxis. Importantly this can be accomplished with rapid hematopoietic engraftment and without increased GVHD incidence in patients without HLA-matched donors.

Disclosures:
Off Label Use: bortezomib for GVHD control.
HERG K+ Channels Promote Angiogenesis by Enhancing the Expression Level of VEGF in Leukemia Cells in Vitro.
Authors: Li Huiyu , Jie Shenghua , Tian Yuan , Gao Shaoyang , Guo Dongmei , Guo Linlin , Huang Shiang 
Published: October 2019

Abstract
Abstract 4818

Introduction
FOur previous studies demonstrated that HERG1 K+ channels are aberrantly expressed in leukemia cells. Recent studies also indicate the leukemia cells to have influence on angiogenesis. If there are any involvements of HERG1 K+ channels on the leukemia-induced angiogenesis are not yet investigated. In this study, the effect of HERG1 K+ channels in K-562 cells on angiogenesis was measured by the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), acknowledging that these are critical steps for angiogenesis. The possible mechanism of HERG K+ channels on leukemic cells in angiogenesis is also investigated by measuring expression level of VEGF in both K-562 cells and primary leukemic cells.

Methods
K-562 cells were cultured in the medium containing various concentration (0,10.20,40uM) of E-4031, a HERG1 K+ chnanel special inhibitor. HUVECs were seeded in the conditional medium and HUVEC proliferation was measured by the CCK-8 cell proliferation assay. HUVEC cell migration was performed by Boyden chamber (Trans-well). The HUVECs were seeded in the up-chamber and the conditional medium was in down-chamber. The angiogenesis of HUVECs cultured in conditional medium were measured by endothelial tube formation in Matrigel in vitro. The role of HERG K+ channels on VEGF secretion by leukemic cells was determined by ELISA and VEGF mRNA expression of leukemic cells were examined by RT-PCR.

Results
The results showed that blocking HERG K+ channels on K-562 cells could inhibit the capacity of K-562 cells to induce human HUVEC proliferation, migration and tube formation in a concentration manner in vitro. This suggests that HERG1 K+ channels could influence the cross-talk between the leukemic cells and vascular endothelial cells. Further analyses revealed that HERG1 K+ channels can increase the capacity of K-562 cells and primary leukemia cells to produce VEGF with up-regulation of VEGF mRNA. The similar results were also obtained from other tumor cells.

Conclusions
We demonstrated that HERG1 K+ channels on the membrane of leukemic cells have a promoting effect on angiogenesis. The mechanism is that HERG1 K+ channels can increase the level of VEGF expressions. This may be a critical step of HERG1 K+ channels on tumor induced angiogenesis.

Disclosures:
No relevant conflicts of interest to declare.
Spherocytic Hemolytic Anemia Caused by Disruption of GATA1-FOG1 Interaction.
Authors: Shimizu Ritsuko , Hasegawa Atsushi , Yamamoto Masayuki 
Published: October 2019

Abstract
Abstract 775
Transcription factor GATA1 is essential for erythroid/megakaryocytic cell differentiation. Gene ablation studies have revealed that GATA1 plays essential roles in the differentiation of erythroid and megakaryocytic lineages. Two functional zinc finger domains have been identified within the GATA1 molecule, and N-terminal finger (NF) is required for the association with cofactor FOG1 and also DNA recognition. Several substitution mutations in the GATA1 NF that diminish association of GATA1-FOG1 have been identified in patients with thrombocytopenia and anemia. We previously established a genetically engineered mouse model, which mimics a human disease X-linked thrombocytopenia with inherited GATA1 mutation, utilizing the transgenic complementation rescue approach. GATA1-deficient mice were successfully rescued from embryonic lethality by excess expression of mutant GATA1 (GATA1V205G) and showed severe thrombocytopenia with impaired cytoplasmic maturation of megakaryocytes resembling the human disease. However, these mice did not show dyserythropoietic phenotype except for the attenuated erythropoiesis under stress conditions. On the contrary, GATA1-deficient mice rescued by transgenic expression of GATA1V205G at the level comparable with that of the endogenous GATA1 hardly survived though the postnatal stage. Accordingly, we analyzed rescued embryos during perinatal period. At 18.5 embryonic days, expected number of rescued embryos survived although they showed macroscopic anemia, indicating that embryonic erythropoiesis was not fully sustained by transgenic expression of GATA1V205G at the endogenous level. Surprisingly, rescued newborns suffered from severe anemia and jaundice. Serum indirect bilirubin level was significantly elevated and circulating erythrocytes showed abnormal morphology characterized as spherocytes by means of scanning electron microscopic observation. The expressions of Band3 gene/protein were strikingly diminished in the rescued erythroid cells, while expression of the other membrane related genes varied in individuals. Thus, these results indicate that hemolytic event associated with the lack of Band3 and dysfunction of erythrocyte membrane is induced during perinatal period, and GATA1 maintains the erythroid membrane homeostasis through interaction with FOG1.

Disclosures:
No relevant conflicts of interest to declare.
Spry1 Plays Selective Hematopoietic Roles as An Erythropoietin - Modulated Positive Regulator of Erythropoiesis.
Authors: Sathyanarayana Pradeep , Pradeep Anamika , Licht Jonathan D. , Wojchowski Don M. 
Published: October 2019

Abstract
Abstract 777
The four vertebrate Sprouty (Spry1-4) proteins are molecular adaptors, best known as negative regulators of MAP kinase activation mediated by FGFR, VEGFR and RET. Prior studies in human hematopietic stem cells and zebrafish implicated Spry proteins in stem cell development. Presently, we have ascertained the role of Spry1 in erythroid development using cellular models and in knockout mice. Treatment of UT7 erythropoietin-responsive cells led a strong increase in phosphorylation of Spry1 and Spry2 on critical N-terminal tyrosine sites of these proteins (Y53 and Y55, respectively). UT7 cells engineered to constitutively express Spry1 also demonstrated decreased ERK activation in response to erythropoietin treatment. Spry expression was measured in developing primary bone marrow (pro)erythroblasts by real time PCR. Spry1 was expressed most prominently in erythroblasts at a level 40 times higher than Spry 2-4. Furthermore, Spry1 expression rose markedly as erythroblasts matured. To determine the role of Spry1 in murine hematopoiesis, conditional, LoxP flanked allele of Spry1 was crossed with Mx1-Cre transgenic mice and Spry1 was deleted in murine marrow by injection of mice with poly pIpC. Efficient deletion of the Spry1 gene in murine marrow did not affect lymphocytes or granulocytes and selectively led to an increased reticulocyte count (8.9% +/- 0.2% in Spry1 deleted vs. 4.9 +/- 0.5% in control mice, p<0.002). Deletion of Spry1 led to activation of splenic erythropoiesis with a four fold enrichment of CD71high, Ter119pos precursors in Mx1-Cre; Spry1flox/flox animals compared to Mx1-Cre;Spry1flox/+ animals. In ex vivo expansion cultures, however, erythroid progenitors, were significantly compromised in their intrinsic capacity to form KitnegCD71highTer119neg and KitnegCD71highTer119pos erythroblasts. Collectively these data suggest that during hematopoiesis, SPRY1 acts selectively as a non-redundant novel positive effector of EPO- dependent red cell formation.

Disclosures:
No relevant conflicts of interest to declare.