bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-Term Follow-up of Patients with HIV-Related Diffuse Large B-Cell Lymphoma (DLBCL) Treated in the Phase II Study with Rituximab and CHOP (R-CHOP)
Authors: Ribera Josep-Maria , Morgades Mireia , Oriol Albert , González-Barca Eva , Miralles Pilar , Lopez-Guillermo Armando , Gardella Santiago , López Andrés , Abella Eugènia , Xicoy Blanca , Garcia Marta , Feliu Evarist 
Published: October 2019

Abstract
Abstract 4980

Background and objective.
In the highly active antiretroviral treatment (HAART) era R-CHOP based chemotherapy has proven to be feasible and effective in HIV-related DLBCL. However, the available information on long-term follow-up of patients in remission of lymphoma is scarce. In addition, solid tumors constitute an emerging cause of cancer in HIV-infected patients under HAART. The follow-up of patients in complete response (CR) included in a phase II clinical trial of R-CHOP every 21 days conducted by the Spanish PETHEMA, GESIDA, GELTAMO and GELCAB groups (Ribera JM et al. Br J Haematol 2007; 140: 411–419) has been analyzed.

Patients and methods.
Out of 81 patients included in the trial 55 patients were in CR. The following data were recorded in these patients: NHL relapse, opportunistic infections (OI) and other cancers. Cumulative probabilities of OI and second cancers, as well as overall survival (OS) and event-free survival (EFS) were calculated.

Results.
Median follow-up of alive patients was 6.4 yr (range: 4.6–9.5). One patient was lost of follow-up in CR, 8 relapsed, 5 had OI (meningoencephalitis [2], Pneumocystis jiroveci pneumonia [1], varicella pneumonia [1], pneumoccal pneumonia [1], esophageal candidiasis [1], and CMV colitis [1]; 2 patients suffered 2 OI during their evolution) and 5 developed a second cancer (invasive carcinoma of cervix [1], squamous lung cancer [1], lung adenocarcinoma [1], pancreatic adenocarcinoma [1], and metastatic sarcoma of unknown origin [1]). Eight-year cumulative probability for OI was 15% (95%CI: 7%-23%) and for second cancer was 12% (95%CI: 2%-22%). Fourteen patients have died: 5 due to lymphoma relapse, 3 due to OI, 4 due to second cancer and 2 due to other reasons (sudden death and assassinate). Eight-year OS probability for the 55 patients in first CR of the lymphoma was 67% (95%CI: 48%-86%) and EFS probability was 59% (95%CI: 42%-76%).

Conclusions.
HIV-infected patients with DLBCL treated with R-CHOP and HAART followed for long-time have a significant frequency of OI and second cancers, with impact on their survival probability.
Supported in part with grants RD06/0020/1056 from RTICC, Instituto Carlos III, 36606/06 from FIPSE and P-EF/10 from FJC.

Disclosures:
No relevant conflicts of interest to declare.
Population Pharmacokinetics Study of a New Humanized Anti-CD20 Monoclonal Antibody AME-133v (LY2469298) in Patients with Previously Treated Follicular Lymphoma (FL)
Authors: Cronier Damien , Radtke David , Carpenter Susan P. , Wooldridge James 
Published: October 2019

Abstract
Abstract 4982

Background:
AME-133v is a humanized monoclonal antibody that was engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab in vitro. The safety, pharmacokinetics (PK) and preliminary efficacy of AME-133v were assessed in a Phase 1/2 clinical trial in patients with previously treated follicular lymphoma (FL). The objective of this study is to characterize the pharmacokinetics (PK) of AME-133v in the target patient population.

Methods:
5 dose levels of AME-133v (2, 7.5, 30, 100, and 375 mg/m2) were tested in a total of 67 patients with previously treated CD20+ FL. AME-133v was administered intravenously in four weekly infusions. Blood samples were obtained pre-dose and 1, 3–5 days after infusion 1, pre-dose and post-dose during infusions 2, 3 and 4, and 1, 5 and 9 weeks after infusion 4. The PK database (399 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. A number of covariates including demographic characteristics and the FcγRIIIa receptor genotype were evaluated for their influence on the AME-133v population PK parameters.

Results:
Owing to serum concentrations values falling below the limit of detection, the 2 mg/m2 dose group was not included in the analysis. The basic model selected was a two-compartment pharmacokinetic model with first-order elimination. However, a different typical value had to be determined for CL in each dose group. The typical values of V1, Q and V2 were 2.99 L, 0.94 L/day, and 3.31 L, respectively. The typical value for CL was 0.70, 0.53, 0.26, 0.27 L/day-1 for 7.5, 30, 100 and 375 mg/m2, respectively, which indicates a linearization of the elimination rate of AME-133v at doses of 100 mg/m2 and above. Inter-individual variability was moderate to high with CVs of 45.9, 34.1 and 50.0% on CL, V1 and V2, respectively. The only covariate found to influence the PK of AME-133v was BSA which explained 9.6% of the variability observed on V1. The form of the FcγRIIIa receptor was not found to have a significant effect on the PK of AME-133v.

Conclusions:
The PK of AME-133v were best described by a 2-compartment model. Clearance was found to be dose-dependent with a linearization of the elimination rate at doses of 100 mg/m2 and above. BSA has a statistically significant influence on V1 whereas the FcγRIIIa genotype does not seem to influence the disposition of AME-133v.

Disclosures:
Cronier: Eli Lilly and Comany: Employment, Equity Ownership. Off Label Use: AME-133v is an investigational agent. Radtke:Eli Lilly and Comany: Employment, Equity Ownership. Wooldridge:Eli Lilly and Company: Employment, Equity Ownership.
Pernicious Anemia Mimicking MDS by Del(3p) in Cytogenetics and Monocytic Leukemia in Trephine Biopsy by Highly Expression of CD163 Positive Cells
Authors: Parmentier Stefani , Meinel Jörg , Jakob Christiane , Frömmel Anke , Mohr Brigitte , Ehninger Gerhard , Schaich Markus , Platzbecker Uwe 
Published: October 2019

Abstract
Abstract 5038

Case Report
We report of a 53 year old woman who presented repeatedly with syncopes over a period of 3 months. Laboratory results revealed severe pancytopenia (Hb 4.6 mmol/l (7.4 g/dl), WBC 1.22 Gpt/L, platelet count 13 Gpt/L) and severe hemolysis (haptoglobin < 0.20 g/l, normal range 0.3–2.0 g/l; LDH 33.1 μmol/s*l, normal range 2.25–3.55 μmol/s*l). Routine examination of the bone marrow aspirate showed typical features of megaloblastic erythropoiesis, which could be confirmed by a low serum cobalamin level (53 pg/ml, normal 211–911 pg/ml) and the presence of anti-intrinsic factor antibody (16.84 U/ml). Additionally, atrophic gastritis was seen in biopsies taken of gastric mucosa. The diagnosis of pernicious anemia was suspected and the patient treated with cobalamin. Except for hemoglobin, the peripheral blood counts recovered within one week. Meanwhile, cytogenetics from the bone marrow revealed metaphases with del(3p) and histopathological results were suspicious of an increased number of blast cells with highly expression of CD163 possibly mimicking MDS or (acute) monocytic leukemia. Therefore, bone marrow examination was repeated two weeks after recovery, which still showed dysplastic changes paralleling hematopoietic recovery but no increased number of blast cells. Additionally, the cytogenetic aberration had disappeared.

Discussion
Diagnostic work-up for megaloblastic anemia rarely includes cytogenetic analysis of bone marrow cells. Therefore, the finding of a transient cytogenetic aberration has possibly not reported frequently before in the literature. In our case, the initial finding of del(3p) appears to be due to ineffective hematopoiesis caused by vitamin B12 deficiency which leads to impaired DNA synthesis and genomic instability. This might be an explanation for this cytogenetic abnormality which disappeared after substitution of cobalamin. CD163 is exclusively expressed on monocytes and macrophages and with signs of (slightly) increased blast counts might mimic (acute) monocytic leukemia. However, in pernicious anemia with severe hemolysis as seen in this case it might reflect an acute phase reaction, as CD163 represents a signal-inducing macrophage receptor that scavenges haemoglobin by mediating endocytosis of haptoglobin-hemoglobin complexes.
In conclusion, vitamin B12 deficiency might be associated with cytogenetic abnormalities and thus in addition to the bone marrow morphology feign certain haematological diseases.

Disclosures:
No relevant conflicts of interest to declare.
Anti-CTLA-4 Antibody Is Not Able to Trigger Apoptosis in CTLA-4 Expressing Myeloid Tumor Cells
Authors: van Bijnen Sandra , Rogkoti Maria , Withaar Marian , de Witte Theo , Muus Petra , Dolstra Harry 
Published: October 2019

Abstract
Abstract 5054
Cytoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a co-inhibitory molecule normally expressed on activated effector T cells and a subset of regulatory T cells. However, it has been reported also to be expressed on acute myeloid leukemia (AML) cells, CD34+ hematopoietic progenitor cells after stimulation as well as several solid tumor cell types. Furthermore, CTLA-4 engagement with recombinant CD80 and CD86 ligands has been shown to induce apoptosis in AML cells (Laurent et al. Br J Haematol 2007). In this study, we investigated CTLA-4 expression on different cell populations in bone marrow aspirates of myelodysplastic syndrome (MDS) patients, and explored the possibility of targeting CTLA-4 for apoptosis induction using the CTLA-4 antibody tremelimumab. Flow cytometry analysis showed CTLA-4 surface expression on immature CD34+, CD117+ and CD33+ myeloid cells, as well as CD14+ monocytic cells from MDS patients (n=11). In addition, CTLA-4 was expressed by both CD4+ and CD8+ T cells in bone marrow of both low and high risk MDS patients. In order to address whether anti-CTLA-4 antibody is able to induce apoptosis in myeloid leukemic progenitor cells, we incubated the CTLA-4-expressing myeloid cell lines HL-60 and KG1a in vitro for various time points (24h, 48h, 72h) with 25 microgram/ml tremelimumab. However, anti-CTLA-4 antibody alone as well as cross linking with a secondary antibody was unable to induce apoptosis, while serum-free conditions and irradiation induced high numbers of Annexin V and/or 7AAD positive cells. These data indicate that the anti-CTLA-4 antibody tremelimumab is unable to induce an apoptotic signal into CTLA-4-expressing myeloid tumor cells.

Disclosures:
No relevant conflicts of interest to declare.
Multiple Myeloma Variant with Ascites and Cytoplasmic Crystalline Granules in Plasma Cells
Authors: Rodriguez Cesar , Janckila Anthony , Potenziani Sylvia , Sharma Vivek R. 
Published: October 2019

Abstract
Abstract 5088

CASE REPORT:

CLINICAL HISTORY:
A 62-year-old male patient who presented with anemia and findings of monoclonal gammopathy of IgA type was referred to the Hematology clinic for work-up and management of possible multiple myeloma. At the same time, the patient was being managed by the Gastroenterology service with diuretics and recurrent paracentesis for an ongoing significant ascites of unclear etiology. These interventions had been performed for a year on a biweekly basis.

CLINICAL WORK-UP:
The patient had IgA gammopathy with a monoclonal protein level of 1.2 Gm/dL and findings on skeletal survey consistent with lytic lesions in the pelvic bones.

PROCEDURE:
A bone marrow biopsy obtained from the patient revealed a plasmacytosis of 15% with atypical crystalline cytoplasmic inclusions seen in the majority of plasma cells and some histiocytes as well. The transudative ascitic fluid was analyzed for crystalline deposits, but these could not be conclusively detected even though there were inclusions seen in some macrophages that may represent remnants of the crystals.

TREATMENT:
The patient was diagnosed with IgA myeloma given the above findings and was treated with a combination of Revlemid, Velcade and Dexamethazone with good response in terms of his IgA monoclonal protein as well as in significant improvement in his ascites, which essentially resolved. He no longer required therapeutic paracentesis upon initiation of chemotherapy and was able to get weaned off of diuretics as part of his treatment.

CONCLUSION:
This case represents what we believe to be a rare variant of multiple myeloma that presented with monoclonal gammopathy in the blood as well as concomitant ascites. The bone marrow showed plasma cells containing crystalline inclusions. The precise nature of these inclusions is presently unknown, however it is felt most likely to be precipitated immunoglobulins. We plan to investigate this further. For reasons that are not entirely clear, this particular biology appears to induce a reactive process in the peritoneum causing a development of ascites. The resolution of such ascites with treatment directed toward the myeloma seems to indicate that the two are related. A case similar to this was reported by Doctors Martin, et al in 1987 with a patient presenting with similar type of crystalline inclusions in plasma cells with clinically associated ascites.1 There was no information available on treatment effect and so it was not possible to tie the clinical presentation of the myeloma and ascites together.

Disclosures:
No relevant conflicts of interest to declare.
Sulforaphane Synergistically Enhances the Cytotoxicity of Arsenic Trioxide in Multiple Myeloma Cell Lines Through Generation of ER Stress
Authors: Doudican Nicole A , Mazumder Amitabha , Orlow Seth J 
Published: October 2019

Abstract
Abstract 5140
Persistent paraprotein production in plasma cells necessitates a highly developed rough endoplasmic recticulum (ER) that is exquisitely sensitive to perturbations in protein synthesis. Targeting ER stress- related signaling has been clinically validated in the treatment of multiple myeloma (MM) as evidenced by the response to treatment with bortezomib (BTZ). Despite impressive response rates, BTZ carries the potential for serious side effects, and the development of resistance to BTZ is a clinical issue. We therefore sought to identify novel drug combinations that effectively generate ER stress. Here, we report that sulforaphane, a naturally occurring isothiocyanate found in cruciferous vegetables, synergistically enhances the cytotoxicity of arsenic trioxide (ATO), an agent that has shown clinical activity in MM, in a panel of MM cell lines. As single agents, both 1 μM sulforaphane and 0.5 μM ATO have a modest effect on cellular proliferation in a panel of MM lines. However, when the agents are administered in combination, cellular proliferation is dramatically reduced. For example, in PCNY-1 MM cells, 1 μM sulforaphane has no effect and 0.5μM ATO causes a 29% reduction in proliferation. However, when administered together, the agents enhance growth inhibition to 73%, with a CI of 0.632 indicative of synergy. Four out of 5 MM cell lines tested displayed sulforaphane and ATO synergy. Combination treatment resulted in enhanced apoptotic induction as demonstrated by cleavage of PARP. Enhanced induction of ER stress signaling and activation of the unfolded protein response (UPR) upon combination treatment was demonstrated by enhanced expression of the molecular chaperone HSP90 along with increased phosphorylation of PERK (an ER transmembrane kinase and proximal effector of the UPR) and eIF2 (translational initiation factor). Additionally, increased splicing of XBP1 (a transcription factor of UPR target genes) was apparent upon combination treatment as compared to treatment with either agent alone. Our results show that sulforaphane can synergistically sensitize MM cells to the cytotoxic effects of ATO through promotion of ER stress generating mechanisms. Based upon these promising results, further evaluation of this safe, natural product as an ATO sensitizer in a clinical trial of MM patients is warranted. Additionally, this approach holds the promise as a means to identify and clinically validate natural products effective in the treatment of MM and/or inhibition of progression of asymptomatic MM.

Disclosures:
No relevant conflicts of interest to declare.
DISTINCT CLINICOLABORATORY CHARACTERISTICS of the t(14;19)(q32;q13)-POSITIVE SPLENIC MARGINAL ZONE LYMPHOMA
Authors: Julhakyan Hunan , Magomedova Aminat , Kravchenko Sergey K , Obukhova Tatyana N , Samoylova Rima , Kaplanskaya Irina B 
Published: October 2019

Abstract
Abstract 5200

Background:
Splenic marginal zone lymphoma (SMZL) is a well recognized B-cell neoplasm which is characterized by splenomegaly, bone marrow involvement, immunologically by typical phenotype of marginal zone cells. The most frequent cytogenetic findings are involvement of chromosomes 1, 3, 7(usually deleted in 7q) and 8. The t(14;19)(q32;q13) is a rare cytogenetic abnormality with bcl-3 rearrangement that has been reported in other B-cell lymphomas.

Aims:
To describe the clinical, morphological, immunophenotypic findings in SMZL associated with t(14;19)(q32;q13).

Methods and results:
In Hematological Research Centre, Moscow between January 2001 and May 2011 three cases SMZL with t(14;19)(q32;q13) were identified. All patients were males with age 51, 58, 67 y.o. Lymphoma presented with B-symptoms, high level of lactate dehydrogenase (LDH), hepatosplenomegaly and regional lymphadenopathy (enlarge splenic hilar lymphnodes). The hemoglobin was 92 g/l, 110 g/l, 122 g/l. All patients had normal count of leukocytes with an absolute lymphocytosis (lymphocytes count 72 × 109 g/l, 79 × 109 g/l, 83 × 109/l) and thrombocytopenia. Morphological examination of peripheral blood and bone marrow lymphocytes showed that all lymphocytes are atypical with wide cytoplasm and nuclear indentation. In all cases there was nodular type of bone marrow involvement, composed of majority medium sized cells. Immunophenotypic analysis has shown the expression of mature B-cells antigens (CD19, CD20, CD22, FMC7, sIg) and absence of ÑD10, CD23, CD5, CD43, CyclinD1.
Two patients were treated with CHOP-regimen without any response. They progressed with spleen enlargement and decreased of thrombocytes counts. All 3 patients undergo splenectomy. Weight of spleen was 1800 g, 2083 g, 2850 g. Splenic section generally show massive nodular pattern (involvement of the white and red pulp) associated with diffuse invasion of the sinuses. In all cases discovered high Ki-67. All patients demonstrated progression after splenectomy during 3–6 months that was characterized by increase of leukocytes count (range 45,4 – 101,8 × 109 /l), high level of LDH, appearance of peripheral and visceral lymph nodes. Considering the increase leucocytes, presence of lymphadenopathy in all cases CHOP, FMC regimen were used. All patients died of disease progression and infectious complications. Time of observation was 21, 30, 34 months.

Conclusions:
The t(14;19)(q32;q13)-positive SMZL is distinct variant which is characterized by rapid progression after splenectomy, poor responses to chemotherapy and short survival. So t(14;19)(q32;q13) may be regarded as a poor prognostic factor.

Disclosures:
No relevant conflicts of interest to declare.
Endocrine Late Sequelae in Long-Term Survivors of Childhood Non-Hodgkin Lymphoma
Authors: van Waas Marjolein , Neggers Sebastian J.C.M.M. , te Winkel Mariel Lizet , Beishuizen Auke , Pieters Rob , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Abstract 5215

Introduction.
Currently, the 5-year survival for childhood NHL is ∼80%. Because of this high survival rate and since treatment is administered in a growing and developing individual, long-term side effects are an important issue. Studies on endocrine long-term effects in survivors of childhood non-Hodgkin lymphoma (NHL) are scarce and often limited by small sample sizes, or by the fact that data of NHL survivors have been combined with that of survivors of other malignancies. Aim of this study was to investigate the long-term endocrine effects of treatment for childhood NHL.

Methods.
A single centre cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 yrs (9–40 yrs) and time after cessation of therapy 12 yrs (4–30 yrs). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMDTB) and lumbar spine (BMDLS) were measured. Bone mineral apparent density of the lumbar spine (BMADLS) was calculated to correct for bone size. Thyroid stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), Inhibin-B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls.

Results.
Height was lower in survivors at follow-up (mean SDS −0.36, P=0.002), but further analysis showed that shorter stature was already present at diagnosis (mean SDS −0.28, P=0.023). BMI, percentage fat, BMC, BMDTB, BMDLS and BMADLS were not different from controls. LBM was lower in survivors (mean SDS −0.47, P=0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three out of 20 adult females had low AMH levels and 55% (23/42) of adult males had low Inhibin-B levels.

Conclusion.
Twelve years after cessation of therapy, survivors of NHL did not develope adiposity, osteopenia or osteoporosis or thyroid disease. Male NHL survivors seem to be at risk for infertility.

Disclosures:
No relevant conflicts of interest to declare.