bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Signature Distinguishes Between Primary Mediastinal B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma with Primary Involvment of Mediastinal Lymph Nodes
Authors: Mangasarova Jana K , Misuyrin Andrew V , Magomedova Aminat U , Kravchenko Sergey K
Published: October 2019

Abstract 2654

Background.

Primary mediastinal (thymic) B-cell lymphoma (PMBL) has been recognized as a subtype of diffuse large B-cell lymphoma (DLBCL). It has its distinctive clinical and morphological features but differs from other types of DLBCL due to peculiar immunophenotype and gene expression profile. PMBL have a distinct gene signature with several highly expressed genes including MAL, JAK2, PDL1, PDL2 and TRAF1. PMBL molecular signature was associated with a more favorable survival compared to DLBCL cases with a non-germinal and germinal-center profile, supporting a distinct natural history for PMBL [A. Rosenwald et al., 2003, G. Lenz et al., 2008].

Aim.

The aim of our study was to determine whether the quantitative expression analysis of JAK2, MAL, PDL1, PDL2 and TRAF1 genes may distinguish PMBL cases from other variants of DLBCL with primary involved of mediastinal lymph nodes.

Patients and methods.

31 patients with DLBCL with primary involvement of mediastinal lymph nodes and 12 patients with DLBCL without involvement of mediastinal lymph nodes were enrolled in the study. The diagnosis was made by morphological and immunophenotypic analysis of lymph nodes biopsy samples. Six healthy donors of lymphocytes constituted control group. The expression of JAK2, MAL, PDL1, PDL2 and TRAF1 genes was analyzed with RQ-PCR TaqMan hydrolyzing probes.

Results.

Normal median value of JAK2, MAL, PDL1, PDL2 and TRAF1 gene expression have been established according the data obtained in the set of normal donors. The gene was considered to be overexpressed if its value was more than normal median value + 3SD. In 12 patients with DLBCL without involvement of mediastinal lymph nodes there was no overexpression of MAL, PDL1 and PDL2 genes. In this group only 1 of 12 (8%) pts has the overexpression of JAK2 and 2 out of 12 (16%) pts the overexpression of TRAF1. In patients with DLBCL with primary involvement of mediastinal lymph nodes JAK2 gene was overexpressed in the 18/31 cases (58%), MAL–in the 6/31 (19%), PDL1–in the 2/31 (6%), PDL2–in the 5/31 (16%) and TRAF1–in the 2/31 (6%). Based on the overexpression of more than 3 genes we have separated from DLBCL group (31 cases) a distinct group with primary mediastinal (thymic) B-cell lymphoma 18/31 (58%) patients. So, in PMBL we revealed significant overexpression of at least 3 genes in 18/18 pts whereas in DLBCL with primary involvement of mediastinal lymph nodes no cases have such expression.

Our data suggest that the quantitative molecular analysis of JAK2, MAL, PDL1, PDL2 and TRAF gene expression enables to distinguish PMBL from DLBCL with primary involvement of mediastinal lymph nodes.

Disclosures:

No relevant conflicts of interest to declare.
Intrinsic Survival Capacity of Cord Blood T cells is heterogeneous and Can Be Promoted by Repeated Low-Doses of Recombinant Interleukin-7,
Authors: Deberranger Eva , Pascal Laurent B , Trauet Jacques , Choufi Bachra , Thiant Stephanie , Dessaint jean-Paul , Yakoub-Agha Ibrahim , Labalette Myriam
Published: October 2019

Abstract 3227

Background:

Umbilical cord blood (CB) transplantation is known to be associated with delayed and defective immune reconstitution, in part because recent thymic emigrants (RTEs), the most common subset among CB T cells, have limited intrinsic survival. Interleukin-7 (Il-7) has been reported to increase the initial recovery of the graft-derived T-cells compartment. The aim of this study was to investigate CB-derived T-cell survival and to define a minimal effective dose of recombinant human IL-7 (rIL-7), considering that in addition to its anti-apoptotic effect, IL-7 may enhance immune reactions that occur in the host, including uncontrolled acute GVHD.

Methods:

Fifteen CB were obtained immediately after normal-term delivery, using the same procedure as for CB banking. T cells were isolated within 12 hours by negative magnetic bead sorting and cultured for 2 weeks either directly or after being frozen in order to recapitulate clinical procedures. Unstimulated T cell cultures were conducted in parallel in medium (RPMI supplemented with 10% normal AB serum) alone or supplemented with a range of rIL-7concentrations added either only once at day 0 (100 to 1000 pg/mL) or every day (10 to 100 pg/mL). Cell viability was assessed by flow cytometric scatter analysis and staining with 3,3'-dihexyloxacarbocyanine iodide [DiOC6(3)] and propidium iodide.

Results:

In basic culture conditions, the majority of T cells had died over 2 weeks, but there was a marked heterogeneity in cell survival, as proportions of viable T cells varied from 2% to 50% (median 15%) at day 6 of culture. Interestingly, the same intrinsic characteristics of survival were observed in T cells that underwent beforehand a freezing-thawing procedure.

In cultures supplemented with rIL-7, we confirmed the efficacy of rIL-7 in maintaining CB T cell survival. A minimal dose of 20 to 50 pg/mL of IL-7 added daily was sufficient to induce the prolonged survival of CB T cells, with more than 95% of viable cells at day 6. Noteworthy, these concentrations allowed prolonged survival of CD T cells without inducing any cell proliferation, as shown by the absence of CFSE dilution. Similar results were observed comparing CB cells that had been frozen or not.

Conclusion:

Repeated low-doses of rIL-7 are required to preserve the survival capacity of CB T cells without inducing their proliferation. These results could represent a framework for clinical studies aiming at improving T cell reconstitution following allogeneic CB transplantation. Repeated administration of low-doses of rIL-7 might be especially useful in patients with low serum levels of IL-7 after conditioning.

Disclosures:

No relevant conflicts of interest to declare.
A Multicenter, Open-Label Study of Posaconazole Oral Suspension in Treatment of Patients with Invasive Fungal Infection Refractory to or Intolerant of First-Line Therapy,
Authors: Huang Xiaojun , Wang Fengrong , Chen Yuhong , Liu Ting , Wang Jianxiang , Hu Jianda , Jin Jie , Chen Fangping , Wang Shujie , Shen Zhixiang , Yu Li , Yu Kang , Liang Yingmin
Published: October 2019

Abstract 3241

Background

Invasive fungal infection represents one major health threat for patients with a compromised immune system.

Methods

We performed a multicenter, open-label clinical study of posaconazole oral suspension in the treatment of 63 patients with invasive fungal infection that was refractory to or intolerant of first-line therapy. The primary efficacy end point was the cumulative response rate at the end of posaconazole treatment. The safety end points were adverse events (AEs), laboratory test results, and vital sign measurements, as well as patients' rate of withdrawal because of AEs or laboratory abnormalities.

Results

Of the 63 patients enrolled in the study, 62 (98.4%) were treated with study drug and included in the safety set. From those 62 patients, 59 patients entered the full analysis set for efficacy data assessment. A total of 47 patients were included in the per-protocol set. The cumulative clinical response rates at weeks 4, 8, and 12 of treatment were 69.49% (41/59, 95% confidence interval [CI]: 56.13–80.81), 62.71% (37/59, 95% CI: 49.15–74.96), and 64.41% (38/59, 95% CI: 50.87–76.45), respectively. Cumulative fungal pathogens eradication rates at week 4, week 8, and the end of treatment (week 12) were 47.06% (95% CI: 22.98–72.19), 47.06% (95% CI: 22.98–72.19), and 52.94% (95% CI: 27.81–77.02), respectively. At the end of treatment (week 12), 2 patients had died; the cumulative survival rate was 96.61% (95% CI: 88.29–99.59). The incidences of AEs, adverse reactions, and SAEs were 79.0%, 32.3%, and 8.1%, respectively. None of the serious adverse reactions were related to the study drug.

Conclusions

Posaconazole is effective in treating patients with refractory invasive fungal infection. As a novel broad-spectrum triazole antifungal with a good long-term safety profile, posaconazole can be used to treat patients with fungal infection relapse after antifungal treatment, patients with fungal infection resistant to routine antifungal treatment, patients with fungal infection intolerant of routine antifungal treatment due to side effects, and patients with organ dysfunction (e.g., renal dysfunction). (ClinicalTrials.gov number, NCT00811642)

Disclosures:

No relevant conflicts of interest to declare.
Predictors of Clinically Significant Bleeding in Patients with Aortic Stenosis,
Authors: Blackshear Joseph L , Chen Dong , Thomas Colleen S
Published: October 2019

Abstract 3315

Background:

Acquired von Willebrand syndrome (AVWS) is a frequent cause of bleeding in patients with severe aortic stenosis (AS). The goals of this study were to understand the incidence and patterns of bleeding in patients with various degree of AS and identify predictors for bleeding.

Methods:

Ninety-one patients (59 men, median age 79 years) with mild, moderate or severe aortic stenosis (AS) (n=64) or heart valve replacement (n=27) were studied. Clinically significant bleeding was determined based on the 2008 NHLBI VWD diagnostic guideline (Haemophilia. 2008, 14(2):171–232). We recorded blood counts, vital signs, mean gradient, peak aortic velocity, aortic valve area (AVA) and valve area index (AVAi), time velocity integral ratio (TVI ratio), VWF antigen (VWF:Ag), VWF activity by latex immunoturbidity assay (VWF:Lx), VWF multimer analysis, and closure times of platelet function analysis ADP and epinephrine cartridges (PFA–CADP and –CEPI). VWF high molecular weight multimer (HMWM) losses were graded as normal/mild or severe when compared to pooled plasma samples from normal donors. Associations with bleeding tendency were explored using single variable and multivariable logistic regression models.

Results:

Of the 91 patients, 29 (32%) were taking warfarin, and 55 (60%) were taking aspirin. None received a thienopyridine. Clinically significant bleeding was seen in 27 (30%) patients with gastrointestinal (GI) bleeding being most common (n=13). Nine patients who bled required hospitalization. Bleeding tendency was more common in patients with a severe loss of HMWM (OR=3.18, 95% CI: 1.06–9.71, P=0.039) and in patients with AS-associated symptoms (OR=3.02, 95% CI: 1.14–8.24, P=0.027). No other echocardiographic, laboratory, or clinical features demonstrated a statistically significant association with bleeding tendency.

Conclusion:

The incidence of clinically significant bleeding in this population was about 30% with GI being the most common site. Bleeding tendency was associated with severe HMWM loss and AS-associated symptoms. This study underscores the importance of acquisition of a history of bleeding, cardiac symptoms, and VWF multimer analysis in clinical management of AS patients.

Disclosures:

No relevant conflicts of interest to declare.
Mechanistic Determinants of the Acute Coagulopathy of Trauma (ACoT) in Patients Undergoing Emergency Surgery,
Authors: Cotton Bryan A , Sixta Sherry L , Wade Charles E , Holcomb John B , Matijevic-Aleksic Nena
Published: October 2019

Abstract 3319

Introduction:

Acute coagulopathy of trauma (ACoT) is a highly lethal phenomenon whose mechanisms have yet to be clearly defined. While likely multi-factorial, it has been reported to only occur in the presence of blunt injury. The purpose of this study was to identify variables that might influence or contribute to the early development of ACoT.

Methods:

Retrospective review of all patients admitted to a Level 1 trauma center 01/2004–12/2009 who underwent emergent laparotomy. Emergent laparotomy was defined as laparotomy performed within two hours of admission. ACoT(+) was defined as arrival INR >= 1.5, while ACoT(−) was defined as arrival INR<1.5. Univariate and multivariate analyses performed. Primary outcome was the identification of those factors predicting the presence of ACoT on admission.

Results:

1218 patients were included, 337 (27%) presented with ACoT(+), 881 (73%) did not. The groups had similar demographics and pre-hospital and ED fluids. Arrival base deficit (median 8.5 vs. 4.0) and ISS (25 vs. 16) were higher in ACoT(+) as were intra-operative RBC (median 4 vs. 0 U) and plasma (3 vs. 0 U); all p<0.05. 40% of ACoT(+) patients sustained penetrating injury. Six-hour (12% vs. 1%), 24-hour (15% vs. 1%), and 30-day (23% vs. 4%) mortality were significantly greater in ACoT(+); all p<0.001. Linear regression found INR values independently associated with arrival base deficit (p<0.001) but not ISS. Controlling for age, gender, mechanism of injury, and pre-hospital resuscitation, multiple logistic regression demonstrated that arrival base deficit was an independent predictor of developing ACoT.

Conclusion:

The current study found ACoT independently associated with metabolic (base deficit), physiologic (blood pressure) and anatomic insults (ISS). Attempts to address ACoT should focus on correcting each of these components. Moreover, contrary to prior data, 40% of ACoT(+) patients sustained penetrating mechanism.

Disclosures:

No relevant conflicts of interest to declare.
Preclinical Immunogenicity Assessment of Baxter‘s Recombinant Factor VIIa,
Authors: Horling Frank M , Lenk Christine , Ahmad Rafi Uddin , Weiller Markus , Schuster Maria , Schwarz Hans Peter , Reipert Birgit M
Published: October 2019

Abstract 3327

Baxter has developed a recombinant FVIIa (rFVIIa) product for the treatment of hemophilia patients with factor VIII or factor IX inhibitors. Before entering clinical development we assessed the immunogenic safety profile of the new product candidate BAX 817 using two novel mouse models that mimicked specific aspects of the situation in patients.

Several comparative preclinical immunogenicity studies were conducted to assess the immunogenicity profile of Baxter`s rFVIIa BAX 817 in comparison to a licensed recombinant FVIIa product. Three different mouse models were used for this purpose. The first model expresses specific immune tolerance against human FVIIa and, therefore, mimics the situation in both hemophilia A and hemophilia B patients. Using this model, we asked if Baxter‘s rFVIIa is able to maintain immune tolerance to human FVIIa.

The second model is a hemophilia A model that mimics the situation in an important fraction of hemophilia A patients with FVIII inhibitors. This model expresses a human MHC-class II haplotype (HLA-DRB1*1501) that was previously shown to be associated with an increased risk for the development of FVIII inhibitors.

The third model represents a normal wildtype C57BL/6 mouse.

All mice were treated with 8 weekly doses of either Baxter‘s rFVIIa BAX 817 or a licensed recombinant FVIIa product. Total anti-FVIIa antibodies were analyzed prior to the first dose as well as after the 4th and the 8th dose using ELISA assays.

Baxter`s rFVIIa BAX 817 and a licensed recombinant FVIIa product induced similar titers of anti-FVIIa antibodies in C57BL/6 wildtype mice and in hemophilic HLA-DRB1*1501 mice. In addition, both Baxter`s rFVIIa BAX 817 and a licensed recombinant FVIIa product were able to maintain specific immune tolerance in a novel mouse model that is immunologically tolerant to human FVIIa.

Based on the data obtained we conclude that both Baxter‘s rFVIIa BAX 817 and a licensed recombinant FVIIa product have a comparable immunogenic safety profile.

Disclosures:

Horling: Baxter Innovations GmbH: Employment. Lenk:Baxter BioScience: Employment. Ahmad:Baxter BioScience: Employment. Weiller:Baxter BioScience: Employment. Schuster:Baxter Innovation GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Reipert:Baxter Innovations GmbH: Employment.
Prospective Evaluation of plasma Levels of FVIII in Patients with venous Thromboembolism,
Authors: Bittar Luis Fernando , Fonseca Bruna Mazetto , Montalvão Silmara Lima , de Andrade Orsi Fernanda Loureiro , de Paula Erich V , Annichino-Bizzacchi Joyce M
Published: October 2019

Abstract 3348

Introduction:

Venous thromboembolism (VTE) is a multifactorial disease, and increased levels of coagulation factor VIII (FVIII) has been demonstrated as risk factor for first and recurrent episodes of VTE. Some authors reported that these high levels of FVIII were still persistent after 4 years of the episode, but median follow-up in these studies are relatively short. The aim of the study was investigate if after a long-term follow-up of 4–15 years (median of 10 years), patients with high levels of FVIII after anticoagulant treatment still showed this alteration.

Design and Methods:

Previously, we selected 174 adult patients with a first episode of acute VTE between January 1990 and September 2004. One hundred seventy four healthy adult individuals selected from blood donors were chosen as controls, from the same geographic area of origin. Of this group of VTE patients, 68 patients with plasma FVIII: C levels above the 90th percentile were selected. FVIII levels (FVIII:C) were measured by a one-stage clotting assay with FVIII-deficient plasma in duplicate in an automated coagulometer. Levels were measured twice, in 2004 and then in 2011. C-reactive protein (CRP) levels were determined in the same samples by a nephelometric method to evaluate the influence of inflammation on FVIII levels. For individuals with CRP values higher than 1mg/dL, an additional blood sample was analyzed. High FVIII levels were only considered for further analysis when in the presence of normal CRP levels. The presence of post-thrombotic syndrome (PTS) was evaluated and classified clinically by the Clinical-Etiologic-Anatomic-Pathophysiologic (CEAP) classification System.

Results:

68 patients with VTE and high levels of FVIII (19M:49F) with a median age of 47 years (range 20–70) were included in the study. The control group consisted of 59 subjects (42M:17F) with a median age of 35 years (range 21–56 years). VTE was spontaneous in 26 (38.2%) patients and secondary to an acquired risk factor in 61.8%. In the 1st evaluation, in 2004, patients with VTE had higher plasma levels of FVIII:C (median 235.8 IU/dL vs. 127.0 IU/dL; p<0.001) compared to controls. In 2011, seven years after the first evaluation and after a median follow-up of 10 years after the first VTE episode, this difference was still present (median 144.6 IU/dL vs. 96.4 IU/dL; p<0.001). Patients with severe PTS (167 IU/dL) showed higher plasma levels of FVIII when compared with patients without PTS (median 141.4 IU/dL), mild PTS patients (median 142.8 IU/dL), and moderate PTS patients (median 143.2); p=0.04.

Conclusions:

Our results show that even after a median of 10 years of VTE, patients still have increased levels of FVIII. Moreover, there seems to be a relationship between severe post-thrombotic syndrome and increased plasma levels of FVIII.

Disclosures:

No relevant conflicts of interest to declare.
MT1-MMP Regulates Hematopoiesis Through HIF-Mediated Chemo-/Cytokine Release From the Bone Marrow Niche,
Authors: Nishida Chiemi , Kusubata Kaori , Tashiro Yoshihiko , Gritli Ismael , Sato Aki , Ohki-Koizumi Makiko , Seiki Motoharu , Nakauchi Hiromitsu , Heissig Beate , Hattori Koichi
Published: October 2019

Abstract 3409

Stem cells reside in a physical niche, a particular microenvironment. The organization of cellular niches has been shown to play a key role in regulating normal stem cell differentiation, stem cell maintenance and regeneration. Various stem cell niches have been shown to be hypoxic, thereby maintaining the stem cell phenotype, e.g. for hematopoietic stem cells (HSCs) or cancer stem cells. The bone marrow (BM) niche is a rich reservoir for tissue-specific pluripotent HSCs. Proteases, such as matrix metalloproteinases (MMPs) can modulate stem cell fate due to their proteolytic or non-proteolytic functions (abilities). We have investigated the role of membrane-type1 matrix metalloproteinase (MT1-MMP), known for its role in pericellular matrix remodeling and cell migration, in hematopoiesis. MT1-MMP is highly expressed in HSCs and stromal cells. In MT1-MMP−/− mice, release of kit ligand (KitL), stromal cell derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo) and interleukin-7 were impaired resulting in erythroid, myeloid and T and B lymphoid differentiation. Addition of exogenous rec. KitL and rec. SDF-1 restored hematopoiesis in vivo and in vitro. Further mechanistic studies revealed that MT1-MMP in a non-proteolytic manner activates the HIF-1 pathway, thereby inducing the transcription of the HIF-responsive genes KitL, SDF-1 and Epo.

These results suggested MT1-MMP as a critical regulator of postnatal hematopoiesis, which as a modulator of the HIF pathway alters critical hematopoietic niche factors necessary for terminal differentiation and or migration. Thus, our results indicate that MT1-MMP as a key molecular link between hypoxia and the regulation of vital HSC niche factors.

Disclosures:

No relevant conflicts of interest to declare.
Hypoxic Hematopoietic Stem and Progenitor Cells Reside in Structurally Diverse Perivascular Niches in the Bone Marrow,
Authors: Nombela-Arrieta Cesar , Pivarnik Gregory , Winkel Beatrice , Harley Brendan , Mahoney John E , Lu Jiayun , Protopopov Alexei , Silberstein Leslie E
Published: October 2019

Abstract 3417

The identification of specific microenvironments, in which Hematopoietic Stem and Progenitor Cells (HSPCs), reside within the BM is a major challenge in stem cell biology. Yet the extreme rarity of HSCs, their dynamic nature, and the lack of unique specific markers to identify them, have precluded an accurate definition of HSC niches to date. Using Laser Scanning Cytometry, a powerful emerging quantitative imaging technology that enables analysis of whole femoral sections at the single cell level, we have mapped the global distribution of hematopoietic stem and progenitor cells within femoral bone marrow cavities, and analyzed their inmediate surrounding microenvironment.

Systematic mapping of the global distribution of endogenous HSPC-enriched populations in the BM, revealed an accumulation of these cells inside endosteal regions (ER <100μm from inner bone surface), but not necessarily in contact with endosteal surfaces. Interestingly, the vast majority of HSPCs were found in direct association with BM micrrovessels, further supporting previous work, which suggested bone marrow endothelium as a major component of HSPC niches. By employing a novel imaging approach, we provide a three-dimensional (3D) microscopic overview of the unique BM vascular network found in endosteal zones, which contain the transition of bone-lining arterioles and capillaries to the sinusoidal network. Of note, HSPC association to vascular structures is not restricted to sinusoids. A significant fraction of HSPCs lied adjacent to non-sinusoidal endothelium. Using five-color imaging cytometry and pimonidazole incorporation, we have assessed the hypoxic state of HSPCs in different BM microenvironments. Our in situ analysis reveals that intracellular hypoxia is a hallmark of HSPCs, independent of their distance to bone surfaces, and more importantly, regardless of their perivascular localization. These studies provide unequivocal anatomical evidence for the intrinsic rather than environmental regulation of intracellular hypoxia in HSPCs and challenge the hypothesis of a “super hypoxic” HSPC niche.

Disclosures:

No relevant conflicts of interest to declare.
Telomere Elongation In Vivo and Clinical Response Upon Androgen Treatment in a Patient with Aplastic Anemia and a Heterozygous hTERT Gene Mutation,
Authors: Brümmendorf Tim H , Ziegler Patrick , Akkad Jamil , Brassat Ute , Vankann Lucia , Panse Jens , Wilop Stefan , Balabanov Stefan , Schwarz Klaus , Martens Uwe M. , Schrezenmeier Hubert
Published: October 2019

Abstract 3427

Telomere length both reflects and limits the replicative life-span of normal somatic cells and critically shortened telomeres are associated with a variety of disease states. In patients with aplastic anemia telomere lengths in granulocytes and lymphocytes can be found to be significantly shorter as compared to age-adjusted controls. Telomere shortening in peripheral blood cells therby mirrors telomere shortening in the underlying hematopoietic stem cell reserve, which can be severely diminished in acquired bone marrow failure syndromes. Genetic aberrations such as mutations in the gene for dyskerin or in subunits of the telomerase-complex such as the RNA subunit hTERC or mutations in the human telomerase gene (hTERT) have been described and linked to critically short telomeres found in blood cells.

We report here on a 51 year old male patient with moderate aplastic anemia (AA) and a non-synonymous variation of codon 1062 of the hTERT gene (pAla1062Thr). Cells with deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-AP), i.e. cells with a PNH phenotype, were detected (1.2% of erythrocytes, 8% of reticulocytes and 15% of neutrophils). The patient was found to have dramatically shortened telomere length below 1% percentile of normal individuals both in lymphocytes (4.28 +/− 0.02 kbp) and granulocytes (4.14 +/−0.1 kbp). Based on the clinical presentation (i.e. predominance of red blood cell transfusion dependence and thrombocytopenia, but absence of immediate risk e.g. of infections or bleeding) we decided to initiate androgen treatment rather than to initiate standard immunosuppression.

The initially red blood cell transfusion dependent and thrombocytopenic patient became completely red blood cell transfusion independent after twelve months of ongoing androgen treatment. A significant proportion of GPI-AP deficient red cells and reticulocytes could no longer be detected and only a very small proportion of GPI-AP deficient granulocytes (<1%) persisted.

The clinical and hematological improvement during androgen therapy was mirrored by a continuous and persistent lengthening of telomere length in total peripheral blood mononuclear cells (MNCs) measured by qPCR as well as in both leukocyte subpopulations measured by Flow-FISH.

To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo.

Disclosures:

No relevant conflicts of interest to declare.
Safety and Efficacy of the Novel Combination of Panobinostat (LBH589) and Everolimus (RAD001) in Relapsed/Refractory Hodgkin and Non-Hodgkin Lymphoma,
Authors: Younes Anas , Copeland Amanda , Fanale Michelle A. , Fayad Luis , Romaguera Jorge E , Kwak Larry W , Neelapu Sattva S. , Hagemeister Fredrick , Pro Barbara , de Castro Faria Silvana , Ji Yuan , Berry Donald , Buglio Daniela , Medeiros L. Jeffrey
Published: October 2019

Abstract 3718

Based on preclinical experiments that demonstrated in vitro synergism between pan-deacetylase (DAC) inhibitor Panobinostat (LBH589) with mTOR inhibitor Everolimus (RAD001) in Hodgkin and non-Hodgkin lymphoma cell lines, we conducted a phase I/II study to determine the safety and efficacy of this novel regimen. Patients were eligible if they had relapsed or refractory Hodgkin or non-Hodgkin lymphoma regardless of the number of prior regimens, including autologous and allogeneic transplantation. Everolimus was self administered orally daily and Panobinostat three times weekly on 4 dose escalation levels [Table 1]. To date, a total of 30 patients have been treated. The histologic subtypes include small lymphocytic (n=1), follicular (n=2), mantle cell (n=3), hodgkin (n=12), diffuse large B-cell (n=7), T-cell (n=3), one discordant Hodgkin/marginal zone lymphoma and one discordant Hodgkin/large cell lymphoma. The median number of prior therapies is 3 with 11 patients receiving prior autologous transplantation. 30 patients received at least 1 dose and are evaluable for safety and 28 are evaluable for response. The DLT was thrombocytopenia observed in the 4th cohort with a dose of 30mg Panobinostat and 10mg of Everolimus. Therefore, 6 patients were treated at the lower dose level of 20mg Panobinostat and 10mg Everolimus which was determined to be the maximum tolerated dose (MTD) and starting dose in the phase II portion of the study. To date, 16 patients have been treated in the phase II portion of the study. Treatment side effects are manageable with the following grade 3/4 adverse events most commonly observed: thrombocytopenia 48%, neutropenia 48% and anemia 20%. One death occurred on study, possibly related to pulmonary embolus. 20 out of 28 evaluable patients (71%) had tumor reduction ranging from -12% to -72% of whom 50% had PR or CR. Our data demonstrate safety and promising clinical activity of this novel combination in a variety of lymphomas. The phase II portion continues to enroll patients to determine the efficacy of this novel regimen.

Dose Level Everolimus Panobinostat N 1 5mg 10mg 3 2 5mg 20mg 3 3 (MTD) 10mg 20mg 6 4 10mg 30mg 2 Phase II 10mg 20mg 16

Disclosures:

Neelapu: celgene: Research Funding. Pro:Celgene: Consultancy, Honoraria.
IPSS Independent Prognostic Value of Plasma CXCL10, IL-7 and IL-6 Levels in De Novo Myelodysplastic Syndromes,
Authors: Pardanani Animesh , Finke Christy , Lasho Terra L , Al-Kali Aref , Begna Kebede , Hanson Curtis A. , Tefferi Ayalew
Published: October 2019

Abstract 3795

Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (IL-2R, IL-8, IL-12, IL-15 and CXCL10) and large cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). In order to examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex ELISA to measure 30 plasma cytokines in 78 patients with primary MDS. Compared to normal controls (n =35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (p<0.01), IL-7 (p=0.02) and IL-6 (p=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the international prognostic scoring system (IPSS), age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (p<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (p=0.01). Comparison of plasma cytokines between MDS (n =78) and primary myelofibrosis (n =127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically-relevant plasma cytokine signatures in hematologic malignancies.Figure:Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).Figure:. Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).

Disclosures:

No relevant conflicts of interest to declare.
Cladribine Alone and in Combination with Cyclophosphamide or Cyclophosphamide and Mitoxantrone in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): Long-Term Follow-up of the the Polish Adult Leukemia Group (PALG CLL2) Study,
Authors: Robak Tadeusz , Blonski Jerzy , Jamroziak Krzysztof , Calbecka Malgorzata , Dwilewicz-Trojaczek Jadwiga , Boguradzki Piotr , Dmoszynska Anna , Kowal Malgorzata , Kloczko Janusz , Piszcz Jaroslaw , Stella-Holowiecka Beata , Sulek Kazimierz , Kuliczkowski Kazimierz , Potoczek Stanislaw , Warzocha Krzysztof , Lech-Maranda Ewa , Skotnicki Aleksander , Magdalena Piotrowska , Moskwa Andrzej , Zawilska Krystyna M , Gora-Tybor Joanna
Published: October 2019

Abstract 3915

Purpose.

In 2006 we have published an early report of the prospective, randomized, multicenter study (PALG CLL2) comparing the efficacy and toxicity of cladribine alone and in combination with cyclophosphamide (CC) or cyclophosphamide plus mitoxantrone (CMC) in 508 previously untreated patients with progressive and advanced CLL (Blood. 2006;108:473–9). In this early analysis we found that CMC induced higher CR rate than CC (36% vs. 21%, p=0.004), but no differences in overall response (OR), progression-free survival (PFS) and overall survival (OS) among treatment groups were observed. The aim of the present study was to verify whether long-term follow-up might change originally published data on PFS or/and OS as well as to compare the rate of late complications including secondary neoplasms and Richter's syndrome. Methods. In PALG CLL2 study PFS was defined as the time from the end of first–line therapy to disease progression or death from any cause. OS was measured from the time of randomization to death or last contact. OS and PFS were calculated according to the method of Kaplan and Meier and compared between groups by the log-rank test. Only patients with pathologically-proven tumours diagnosed after chemotherapy initiation were considered as having secondary neoplasms or Richter's syndrome. Frequencies of secondary tumours were compared by chi2 test. Results. The median time of follow-up as of Januar y 2011 was 45.6 months (95% CI: 39.9–51.4). The results of comparison of survival times and late complications in different study arms are shown in Table 1 and Figure 1. Conclusions. Long term results for 508 r andomized patients confirm that cladribine alone, CC and CMC regimens produce comparable PFS and OS in previously untreated progressive CLL. The risk of secondary tumours does not differ in the investigated treatment groups.

Disclosures:

No relevant conflicts of interest to declare.
Pomalidomide (Pom) in Relapsed and Refractory Multiple Myeloma (RRMM) - theUARK Compassionate Use Protocol,
Authors: Usmani Saad , Waheed Sarah , Szymonifka Jackie , Panozzo Susan , Petty Nathan M , Steward Doug , Nair Bijay , Alsayed Yazan , Hoering Antje , Crowley John , Barlogie Bart
Published: October 2019

Abstract 3995

Background:

Pom is a third generation immunomodulatory drug (IMiD) which has demonstrated safety and efficacy in RRMM with prior exposure/resistant to other IMiDs and bortezomib. This is the first report on the UARK Pom compassionate use experience in RRMM. Methods: First cycle Pom was given at 4mg orally Days 1–21 every 28 days; dexamethasone (DEX) was given to 9/23 patients at doses varying from 12 to 40 mg on schedules ranging from Days 1–4, weekly, twice a week, or three times a week. In the absence of at least PR, Pom dose was escalated to 5mg. 1patient also received bortezomib and 1 patient received bortezomib and cytoxan. Cox regression modeling was employed for univariate and multivariate analyses, whereas Kaplan-Meier curves were used for overall survival (OS) and progression free survival (PFS). Results: 23 patients with RRMM were enrolled. Baseline characteristics included age >=65yr in 43%, ISS stage >=II was seen in 78% of patients, cytogenetic abnormalities (CA) within 6 months in 80%, and GEP-defined high risk in 41% of patients. 22/23 patients (96%) had prior autologous stem cell transplant. 19/23 patients (83%) had at least 2 transplants. All 23 patients had disease progression after having received regimens containing bortezomib, thalidomide, lenalidomide, melphalan and steroids. At least 1 cycle of treatment was administered to all 23 patients enrolled, 52% of patients received >1 cycle of treatment and only 13% received =>5 cycles. 10 patients (43%) discontinued therapy primarily due to progression or death. 5/23 (22%) patients achieved PR, 57% had stable disease. A trend towards PFS benefit was observed in patients receiving cycle 2 (HR=0.30, p=0.215) on univariate analysis and multivariate analysis (HR=0.40, p=0.48) after adjusting for GEP-defined risk status (HR=2.69, p=0.16). Most common toxicities, counting all toxicities (>=grade 3) were: thrombocytopenia (70%), leukopenia (61%), anemia (43%), hypophosphatemia (35%) and hypokalemia (26%). Overall and progression- free survival at 12 months were 52% and 30%, respectively. Conclusions: Pom demonstrates anti-myeloma activity in this advanced RRM population, especially in a sub-population with GEP-defined low-risk disease.

Disclosures:

Barlogie: Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.
Incidence Rates of the Leukemias in the United States Are Significantly Associated with Birth Cohort,
Authors: Rosenberg Philip S , Anderson William F.
Published: October 2019

Abstract 4203

BACKGROUND:

Leukemia (all types) is a common cancer in the United States (US) with 44,600 new cases expected in 2011. There are currently only a few established risk factors for any major type. If leukemia risks are substantially modulated by known or unknown environmental and lifestyle exposures, then incidence rates in the population should vary significantly by birth cohort. However, prior studies have not examined birth cohort effects using contemporary data and methods.

METHODS:

We used nationally representative data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program for 1992 – 2008 (68,481 leukemias and 6.6×108 person-years of follow-up). For each major type in male and female pediatric (ages 0 – 17) and adult (ages 18 – 85) populations, we estimated the average annual percentage change in incidence attributable to calendar period and/or birth cohort (net drift), and the significance of unique (non-linear) birth cohort effects, using age-period-cohort statistical models and Poisson regression.

RESULTS:

In adults, birth cohort effects for AML were significant in men (P = 0.002) and borderline significant in women (P = 0.053). Compared to men born during 1947 – 1951, men born in the 1920s–1930s were 1.4-fold more likely to develop AML; AML rates were stable in men born after 1951. Birth cohort patterns for AML were qualitatively similar in women compared to men. For CLL, birth cohort effects were highly significant in men (P=5.7×10−6), peaking among men born circa 1939 and falling by 38% among men born circa 1963. In contrast, birth cohort effects for CLL were almost completely absent in women. For CML, incidence declined steadily by 1.3%/year among men (P = 0.0003) and by 1.5%/year among women (P = 0.0008). For ALL, incidence increased steadily by 2.0%/year among women (P = 0.001); birth cohort patterns were similar in men but not statistically significant (P = 0.36). In the pediatric population, AML rates were stable over time. In contrast, ALL rates increased by 1.4%/year among males (P = 0.001) and by 1.1%/year among females (P=0.04).

CONCLUSIONS:

In the US, leukemia risks increase or decrease substantially by birth cohort for each major leukemia type except adult female CLL and pediatric AML, on the order of 1–2%/year or 20–40% per generation. These results are consistent with the hypothesis that leukemia risks are substantially affected by known (i.e. smoking, certain chemicals) or suspected (i.e. obesity) environmental and lifestyle exposures, a number of which are potentially modifiable.

Disclosures:

No relevant conflicts of interest to declare.
Incidence of Vascular Outcomes in Patients with Atrial Fibrillation,
Authors: Gallagher Arlene M , Murray-Thomas Tarita , Clemens Andreas , Diana Ackermann , Bartels Dorothee B
Published: October 2019

Abstract 4223

Objective:

To describe the characteristics of patients with recently diagnosed atrial fibrillation (AF) and to estimate the incidence of vascular outcomes in patients with AF.

Methods:

A cohort study in newly diagnosed AF patients (2005–2010) without heart valve replacement/problems was performed in the General Practice Research Database (GPRD), UK. Linked data to the Hospital Episode Statistics (HES) and death certificates from the Office of National Surveillance (ONS) were included. Current vitamin K antagonists (VKA) treatment was defined as a valid prescription/INR measurement during the last 28 days, recent as a treatment period from 28 to 90 days after the last prescription/INR measurement, and past treatment as more than 90 days after last treatment/INR measurement. No treatment was the time between diagnosis of AF and first prescription/INR measurement, or the whole follow-up for patients that have never been treated. Vascular outcomes – first ever recorded – were assessed as primary hospital admission diagnosis recorded in HES, i.e. myocardial infarction (MI), stroke, and systemic peripheral arterial embolism (SPAE).

Results:

Data from 16,513 AF patients could be linked; 48% were female, the mean age (std) was 74 (12) years, the median duration of follow-up was 1.7 years (range 0–5). According to CHADS2 score 21% were at low risk, 65% at moderate and 14% at high risk for stroke. Overall 55.8% of the patients had at least one period of VKA use.

Overall, 1,151 vascular events were recorded (403 MIs, 716 strokes, 68 SPAE). The incidence (per 100 patient years (95% CIs)) of vascular events was 3.8 (3.5 – 4.0), 1.3 (1.2 – 1.4) for MI, 2.3 (2.1 – 2.5) for stroke and 0.2 (0.2 – 0.3) for SPAE. Stratification by period of VKA use resulted in incidences for current, recent, past and non users for MI of 0.7 (0.6 – 0.9), 0.7 (0.4 – 1.2), 1.1 (0.8 – 1.5), 1.9 (1.7 – 2.1), for stroke of 0.9 (0.8 – 1.1), 2.2 (1.6 – 2.9), 2.4 (1.9 – 2.9), 3.4 (3.1 – 3.7), and for SPAE of 0.2 (0.2 – 0.3), 0.2 (0.1 – 0.3), 0.3 (0.1 – 0.6), 0.2 (0.1 – 0.3), 0.2 (0.2 – 0.3).

Conclusion:

In this cohort study, a trend towards lower incidences of vascular events, specifically stroke and MI, was detected during VKA use compared to past/no use. No causal conclusions can be drawn from these crude incidence estimates, but the trends are in line with the clinical expectations of anticoagulation in AF patients.

Disclosures:

Clemens: Boehringer Ingelheim Pharma GmbH & Co. KG: Employment. Diana:Boehringer Ingelheim GmbH: Employment. Bartels:Boehringer Ingelheim GmbH: Employment.
Lenalidomide Followed with Donor Lymphocytes Infusion (DLI) After Allogeneic Stem-Cell Transplantation (Allo-SCT) with Reduced-Intensity Conditioning in Patients with High Risk Multiple Myeloma
Authors: El-Cheikh Jean , Crocchiolo Roberto , Ladaique Patrick , Furst Sabine , Castagna Luca , Faucher Catherine , Granata Angela , Oudin Claire , Lemarie Claude , Calmels Boris , Stoppa Anne Marie , De Colella jean Marc schiano , Duran Segolene , Chabannon Christian , Blaise Didier
Published: October 2019

Abstract 4310

Purpose:

Relapse remains the main issue after allogeneic stem cell transplantation (Allo-SCT) in high risk Multiple Myeloma (MM) patients. The aim of this study is to assess the anti-myeloma effect of lenalidomide followed by donor lymphocyte infusion (DLI) as adoptive immunotherapy after transplantation.

Patients and methods:

Twelve patients with refractory and high risk myeloma were analyzed. Median age at transplantation was 56 years (46–64); 6 patients (50%) received lenalidomide before Allo-SCT. All patients received a RIC including Fludarabine 30 mg/m2 5 days, ATG 2,5 mg/kg for 2 days and Busilvex 3.2 mg/kg/day (3 days in 6 patients and 2 days in 6 patients). All but one received peripheral blood stem cells (PBSC). Donor was HLA id in 6 patients and matched unrelated in 6 patients. It is our standard long term practice to consider post-transplant DLI in patients with progressive or persistent disease after day 100 if no GVHD signs were evident. In 2010, we introduced the use of lenalidomide after day 100 in patients with MM presenting the same characteristics. Doses ranged from 10 to 25 mg/day. Lenalodomide treatment could be completed with DLI, administered afterward, at least after 2 cycles.

Results:

The median time between Allo-SCT and lenalidomide was 10 months (3–38). The median initial dose of lenalidomide was 15 mg (10–25). Patients received a median of 6 cycles (1–10). Nine patients (60%) received an escalating dose of DLI; 1 × 107/Kg of CD3+cells for the first DLI and 1 × 108/Kg of CD3+cells for the second DLI. One patient with GVHD (after tapering of the cyclosporine A and only after 10 days of lenalidomide) and two patients with progressive disease after lenalidomide did not receive DLI.

The toxicity related to lenalidomide was mainly haematological (grade II in 4 patients (33%) and grade I in 3 patients (25%); 7 patients (58%) had moderate asthenia. One patient developed a reversible renal insufficiency after 10 cycles of lenalidomide, none of our patients developed thrombo-embolism under treatment.

At the last follow up, 9 patients are alive and all of them are under ongoing treatment. Four patients achieved complete remission (CR) and five patients partial remission at last evaluation. The 1 and 2 years probability of the progression-free survival (PFS) was 75% and 50% and overall survival (OS) was 83 % and 69% respectively. The median OS was not reached and the median PFS was 23 months.

Conclusions:

These data show that lenalidomide has an acceptable toxicity. Combination with DLI should be further evaluated in a larger cohort of patients.

Disclosures:

No relevant conflicts of interest to declare.