bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining Measures of Proliferation for Use in Risk Stratification of Myeloma
Authors: Coyne Mark R.E. , Wellik Linda , Braggio Esteban , O'Dwyer Michael E , Santocanale Corrado , Valdez Riccardo , Bergsagel P.Leif , Chesi Marta
Published: October 2019

Abstract 5093

A relative increase in proliferation is now accepted as the most important measure in risk stratification of myeloma.

Attempts to include measures of proliferation in different stratification strategies have been met with obstacles largely influenced by their practicality and economic viability in the clinical setting.

The plasma cell labelling index (PCLI) is the gold standard used in myeloma; however it is still only used in a minority of centers across the globe. New surrogate markers of proliferation, such as serum biomarkers and transcription-based methods, are under investigation but few have evolved to become part of a uniform strategy in the stratification of myeloma. The gene-expression based proliferation indices (gPI) described by Bergsagel et al, Shaughnessy et al and Hose et al all show similar correlation with PCLI. Studies comparing all currently available methods are lacking.

In a cohort of 70 patients, PCLI and gPI were compared with two immunohistochemistry-based methods of measuring proliferation, Ki67 and a more specific measure of S-phase entry – phosphorylation of minichromosome maintenance protein 2 (pMcm2) at serine 40/41, combined with dual staining of CD138. We observed a similar correlation of gPI wth PCLI to that previously reported (r value; CI – 0.43;0.21–0.61). Both Ki67 and pMcm2 staining showed a stronger correlation with PCLI than with gPI and PCLI (r value; CI – 0.81;0.71–0.88 and 0.86; 0.78 – 0.91 respectively).

PCLI and gPI have already been shown to be an independent predictor of time to progression and overall survival. Although this sample size was too small to test for time to progression or overall survival and thus independence, a logical extrapolation would indicate similar independence and predictions on survival and time to progression.

As Ki67 is routinely used for more proliferative cancers in the clinic, the extension of its use as part of a new stratification system in myeloma provides interesting possibilities for further exploration.

Disclosures:

O'Dwyer: Novartis: Honoraria, Research Funding.
A Phase III Study Comparing Thalidomide/Cyclophosphamide/ Dexa Vs Thalidomide/Dexa Vs Thalidomide/Melphalan/Prednisone In De Novo Multiple Myeloma Patients Not Eligible for ASCT
Authors: Crusoe Edvan , Maiolino Angelo , Bittencourt Rosane , Fantl Dorotea Beatriz , Maciel James , Sampaio Manuella , Quero Adriana , Peres Ana Lucia , Miranda Eliana C M , Mercante Daniel , Parra Flavia , Chiattone Carlos S , Hungria Vania
Published: October 2019

Abstract 5117

Background-

Thalidomide (Thal) is a pro-apoptotic, immunoregulatory and antiangiogenic agent for MM. Although it is used since the 90's, the optimal combined treatment remains inconclusive. This is a preliminary analysis of the first Latin American prospective open-label study comparing three different combinations with Thal for MM patients not eligible for autologous SCT.

Patients and Methods-

Eligible patients were randomized to one of the three arms and received nine 28-days induction cycles. All patients received Thal(100–200mg/d) and one of the following: A- Cyclo (50mg/d)+ Dexa (40mg/D1-4, 15–18 in cycles 1 and 2, D1-4 in cycles 3 to 9), B- Dexa (40mg/D1-4, 9–12, 17–20 in cycles 1,3,5,7 and 9, D1-4 in even cycles) or C- Mel (4mg/m2/7d)+ Pred (40mg/m2/7d). Thereafter, they were randomized to maintenance treatment until progression disease or unacceptable toxicity, as follows: A1-Thal (100mg/d)+Pred (50mg/each other day) or B1-(Thal 100mg/d). All patients received aspirin as thromboprophylaxis and sulpha-trimetroprim as prophylaxis for infection. If indicated, they received biphosphonate monthly for 24 months, and then quarterly. Before study initiation, informed consent was obtained from patients and evaluation was performed at the end of each cycle. The primary endpoint were response rate and response duration. The secondary endpoints were safety, OS and PFS. IMWG index was utilized to analyze response criteria. SPSS 15.0 for windows® were used for statistical analysis.

Results-

Enrolment started on February 2007, and a total of 60 patients have been included. Median age at randomization was 71 (56–84) years-old, and 52% of patients were female. Durie-Salmon stages were 12% II, 82% III and ISS stages were 47% II and 28% III. Fifty-one per cent of patients presented IgG monoclonal component. There were no significant differences comparing response > VGPR and treatment arms after three, six and nine cycles. However, the PFS is significant when compared CTD/MPT and TD arms (p=0.01). There was no difference in OS.

Discussion-

This analysis showed that Thal combinations are effective in MM patient treatment. We have not observed different responses between the tree arms. The progression free survival is significant in favor of alkylating combination than thal+dexa (p=0.01). Toxicity was manageable and balanced between the tree different arms.

We would like to thank Dr. Jesus San Miguel and Dra. Maria-Victoria Mateos who have collaborated in this study.

Disclosures:

No relevant conflicts of interest to declare.
Risk of Skin Rash in Proteasome Inhibitor Bortezomib: A Systematic Literature Review and Meta-Analysis
Authors: Case Emily C , Wu Shenhong , Gerecitano John , Lacouture Mario E
Published: October 2019

Abstract 5120

Background:

Bortezomib (VELCADE) is the first proteasome inhibitor to be approved by regulatory agencies for treatment of multiple myeloma and mantle cell lymphoma. Maculopapular rash is a common, adverse event to bortezomib. Because the summary incidence of bortezomib-induced skin rash is not well known, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk.

Methods:

We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings from 1998 to July 2011, to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m2, 1.5mg/m2, or 1.6 mg/m2 of bortezomib twice weekly for two weeks followed by one week off, in a 21-day cycle. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies.

Results:

A total of 2,469 patients with various hematologic and solid malignancies from 32 clinical trials were included for analysis. Among patients receiving bortezomib, the summary incidences of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in rash incidence with higher doses of bortezomib. In addition, bortezomib was associated with an increased risk in both all grade (RR:19.703, 95% CI: 8.734 to 44.446, p<0.001) and high-grade rash (RR: 5.354, 95% CI: 2.158 to 13.285, p<0.001), in comparison with controls.

Conclusion:

Bortezomib is associated with a significant risk of developing rash. Management of bortezomib-induced rash is critical to prevent a negative effect on quality of life and dose modifications, both of which may affect clinical outcome.

Disclosures:

Wu: Onyx: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Speakers Bureau. Gerecitano:Millenium: Research Funding.
Efficacy and Safety of Once-Weekly Bortezomib Infusion in the Treatment of Relapsed/Refractory Multiple Myeloma
Authors: Kim Hyun-Kyung , Mun Yeung-Chul , Yoo Eun-Sun , Lee Kyoung Eun , Nam Eunmi , Lee Soon Nam , Seong Chu-Myong
Published: October 2019

Abstract 5141

Incorporation of bortezomib in the treatment of multiple myeloma (MM) has significantly imporved patient outcome. Because peripheral neuropathy (PN) leading to dose modification and drug discontinuation seems to be dependent on dose and exposure of bortezomib, some schedules of botezomib therapy were reduced from twice-weekly to once-weekly infusion. We assessed the efficacy and safety of once-weekly bortezomib infusion in the treatment of relapsed/refractory MM.

We compared the outcomes and safety of once- and twice-weekly bortezomib infusion as a second-line treatment for the patients of relapsed/refractory MM in our hospital between 2005 and 2010, retrospectively.

Twenty-nine patients were enrolled including 12 patients who received once-weekly bortezomib infusion on day 1, 8, 15 and 22 of the cycles and 19 patients who received twice-weekly bortezomib infusion on day 1, 4, 8 and 11 of the cycles as a second-line treatment. Dexamethasone alone (n=18), melpahalan with prednisolone (n=4), and thalidomide with dexamethasone (n=7) were administered combined with bortezomib. Median cumulative dose of bortezomib were 32.4mg/m2 and 18.4mg/m2 in the once- and twice-weekly group, retrospectively (p=0.019). There were no significant difference in overall response rate (66.7% in once-weekly vs 47.1% in twice-weekly, p=0.451) and time-to-progression (median 17.2 months in once-weekly vs 7.1 months in twice-weekly, p=0.381). There was a significant difference in the median time-to-onset of grade 2 to 4 PN (4.5 months in once-weekly vs 2.0 months in twice-weekly, p=0.017). The incidence of grade 2–4 PN (50.0% vs 47.1%) and median cumulative dose to onset of grade 2–4 PN (17.9mg/m2 vs 15.3mg/m2) were not different. The incidence of any grade 3/4 toxicity except PN was similar (25.0% vs 41.2%, p=0.449). Progression-free survival in once-weekly bortezomib group was slightly longer than that in twice-weekly bortezomib (median 34.8 months vs median 22.8 months, p=0.074). Overall survival was similar (median 35.2 months vs median 25.1 months, p=0.118), while the overall survival of elderly patients (60 years or above) in once-weekly bortezomib group was slightly longer than that in twice-weekly bortezomib group by Kaplan-Meier analysis (median 38.1 months vs median 20.1 months, p=0.085).

Our data suggest that the onset time of PN was delayed in once-weekly regimen and there was no significant difference overall response, rate of PN, cumulative dose to onset of PN, grade 3/4 toxicity and overall survival between both groups. Because of the larger cumulative dose and the lower rate of dose modification or drug discontinuation due to good tolerability in once-weekly bortezomib than twice-weekly bortezomib, once-weekly bortezomib infusion could be a potential therapeutic approach for patient with MM as a scond-line therapy.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Significance of Bone Marrow Fibrosis in Patients with Polycythemia Vera
Authors: Nazha Aziz , Cortes Jorge E. , Estrov Zeev , Pierce Sherry , Kantarjian Hagop M. , Verstovsek Srdan
Published: October 2019

Abstract 5149

Background:

Polycythemia vera (PV) is a heterogeneous myeloproliferative disease characterized by expansion of morphologically normal red blood cells, granulocytes, and platelets with varying degrees of bone marrow fibrosis (BMF) during the disease course. BMF as a result of abnormal deposition of reticulin and collagen fibers in bone marrow stroma plays a role in the pathophysiology and clinical manifestation of myeloproliferative disorders in general. However, in PV, older age and previous history of thrombosis remain the only two major risk factors for consideration in decisions regarding therapy.

Objectives:

To investigate the characteristics associated with BMF and its prognostic impact on clinical manifestation, overall survival (OS), and transformation to primary myelofibrosis and acute leukemia in patients with PV.

Methods:

We conducted a retrospective chart review analysis of 115 patients who were diagnosed with PV according to World Health Organization criteria and were referred to MD Anderson Cancer Center between May 2000 and December 2009. Results of the first bone marrow biopsy done at MD Anderson were reviewed. BMF was documented according to the European consensus grading system (MF0-3), in which MF-3 is the most severe grade of fibrosis.

Results:

Of the 115 patients, 23 (20%) had MF-0, 46 (40%) MF-1, 36 (31%) MF-2, and 10 (9%) MF-3. Table 1 summarizes patient characteristics and outcomes by grade.

Conclusion:

Severe BMF was associated with higher risk of bleeding and thrombosis and larger spleen in patients with PV. There was no association between BMF severity and the demographic or symptoms of the disease. There was no association between BMF severity and the presence of JAK2 mutation or cytogenetic abnormalities. There was no impact of BMF on OS, EFS, or transformation to myelofibrosis or acute leukemia. However, longer follow-up is needed to investigate further the impact of BMF on OS and transformation-free survival.

Disclosures:

No relevant conflicts of interest to declare.
Combination Treatment of Essential Thrombocythemia with Hydroxyurea and Anagrelide
Authors: Ahn Inhye E. , Natelson Ethan A. , Rice Lawrence
Published: October 2019

Abstract 5177

BACKGROUND:

Hydroxyurea and anagrelide are therapeutic options for essential thrombocythemia (ET) with distinct mechanism of actions and side effect profiles. However, therapeutic goals may not be achieveable due to drug intolerance or disease resistance. Here we report our successful clinical experience with combination treatment with hydroxyurea and anagrelide.

METHODS:

Medical records of six patients who were on the combination treatment for the ET were retrospectively reviewed. All had history of unsuccessful monotherapy with either hydroxyurea or anagrelide.

RESULTS:

All patients were female with median age of 59.5 years. All were positive for the V617_ jak2 mutation. Two had prior major thromboses (portal vein; ischemic stroke), and one had Raynaud's disease. Reasons for failure of hydroxyurea monotherapy were leukopenia and/or inadequate platelet reduction, while reasons for anagrelide failure were palpitations and orthostasis. Rather than discontinue the primary drug, doses were lowered to a tolerable level and the second agent was added. These patients have been treated with the combination of hydroxyurea and anagrelide for a mean duration of 4.89+ years. Combination regimen achieved 64% reduction of platelet counts (mean best platelet counts during treatment 328×109/L), while maintaining adequate leukocyte counts (range 3.64–7.88 × 109/L). Relatively low daily doses of hydroxyurea (mean 684mg/day) and anagrelide (1.7mg/day) were required. Adverse events noted during the combination therapy were one case with rectal bleeding and two cases of myelofibrosis. One patient returned to monotherapy due to persistent headache to low-dose anagrelide. No arterial or venous thromboses bleeding events have occurred.

CONCLUSION:

This is the longest follow-up experience of hydroxyurea and anagrelide combination therapy in ET that has been resistant to monotherapy or where high monotherapy doses could not be tolerated. The low-dose combination regimen was able to achieve clinical and laboratory response in all patients with a low incidence of medication side effects. This strategy is made more attractive by data that hydroxyurea may be more effective in prevent arterial events while anagrelide was found more effective in preventing venous clots, but conclusions on superior efficacy of the combination would require formal study. We recommend that rather than substitute for an agent that has had partial success or is causing dose-related side-effects, the dose can be adjusted and a second agent added.

Disclosures:

No relevant conflicts of interest to declare.
Interim 18f-PDGPET for Aggressive Non-Hodgking's Lymphoma: A Systematic Review and Meta-Analysis
Authors: Caramazza Domenica , Dentali Francesco , Merli Michele , Saccullo Giorgia , Malato Alessandra , Quintini Gerlando , Iannitto Emilio , Passamonti Francesco , Siragusa Sergio
Published: October 2019

Abstract 5183

Background:

The advantage of using interim 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) scan in the clinical work-up of patients with non-Hodgkin's lymphoma (NLH) is unclear. Data from meta-analyses are inconclusive, mainly because of the low number of patients evaluated and heterogeneity among studies. New clinical investigations, focused on this topic, have been recently published. We conducted an updated systematic review on the role of 18PDG-PET for the interim evaluation in patients with aggressive lymphomas.

Materials and Methods:

Medline, Embase, Scopus and Databases were searched for relevant studies through March 2011. We included studies that evaluated FDG-PET performed between the first and the fourth cycle of first-line chemotherapy. Patients were selected when they were evaluated for response assessment with interim 18FDG-PET. For each study, we constructed a 2 × 2 contingency table consisting of true positive (TP), false positive (FP), false negative (FN), and true negative (TN), where all patients were categorized according to whether they were PET positive or negative, and whether they experienced treatment failure. A meta-analysis of the prognostic accuracy was performed.

Results:

We selected 16 out of 46 studies, involving 1256 patients with aggressive NHLs (90% with Diffuse Large B-Cell Lymphoma); 1157 patients met our inclusion criteria and were considered for the final analysis. Interim18FDG-PET, performed after a median of 3 cycles of chemotherapy (range 1–6 cycles), gave true and false negative results in 641 (56 %) and 65 (6%) patients, respectively. Therefore, 18FDG-PET had an overall sensitivity of 0.80 (95% CI, 0.69 to 0.88) and a specificity of 0.84 (95% CI, 0.76 to 0.90) (figure). Heterogeneity among studies was substantial.

Conclusion:

Because of data heterogeneity, interim 18FDG-PET for aggressive NHL patients remains an unproven test for routine clinical practice. Its role should be further evaluated in clinical researches with homogeneous treatments and standardized imaging.

Disclosures:

No relevant conflicts of interest to declare.
Establishment and Characterization of a Novel Human Cell Line of Triple Hit Lymphoma, AMU-ML1, Carrying t(2;18)(p11.2;q21) and t(3;8;14)(q27;q24;q32) That Involve BCL2, BCL6 and MYC
Authors: Tsunekawa Norikazu , Hanamura Ichiro , Yamamoto Hidesuke , Nagoshi Hisao , Wakabayashi Motohiro , Sakamoto Natsumi , Horio Tomohiro , Gotoh Mineaki , Mizuno Shohei , Takahashi Miyuki , Suganuma Kazuto , Goto Mayuko , Hiramatsu Akihito , Watarai Masaya , Shikami Masato , Imamura Akira , Mihara Hidetsugu , Taki Tomohiko , Taniwaki Masafumi , Miwa Hiroshi , Nitta Masakazu
Published: October 2019

Abstract 5210

Mature B-cell lymphomas with both BCL2 and MYC translocations to IG loci are rarely identified and most of them are classified as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (IL) in the new World Health Organization classification.

In this study, we established a novel human lymphoma cell line, AMU-ML1, from pericardial effusion (PE) of a patient with IL before the initiation of chemotherapy and analyzed its characters. A 60-year-old male was admitted to our hospital because of PE and diagnosed as having IL from the atypical lymphocytes in PE. He was treated with rituximab plus hyper-CVAD and other regimens but died of lymphoma approximately 10 months after diagnosis without reaching complete remission.

The cells from patient's PE at diagnosis were cultured in RPMI 1640 supplemented with 20% heat-inactivated fetal bovine serum (FBS). After 5 months of culture, cell proliferation became continuous with 10% FBS and the cell line was designated as AMU-ML1 (Aichi Medical University, malignant lymphoma, no. 1) after confirmation that the cells began growing again after the conventional freeze-thaw procedure.

AMU-ML1 cells were positive for CD10, CD19, CD20, CD79a, HLA-DR and cytoplasmic lambda chain and negative for CD3, CD4, CD5, CD8, CD13, CD23, CD33 and CD56 by flow cytometry analysis and showed a complex karyotypes including t(2;18)(p11.2;q21) and t(3;8;14)(q27;q24;q32) by G-banding analysis. This profile is consistent with the profile of the patient's cells. Spectral karyotyping and fluorescent in situ hybridization analysis of AMU-ML1 cells revealed that t(2;18)(p11.2;q21) was IGL/BCL2 and t(3;8;14)(q27;q24;q32) was BCL6/MYC, MYC/IGH and IGH/BCL6.

Subcutaneous transplantation of AMU-ML1 cells into NOD/scid mice treated with anti-asialo GM1 antibody resulted in formation of primary tumors.

Thus, the AMU-ML1 cell line is useful for studying the biological consequences of IL with triple hit of BCL2, BCL6 and MYC, and possibly invasion to PE of lymphoma.

Disclosures:

No relevant conflicts of interest to declare.
Epidemiology of Mantle Cell Lymphoma: A Population-Based Study in France
Authors: Leux Christophe , Herry Aurélie , Maynadie Marc , Cabrera Quentin , Troussard Xavier , Le Guyader-Peyrou Sandra , Le Gouill Steven , Monnereau Alain
Published: October 2019

Abstract 5222

Introduction:

Mantle cell lymphoma (MCL) is an aggressive and rare B-cell lymphoma entity representing around 5–8% of non-Hodgkin's lymphomas in adults. To our knowledge no data is available on the epidemiology of MCL in France. We aimed to describe incidence, survival and main clinical characteristics of MCL in a French population.

Methods:

Patients diagnosed with MCL were identified in three administrative areas covered by an haematological malignancies registry: the Côte d'Or (from 1988 to 2008), the Basse-Normandie (from 1997 to 2006) and the Gironde (from 2002 to 2006). Main clinical features and management characteristics were collected. World age-standardised incidence rates, observed survival and relative survival were estimated for the period 2002–2006.

Results:

Mantle cell lymphoma was diagnosed in 213 patients over the whole period. Seventy percent of patients were males. Over the period 2002–2006, the age-standardised incidence rate of MCL (per 100,000) was 0.72 in men (n=100) and 0.17 in women (n=35). The median age at diagnosis was 72 years (range: 30–92). Late-stage (III-IV) MCL was diagnosed in 81.5% of patients. MCL international prognostic index (MIPI) was lower or equal to intermediate risk in 36% of patients. The median relative survival time was 41 months (95% confidence interval: 38–62) and was significantly higher in patients with a low or intermediate MIPI (74 months, CI95%: 53–91) than in patients with a high risk (38 months, CI95%: 30–49). Treatment included frontline chemotherapy in 85% patients and 54% patients received rituximab. Ten percent of patients participated in a clinical trial.

Conclusion:

Epidemiological characteristics of MCL in France were quite similar to epidemiological data reported in other industrialized countries. Incidence rates were characterized by a male-to-female ratio of 4:1. Median overall survival was less than 4 years.

Disclosures:

No relevant conflicts of interest to declare.
Thymic Retention of CD4+CD25hi+FoxP3+ T Regulatory (Treg) Cells Is Responsible for Peripheral Treg Deficiency and Platelet and Megakaryocyte Destruction in Active Immune Thrombocytopenia (ITP)
Authors: Semple John W. , Gebremeskel Simon , Aslam Rukhsana , Ni Heyu , Freedman John
Published: October 2019

Abstract 523

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which antibodies and/or cytotoxic T cells are directed against an individual's own platelets and/or megakaryocytes and lead to enhanced platelet destruction in the periphery and reduced platelet production within the bone marrow. It is becoming increasingly clear that the immune dysregulation leading to ITP is primarily due to T cell disturbances and recently, many reports have demonstrated that active ITP is associated with a peripheral deficiency of tolerance-inducing CD4+CD25+FoxP3+ T regulatory cells (Tregs). Using a murine model of ITP that demonstrates both antibody and T cell-mediated platelet and megakaryocyte destruction, we analyzed the role that Tregs may play in active ITP. BALB/c CD61 knockout (KO) mice were immunized against wildtype (CD61+) platelets and 1.5×104 of their splenocytes were transferred ip into CB.17 severe combined immunodeficient (SCID) mice and their platelet counts, phenotype and percentage of CD4+CD25hi+FoxP3+ Tregs were enumerated in various lymphoid tissues at various times after transfer. Results showed that within 2 weeks post-transfer, 16 of 30 transferred mice became thrombocytopenic (<300×109 platelets/L) whereas the remaining mice did not. Bleeding diatheses and mortality occurred in 4 of the 16 thrombocytopenic mice. Of interest, compared with control SCID mice transferred with naïve BALB/c splenocytes or the non-thrombocytopenic SCID mice, the thrombocytopenic mice had significant elevations in thymic weights and percentages of CD4+CD25hi+FoxP3 Tregs by 2 weeks post transfer. Splenic weights in the thrombocytopenic mice increased but at the same rate as control mice, however, the proportion of Tregs in the spleens were significantly less than control non-thrombocytopenic mice. Treatment of the thrombocytopenic mice with 2g/kg intravenous gammaglobulin (IVIg) raised the platelet counts, reduced thymic weights and normalized both the thymic and splenic Treg populations compared with controls. The results suggest that active ITP in this mouse model is associated with a peripheral (splenic) Treg deficiency due to thymic retention of the Tregs. It proposes a new mechanism of Treg deficiency in ITP; Tregs are withheld from the periphery by thymic sequestration.

Disclosures:

No relevant conflicts of interest to declare.
Venous Thromboembolism Following Major Surgery and Risk of Recurrence: A Population-Based Cohort Study
Authors: Kondal Dimple , Kahn Susan R. , Tagalakis Vicky
Published: October 2019

Abstract 5243

Background:

Venous thromboembolism (VTE) which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) is a common complication of major surgery. Little is known of the risk of recurrent VTE following postoperative VTE.

Objectives:

We used the administrative health claims (RAMQ) and hospital discharge (MED ECHO) databases of Quebec, Canada to conduct a population-based retrospective cohort study to describe the time to VTE following general surgery and to assess the risk of VTE recurrence among patients with surgery-provoked VTE.

Methods:

Using a previously defined cohort of individuals who had a first-time discharge diagnosis of VTE between January 1996 and December 2004 in MED ECHO, which systematically records information on all hospital admissions in the province of Quebec, we identified patients who had undergone major surgery in the 3 months prior to the VTE. Subjects were followed from the time of incident VTE until first VTE recurrence, death, or end of study (December 31, 2005).

Results:

Our study population consisted of 9629 patients with new VTE up to 3 months following major surgery. The mean age was 63.9 years (SD=15.2) and 53% were female. General surgery (32%) was the most common procedure. The mean time to VTE after surgery was 29.5 days (SD=62.6) with 30% of events diagnosed after discharge. The 5-year adjusted cumulative risk of recurrence was 7.9%. Patients with VTE diagnosed after discharge had an adjusted relative risk of recurrence of 1.43 (95% confidence interval (1.21, 1.69)) compared to patients with VTE diagnosed before discharge.

Conclusions:

Our results suggest that surgery-provoked VTE occurs frequently after discharge and is associated with an elevated risk of recurrence, and that patients with post-discharge VTE are at a higher risk of recurrence than patients with VTE diagnosed before discharge. Thromboprophylaxis strategies post-discharge should be considered in this population.

Disclosures:

Tagalakis: Sanofi Aventis: Research Funding; Pfizer: Research Funding.
The Phenotypic Expression of Homozygous and Compound Heterozygous Factor V R506Q (Factor V Leiden, FVL) and Factor II A20210G: Ten Years Experience At a Referral Center
Authors: Al-Mondhiry Hamid A B , Nifong Thomas P , Eyster Mary Elaine
Published: October 2019

Abstract 5252

Heterozygous Factor V Leiden, the most common inherited thrombotic disorder with an estimated incidence of about 5% in Caucasian population, poses a moderate risk of first venous thromboembolic (VTE) event. The homozygous and compound heterozygous states are comparatively rare but are thought to be associated with high risk of recurrent VTE. This report describes ten years experience with homozygous and compound heterozygous FVL and Factor II A20210G at a major referral center in central Pennsylvania, USA. Between January 2000 and December 2010, 31 homozygous F VL patients, 2 homozygous FII A20210G, 10 compound heterozygous FVL and F II A20210G and 6 compound heterozygous F VL and protein C (PC), protein S (PS) or antithrombin (AT) deficiency were encountered. The reasons for referral were personal or family history of VTE or a first degree relative diagnosed with any of these conditions. Among these patients, 5 homozygous F VL, 1 compound heterozygous F VL and F II A20210G, and 1 compound heterozygous factor VL and PC deficiency remained free of VTE at age 17–64 years, even though they were exposed to prothrombotic conditions, e.g., surgery, hormones or pregnancy. Two compound heterozygous F VL and PS deficient patients suffered ischemic strokes, one at age 3 ½ years and the other at age 45 years, but no VTE. The other patients suffered lower extremity deep vein thrombosis and/or pulmonary embolism or visceral thrombosis. Most had recurrent events. Our experience highlights the serious thrombotic risks associated with homozygous and compound heterozygous F VL and F II A20210G status but also indicates that some patients remain thrombosis free despite exposure to additional prothrombotic conditions. However, because of referral bias this series of patients may not truly reflect the overall occurrence of VTE in patients with homozygous or compound heterozygous inherited thrombophilia.

Disclosures:

No relevant conflicts of interest to declare.
Venous Thromboembolism in Cancer Patients Following Major Surgery
Authors: Toledano Tierry Haim , Kondal Dimple , Kahn Susan R. , Tagalakis Vicky
Published: October 2019

Abstract 5253

Background:

Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is common in cancer patients and surgery is an important risk factor. The timing of post-operative VTE in cancer patients is uncertain.

Objectives:

We used the administrative health claims (RAMQ) and hospital discharge (MED ECHO) databases of Quebec, Canada to describe the occurrence of post-operative VTE in cancer patients and to explore anticoagulant use following hospital discharge.

Methods:

Using a previously defined cohort of individuals with a discharge diagnosis of VTE between January 1, 1994 and December 31, 2004 in MED ECHO which systematically records information on all hospital admissions in the province of Quebec, we identified patients with a cancer diagnosis in the 12 months preceding the VTE and who had major surgery in the 3 months prior to the VTE. Discharge diagnoses were defined according to the 9th edition International Classification of Diseases codes and surgical procedures according to the Canadian classification of diagnostic, therapeutic, and surgical procedures.

Results:

In all, 2706 patients with VTE had a cancer diagnosis and underwent major surgery in the 3 months preceding the VTE. The mean age was 65.9 years (SD=12.6) and 54% were female. The most common cancer was gastrointestinal (38%), and general surgery was the most frequent procedure (48%). The mean hospital stay was 29.8 days (SD=35.3). The mean time to VTE was 34.8 days (SD=68.3). In all, 34% of VTE events occurred after discharge. Among patients with post-discharge VTE (n=917), 4% had an out-patient anticoagulant prescription at discharge.

Conclusions:

Post-operative VTE in cancer patients often occurs after hospital discharge. This suggests that the risk of VTE extends beyond the immediate postoperative period. Prospective studies are needed to determine the effectiveness and safety of thromboprophylaxis beyond discharge in cancer patients undergoing surgery.

Disclosures:

Tagalakis: Sanofi Aventis: Research Funding; Pfizer: Research Funding.
Infantile SVT in Consequence of a Congenital Antithrombin Deficiency
Authors: Halimeh Susan , Dreher Stephan , Rosenbaum Thorsten , Rekus Martin , Rott Hannelore , Nowak-Gottl Ulrike , Faeser Britta
Published: October 2019

Abstract 5260

The liver-made antithrombin is a natural coagulation inhibitor in human blood. Exceptionally it takes effect in inhibiting the coagulation-supporting factors IIa (thrombin) and Xa. A congenital antithrombin deficiency leads to thrombosis and has to be heterozygous, because homozygous ATIII deficiencies are incompatible with life. Unfortunately it's dominant inherited.

In 1965 a congenital ATIII deficiency was first detected as a hereditary disease. There are two different types, type I describes a less produced ATIII deficiency, type II is a function loss of ATIII. Special testing can define more subclasses.

In cases of congenital ATIII deficiency, vascular blockage (thrombosis) appears, especially in leg veins. Released clots can cause pulmonal embolism, rarely are other arteries affected.

Although this disease is hereditary, it appears mostly between ages of 15 'til 30. Clinical trials showed that 80% of affected patient have a thrombosis or embolism until the age of 40. Has there be no kind of illness appeared until there, it's very improbable to get one becaus eof ATIII deficiency.

Every hundredth below the age of 70, who comes to a health care center has a ATIII deficiency. In total population it's a freqzuency of 1:2000 until 1:5000. Mostly there's a deficiency nown in familary history why they are investigated. The residual activity is between 40 – 60%.

Conclusion:

Most cases of thrombosis are treated with heparine. Heparin binds to ATIII, so ATIII can be much more effective and inhibits thrombin and Xa much more intense. For the future we have to make sure that antithrombin deficiencies especially in childhood have to be treated with phenprocumone.

Disclosures:

No relevant conflicts of interest to declare.
Inhibition of TLR-4 Prevents From Sepsis-Related eNOS/NO Disturbance in Human Platelets
Authors: Ma Liping , Yang Qiuhong , Chang Jianxing , Li Yiqing , Zhang Liping , Luo Xianming
Published: October 2019

Abstract 5264

Objective

Toll-like receptor 4 (TLR-4) has the ability to activate platelet and involve in intravascular coagulation, inflammatory cytokine and oxidative stressors release in sepsis. Nitric oxide (NO) synthesis in platelets is adjusted by iNOS and/or eNOS and contributes to platelet aggregation and adhesion. Our previous study has found that increased platelet aggregation in patients with sepsis was associated with the expression of TLR4 on platelets and NO synthesis in platelets. This study was to investigate whether inhibition of TLR-4 activation on platelets decreases eNOS(endothelial NO synthase)/NO disturbance-related platelet aggregation.

Methods

Blood samples were collected from 10 patients with severe sepsis and 10 healthy volunteers as controls. PRP(platelet-rich plasma) and PPP (platelet-poor plasma) were prepared for platelet aggregation, and platelet suspension (at a concentration of 2×108/mL platelets) for next experimemts. After the platelet suspension from healthy volunteers was incubated with L-Arginine (LA, 10 mM) alone, and LA and L-NAME (NΩ-Nitro-L-arginine methyl ester hydrochloride, 25mg/mL, a nonselective NOS inhibitor) for 1 hour, LPS(10.0μg/ml) was respectively added them. In separate experiments, the platelet suspension was preincubated with anti-TLR-4 Abs (10μg/mL) and then repeat above experiments. The levels of serine phosphorylation in eNOS (p-eNOS) and NO production, and platelet aggregation were determined with Western blotting, nitrate concentration analysis and platelet aggregometer, respectively.

Results

The protein levels of p-eNOS and NO production had 2.2-fold and 1.8-fold of increases in platelets from septic patients, and in vitro had 1.8-fold and 1.7-fold of increases in LA-incubated platelets stimulated with LPS as compared to controls. The p-eNOS expression and NO production were inhibited in the presence of L-NAME. Furthermore, thrombin-induced platelet aggregation was markedly promoted by LPS and L-NAME [(61 □ ‘98) %, (80□ ‘100)% versus (40□ ‘72)% of control) ], and the effect of LPS was abolished by LA pretreatment [(54□ ‘76)% ]. Blockade of TLR-4 didn't alter the elevated levels of p-eNOS and NO under LPS challenge, but the inhibition of L-NAME on p-eNOS and NO was significantly decreased. Importantly, blockade of TLR-4 significantly decreased platelet aggregation induced by LPS, and both LPS and L-NAME, but had no effects on LA pretreatment.

Conclusion

These data suggest that inhibition of TLR-4 may play a role in prevention from sepsis-induced platelet aggregation and maintaining platelet eNOS activity in sepsis.

Disclosures:

No relevant conflicts of interest to declare.
Leukopenia in Patients with Iron Deficiency Anemia
Authors: Lim Yoojoo , Lee Eun Young , Choi In Sil , Kim Tae-Yong , Yoon Sung-Soo , Kim Ki Hwan
Published: October 2019

Abstract 5279

Background:

There is a lack of clinical research regarding the effect of iron deficiency anemia on white blood cells (WBC).This study presents the incidence of leukopenia in patients with iron deficiency anemia and the relationship between the white blood cell count and the level of hemoglobin(Hb).

Patients and Method:

Medical records of patients over 12 years of age with iron deficiency anemia were reviewed. Patients with concomitant disease that may alter the WBC count such as hematologic malignancy, solid tumor, history of gastrectomy, vitamin B12 or folate deficiencies and active inflammation were excluded.

Results:

From January 2006 to December 2010, a total of 516 eligible patients were included. Median age was 47 years with female predominance (80.6%). Leukopenia was found in 91 patients (17.6%). The incidence of leukopenia was significantly higher in patients with hemoglobin level of less than 8 g/dL than those with higher level of hemoglobin (44/183, 24.0% vs. 47/333, 14.1%, P=0.005, Table 1).

The levels of WBC count were found to decrease in accordance with the decrease in hemoglobin level (Pearson's coefficient: 0.178, P<0.001, Figure 1). The decrease in WBC count was seen more often in younger patients. (R=0.104, P=0.018) Also, lymphocytes were found to decrease in both total number(R=0.282, P<0.001) and percentage (R=0.122, P=0.006) within total WBCs in proportion to the decrease in Hb level.

Conclusion:

This study shows the high incidence of leukopenia in patients with iron deficiency anemia. The severity of leukopenia correlates with the decrease of hemoglobin in dose-dependent manner. Among the WBC subsets, lymphocyte count was significantly affected.

Disclosures:

No relevant conflicts of interest to declare.
Azacitidine/Decitabine Synergism with the NEDD8-Activating Enzyme Inhibitor MLN4924 in Pre-Clinical AML Models
Authors: Smith Peter G , Traore Tary , Grossman Steve , Narayanan Usha , Carew Jennifer S , Lublinksky Anya , Kuranda Michael , Milhollen Michael
Published: October 2019

Abstract 578

MLN4924 is an investigational small molecule inhibitor of NEDD8-activating enzyme that has shown clinical activity in a Phase I clinical trial in Acute Myelogenous Leukemia (AML). To identify potential combination partners of MLN4924 we performed a high-throughput viability screen in AML cells with 40 approved and investigational agents. In vitro characterization of AML cell lines revealed two distinct cell cycle phenotypes suggesting alternate mechanism of action following MLN4924 inhibition of NAE. One group demonstrated moderate S-phase accumulation with greater than 4N DNA content consistent with DNA-rereplication as a result of CDT1 dysregulation. The second group demonstrated distinct and rapid accumulation of subG1 cells without S-phase accumulation or DNA re-replication suggesting induction of apoptosis and cell death. These observations led us to choose two cells lines representative of each mechanism to understand potential for synergy in AML cells. Two hypomethylating agents were included in the screen (decitabine and azacitidine) and were found to be synergistic with MLN4924 by Combination Index and Blending Synergy Analysis. These data were confirmed with a second NAE inhibitor that is structurally dissimilar to MLN4924. The combination of azacitidine and MLN4924 were shown to result in significantly increased DNA-damage and cell death compared to single agent alone as measured by Western Blotting and FACS analysis of cell cycle distributions. In vivo studies were performed in HL-60 and THP-1 xenografts using MLN4924 on a clinically relevant dosing schedule twice weekly. Single agent azacitidine at its Maximum Tolerated Dose (MTD) had minimal activity in the HL-60 model and was combined with a sub-optimal dose of MLN4924 that when combined induced complete and sustained tumor regressions. The mechanism for the apparent synthetic lethality in this in vivo model is currently under evaluation; however it is supported by a dramatic elevation in DNA damage and cleaved caspase-3 in vivo in the combination arm. A second xenograft model (THP-1) that was also insensitive to single agent azacitidine treatment underwent complete and sustained tumor regressions when combined with MLN4924. Thus MLN4924 and azacitidine can combine to produce synergistic antitumor activity in pre-clinical models of AML. Coupled with their non-overlapping clinical toxicities these data suggest the potential for future combination studies in clinical trials.

Disclosures:

Smith: Millennium Pharmaceuticals: Employment. Traore:Millennium Pharmaceuticals: Employment. Grossman:Millennium Pharmaceuticals: Employment. Narayanan:Millennium Pharmaceuticals: Employment. Carew:Millennium Pharmaceuticals: Research Funding. Lublinksky:Millennium Pharmaceuticals: Employment. Kuranda:Millennium Pharmaceuticals: Employment. Milhollen:Millennium Pharmaceuticals: Employment.
Inactivation of Polycomb Repressive Complex 2 Components in Myeloproliferative and Myelodysplastic/Myeloproliferative Neoplasms
Authors: Cross Nicholas C.P. , Score Joannah , Hidalgo-Curtis Claire , Jones Amy V , Winkelmann Nils , Skinner Alison , Ward Daniel , Zoi Katerina , Ernst Thomas , Stegelmann Frank , Dohner Konstanze , Chase Andrew J
Published: October 2019

Abstract 617

Single nucleotide polymorphism (SNP) arrays have revealed regions of acquired uniparental disomy (aUPD) as recurrent events in hematological malignancies. Some of these regions are associated with the acquisition of somatic mutations in specific genes but the presumptive targets of many stretches of aUPD remain to be identified. We and others recently identified EZH2 as a target for 7q aUPD in myeloid malignancies, specifically myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN). EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. We reasoned that the other two core PRC2 components SUZ12 and EED may also be mutational targets in these diseases, as well as associated factors such as Jarid2. We identified SUZ12 mutations in 1 of 2 cases with MDS/MPN with 17q aUPD and 2 of 2 myelofibrosis cases with focal 17q11 deletions. All three were missense mutations affecting the highly conserved VEFS domain, necessary for the interaction between SUZ12 and EZH2 and thought to help stabilize the PRC2 complex. Analysis of a further 146 MDS/MPN cases revealed an additional VEFS domain mutant, yielding a total mutation frequency of 2/148 (1.4%). We did not find mutations of Jarid2 or EED in association with aUPD for chromosome 6p or 11q, respectively, however screening additional cases identified missense mutations in EED (1/87; 1%) and Jarid2 (3/148; 2%). All three SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase (HMT) activity as assessed by an in vitro baculovirus expression assay, thus demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes. SUZ12 is located at 17q11.2 close to NF1, a gene that encodes a negative regulator of Ras signalling that has been strongly implicated in the pathogenesis of myeloid neoplasms. Of the cases with SUZ12 mutations, one with del(17q11.2) had mutations of both NF1 and SUZ12. Both of these mutations were clearly inactivating: a frameshift in exon 5 of NF1 and a D605V change in SUZ12 that greatly reduced PRC2 HMT activity. In summary, we have shown that inactivation of the PRC2 can occur through mutation of any of the 3 core components, and that inactivating mutations of EZH2, SUZ12 or EED are seen in 15% of cases of MDS/MPN. These findings emphasize the importance of PRC2 function in hemopoiesis and suggest that deregulation of the epigenetic control of gene expression plays an important role in the development of myeloid disorders.

Disclosures:

No relevant conflicts of interest to declare.