bluuebunny/crossref_metadata_2025_split huggingface dataset:
TET2 mRNA Expression in Bone Marrow Mononuclear Cells of the Patients with Myelodysplastic Syndromes and it's Clinical Significances
Authors: Shao Zonghong , Wang Wei , Fu Rong , Wang Jun , Li Lijuan , Ruan Erbao , Qu Wen , Liang Yong , Wang Guojin , Wang Xiaoming , Liu Hong , Song Jia , Wu Yuhong , Xing Limin , Guan Jing , Wang Huaquan 
Published: October 2019

Abstract
Abstract 5036

Objective
This study was aimed to investigate the expression of TET2 mRNA in the bone marrow mononuclear cells(BMMNC)of patients with myelodysplastic syndrome(MDS)and its clinical significance.

Methods
The mRNA expression of TET2 in bone marrow mononuclear cells(BMMNC) of 25 patients with MDS and 16 controls were detected by RT-PCR. Results The expression of TET2 mRNA in BMMNC was down-regulated in MDS (0.9509±0.3841)compared with that in controls(1.2515±0.3749)(P<0.05), but was no significant difference of BMMNC expression of TET2 among RA, RCMD and RAEB. Patients with higher expression of TET2(≥0.9) presented significantly lower proportion of bone marrow blasts[(1.04±1.68)%] than that [(6.13±8.17)%] of those with lower expression (<0.9) of TET2 (P<0.05). The expression of TET2 mRNA in BMMNC of MDS patients was inversely correlated with malignant clone burden (r=-0.398,P<0.05) and IPSS (r=-0.480,P<0.05).

Conclusions
The mRNA expression of TET2 in BMMNC of MDS patients decreased, which might useful as an important indicator for the evaluation of MDS clone burden.

Disclosures:
No relevant conflicts of interest to declare.
Pulmonary Hypertension May Be a Relevant Comorbidity in Patients with Myelodysplastic Syndromes
Authors: Kqiku Xhylsime , Kovacs Gabor , Reitter Sonja , Sill Heinz , Olschewski Horst 
Published: October 2019

Abstract
Abstract 5039

Background:
Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure and increased pulmonary vascular resistance, leading to right-sided heart failure and death. PH is defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest. PAP values can be non-invasively estimated by Doppler echocardiography while right heart catheterization is needed for definite diagnosis. Hematologic disorders are associated with PH but it is unknown if myelodysplastic syndromes (MDS) bear an increased risk for PH. The objective of this study was to investigate the prevalence of PH in patients with MDS.

Patients and Methods:
From March 2009 to July 2011 consecutive MDS patients were recruited from the Hematology Division of the Medical University of Graz and enrolled in this PH screening program. All patients underwent Doppler echocardiography. PH was suspected if resting systolic pulmonary arterial pressure (SPAP) exceeded 40 mmHg.
Additionally six minute walk distance (6MWD), pulmonary function test (PFT), laboratory tests including N-terminal pro brain natriuretic peptide (NT-proBNP), IPSS Score and WHO functional class were determined.

Results:
Fourty four MDS patients (female:male=18:26, age 70±12 years, disease onset 5±8 years, NYHA functional class I:II:III:IV=21:16:7:0, IPSS low/intermediate-I/intermediate- II/high/unknown=16:14:8:3:3; hemoglobin: 11±2 g/dl, white blood cell count 4±3 g/l; platelet count 159±125 g/l; regular transfusions n=19; WHO Classification: RCUD/RARS/RCMD/MDS del(5q)/RAEBI/RAEB II/MDSU=2:3:21:2:6:6:4 ) were included.
Six patients had elevated SPAP (PH group, SPAP: 56±9mmHg) vs. 38 patients with normal values (SPAP 29±5mmHg). PH group were slightly older (79±9 vs. 69±11 years, p=0.53), had a decreased right ventricular function (TAPSE: 18±5mm vs. 22±4mm, p=0.05), a larger left atrium (46±5mm vs. 36±9mm measured in the parasternal long axis, p=0.005), a slightly decreased left ventricular systolic function (fractional shortening: 30±11% vs. 38±9 %, p=0.1) a significantly lower 6MWD (275±117m vs. 438±105m, p=0.01) and higher NT proBNP (4515±4732 pg/ml vs. 313±252 pg/ml, p=0.001) than patients with normal SPAP. In 4/6 PH group patients a relevant diastolic dysfunction of the left ventricle was suggested by echocardiography.

Conclusion:
According to our data, PH is present in about 15% of MDS patients and is associated with decreased physical capacity and heart failure. This suggests that PH may be considered as a relevant comorbidity in this cohort of patients. The reason of PAP increase may be multifactorial, postcapillary factors probably playing a relevant role.

Disclosures:
No relevant conflicts of interest to declare.
Azacitidine Is Feasible and Safe in Patients with MDS and Co-Existing Plasma Cell Dysplasias (PCD) - Report on 9 Patients From the Austrian Azacitidine Registry (AAR)
Authors: Auberger Jutta , Pleyer Lisa , Weiss Lukas , Egle Alexander , Greil Richard 
Published: October 2019

Abstract
Abstract 5056
Azacitidine (AZA) has been approved for the treatment of higher-risk MDS and therefore marks a cornerstone in the development of hypomethylating agents. Recent clinical trials raise questions regarding optimal sequencing and also about combining hypomethylating agents with other classes of drugs targeting epigenetic processes. It has been postulated that unspecific demethylation of promotors may lead to the activation of oncogenes, and therefore result in an elevated rate of secondary malignancies.
We report on 9 patients from the Austrian Azacitidine Registry (AAR) with co-excisting plasma cell dyscrasias (PCD) receiving treatment with AZA for MDS. Six male and 3 female patients had a median age of 73 years at time of diagnosis of MDS and 73 years at time of diagnosis of PCD. They were diagnosed with Waldenstrom macroglobulinemia (WMG) (n=3), multiple myeloma (n=2) and MGUS (IgG (n=2), IgM (n=1), IgA (n=1)). All PCD were diagnosed either before or at least at the same time as MDS. None occurred after diagnosis of MDS or after treatment initiation with AZA. However, one patient with multiple myeloma likely had treatment–related MDS due to prior treatment with MPT (melphalan, prednisone, thalidomide).
At the time of writing, the mean number of AZA cycles given was 9 (range 1–27). Two patients were concomitantly treated with Rituximab (R) whilst on AZA treatment. Importantly, no additional toxicities occurred and there seemed to be no negative interaction between Rituximab and AZA. In all patients treated with AZA for MDS, M-gradient remained stable, and in some cases significant improvement was noted. One patient even achieved complete remission of WMG following AZA/R treatment (data will be shown; Weiss L et al, J Clin Oncol. 2011 Jul 25 [Epub ahead of print]). Importantly, no progression of PCD was seen in any of the 9 patients treated with AZA, and PCD did not contribute to death in any of these patients.
In conclusion, AZA treatment of MDS in patients with co-existing PCD seems safe, combination with Rituximab seems feasible, no aggravation of PCD was seen and remarkably, one patient with WMG achieved CR following AZA/R.

Disclosures:
Pleyer: Celgene: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.
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
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
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
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
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
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.