bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Under-Treatment of Elderly Medicare Diffuse Large B-Cell Lymphoma Patients
Authors: Satram-Hoang Sacha , Skettino Sandra , Hoang Khang , Guduru Sridhar R , Gunuganti Ashok , Reyes Carolina 
Published: October 2019

Abstract
Abstract 237

Introduction:
Prior real-world data show that a large proportion of the elderly population with diffuse large b-cell lymphoma (DLBCL) are not receiving the recommended therapy for their disease. Over half of the patients diagnosed with DLBCL are over the age of 60 and clinical trials show that patients over the age of 60 respond well to current guideline-based therapy. We set out to examine the patient characteristics associated with receiving recommended therapy and the survival outcomes in an older population in routine clinical practice.

Methods:
We conducted a retrospective cohort analysis of 9866 DLBCL patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 to December 31, 2007, were >66 years, and continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis. Chi-square test for categorical variables and ANOVA or t-test for continuous variables were used to assess differences in patient and disease characteristics by treatment status. Logistic regression modeling assessed the patient characteristics predictive of not receiving treatment. Kaplan-Meier curves and Cox proportional hazards regression assessed survival by treatment type. Date of last follow-up was December 31, 2009.

Results:
There were 7832 (80%) patients who received treatment and 2034 (20%) who did not receive treatment during the study time period. Untreated patients were older at diagnosis with mean age of 81 compared to 76 years in treated patients (p<.0001). As age increased, the treatment rate significantly decreased especially among patients >80 years (Table 1). Untreated patients were also more likely non-white (15% vs. 12%; p<.01), diagnosed with stage IV disease (33% vs. 29%; p<.0001), had higher comorbidity burden, and lived in areas of lower socioeconomic status than treated patients (p<.0001). In the adjusted logistic regression model, increasing age, non-white race, higher comorbidity score, and lower income were predictive of not receiving treatment. The multivariate survival analysis, adjusting for age, sex, race, stage, histology, comorbidity, income, and year of diagnosis, demonstrated a 3-fold higher risk of death in the untreated patients (HR=2.98; 95%CI=2.81–3.16) compared to treated patients.

Conclusions:
This real-world analysis of elderly DLBCL patients confirmed that 20% of them are not receiving treatment, and the rate of under-treatment is even more pronounced among those >80 years. As a consequence, untreated patients had a 3-fold higher risk of death compared to those who received treatment.

Disclosures:
Satram-Hoang: Genentech, Inc.: Consultancy. Skettino:Genentech, Inc.: Employment, Roche Stock Other. Reyes:Genentech, Inc.: Employment, Roche Stock Other.
Aid-Initiated DNA Lesions Are Differentially Processed in Distinct B Cell Differentiation Stages in a Locus-Dependent Manner.
Authors: Chen Zhangguo , Viboolsittiseri Sawanee , Eder Maxwell , Yuan Shunzong , Wang Jing H. 
Published: October 2019

Abstract
Abstract 2376
Activation induced deaminase (AID) initiates U:G mismatches that are subsequently converted into point mutations or DNA double-stranded breaks. AID-mediated DNA alterations in switch (S) regions at the Igh locus frequently occur in both antigen-stimulated germinal center (GC) B cells and cytokine-activated B cells. To investigate whether AID-initiated U:G lesions are differentially processed in a differentiation stage-specific manner at non-Ig loci to maintain genome stability, we established a knock-in model by inserting an Sg2b region into the first intron of proto-oncogene c-myc. We found that the inserted Sg2b region mutated at an extremely low level and did not enhance genomic instability of c-myc locus in antigen-stimulated GC B cells. In contrast, the inserted Sg2b region mutated more frequently and increased c-myc locus abnormalities in cytokine-activated B cells. Furthermore, uracil glycosylase deficiency led to increased mutation frequency at the c-myc locus. These results reveal that AID-initiated lesions are differentially processed via error-free or error-prone repair in a differentiation stage-specific and locus-dependent manner. Our data might provide mechanistic explanation for differential frequency of AID-mediated genetic alterations in distinct subtypes of common B cell lymphomas.

Disclosures:
No relevant conflicts of interest to declare.
Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia.
Authors: DiNardo Courtney D. , Levine Ross L. , Propert Kathleen J , Loren Alison W. , Paietta Elisabeth , Sun Zhouxin , Straley Kimberly , Yen Katharine , Patel Jay P. , Agresta Samuel , Abdel-Wahab Omar , Perl Alexander E , Fernandez Hugo F , Margolis David , Tallman Martin S. , Luger Selina M. , Carroll Martin 
Published: October 2019

Abstract
Abstract 2481

Purpose:
Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival.

Patients and Methods:
Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS).

Results:
Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p &lt; 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels &gt;700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1).

Conclusion:
We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies.

Disclosures:
Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.
Comparison of Fluorescence in Situ Hybridization (FISH) for EVI1 Rearrangement (3q26) and G-Banding in Patients with Acute Myeloid Leukemia with Inv(3) or t(3;3).
Authors: Choi Qute , Lee Dong Soon , Yoon Sung-Soo , Hwang Sang Mee , Kim Seon Young , Kim Jung Ah , She Cha Ja , Choi Jung Eun , Lee Eun Jung , Kwon Jiseok 
Published: October 2019

Abstract
Abstract 2540

Background:
Acute myeloid leukemia (AML) with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) is a distinct subgroup that may present de novo or arise form a prior MDS, characterized by thrombocytosis and marked dysmegakaryopoiesis. Since the presence of inv(3) or t(3;3) suggests poor prognosis in AML and needs for close monitor in MDS, detection of EVI 1 rearrangement (3q26) is crucial. We performed FISH for inv(3) or t(3;3) and compared those results with those of G-banding in AML, both at initial diagnosis and follow-up.

Methods:
We retrospectively reviewed the results of G-banding in 550 patients with AML (2000 Jan-2012 June). Among them, patients who showed 3q abnormalities by G-banding were subjected to FISH analysis for inv(3) or t(3;3) with frozen bone marrow cells. In patients who showed EVI 1 rearrangement by FISH, we performed EVI 1 rearrangement FISH on serial follow-up bone marrow of those patients, for detection of minimal residual cells. We applied 3 kinds of FISH probes (A company, B company, C company) for the detection of EVI 1 rearrangement.

Results:
By G-banding, the frequency of 3q aberrations involving 3q26 was 1.5% (8/550 patients) in AML and the frequency of AML wit recurrent inv(3) or t(3;3) was 0.2% (1/550 patients) in AML. Among 17 consecutive specimen from 8 patients with 3q26 aberration by G-banding, 11 specimen showed EVI 1 rearrangement by FISH, while 8 specimen showed EVI 1 rearrangement by G-banding. Of note, among 8 patients with 3q26 aberration by G-banding, FISH for EVI 1 rearrangement revealed EVI 1 rearrangement in 5 patients. Furthermore, EVI 1 rearrangement (3q26) FISH detected EVI 1 rearrangement in 1 patients among 30 patients with 3q aberrations other than 3q26 by G-banding. Comparison of FISH results among 3 kinds of FISH probes showed marked discordances. Among 26 consecutive specimens in patients with 3q26 aberrations, probe of each company detected 11 (A company), 4 (B company) and 4 (C company), respectively.

Conclusion:
Incidence of AML with inv(3) or t(3;3) involving EVI 1 rearrangement was rare (0.2%). One third of AML with inv(3) or t(3;3) by G-banding did not harbor EVI 1 rearrangement, suggesting involvement of other gene in the same chromosomal region. Comparison of FISH and G-banding during follow-up in the present study revealed that EVI 1 rearrangement FISH is essential for monitoring for minimal residual disease in AML with inv(3) or t(3;3).

Disclosures:
No relevant conflicts of interest to declare.
EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.
Authors: Wang Xiuli , Dai Haiping , WANG Qian , Wang Qinrong , Xu Yang , Jin Zhengming , Liang Jianying , Qiu Huiying , Sun Aining , Ruan Changgeng , Ruan Jia , Chen Suning , Depei Wu 
Published: October 2019

Abstract
Abstract 2544
Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Mir-183 Over-Expression: A Potential Biomarker for Juvenile Myelomonocytic Leukemia (JMML).
Authors: Liu Y. Lucy , Yan Yan , Lensing Shelly Y. , Cooper Todd , Emanuel Peter D. 
Published: October 2019

Abstract
Abstract 2558
Juvenile myelomonocytic leukemia (JMML) is a rare disease of early childhood with a predilection for the monocyte/macrophage lineage. The pathogenesis of JMML is linked to dysregulated signal transduction through the NF1/RAS signaling pathway that is partially caused by genetic mutation of Ras, PTPN11, and c-CBL, or loss-of heterozygosity of Nf1. The hallmark of JMML is that JMML cells are selectively hypersensitive to GM-CSF in vitro. We previously reported that protein deficiencies of PTEN, CREB, and Egr-1 were frequently observed in JMML (67–87%). Recent research indicated that CREB was regulated by miR-34b, and Egr-1 was targeted by miR-183. We hypothesized that microRNAs may play an important role in contributing to the deficiency of these proteins. Using relative-quantitative real-time PCR, we evaluated the expression levels of miR-34b and miR-183 in mononuclear cells from 47 JMML patients. We found that the median level of miR-183 was significantly higher in JMML in comparison to normal controls (median=13.8 vs 4.2, p<0.001); but the median level of miR-34b was only slightly higher in JMML subjects, and not significantly so, compared to normal individuals (median=1.4 vs 1.0, p>0.05). This suggests that miR-34b does not play a significant role in JMML. Since extreme monocyte accumulation is one of the critical characteristics of JMML, we analyzed the correlation between the expression level of miR-183 and the monocyte percentage in the peripheral blood. Strikingly, there was a significant correlation between the expression level of miR-183 and the monocyte percentage in the peripheral blood from 34 patients who had available data (p<0.05). Based on a robust regression analysis, for every unit increase in the square root of RQ miR-183, the monocyte percentage significantly increased by 0.73% (SE=0.32%, p=0.023). This is the first evidence suggesting that microRNAs may contribute to the pathogenesis of JMML. miR-183 may also serve as an important biomarker that can be directly and quantitatively linked to significant clinical parameters in JMML. It also may ultimately provide a target for JMML therapy.

Disclosures:
No relevant conflicts of interest to declare.
Cerebrospinal Fluid Flow Cytometry in Acute Lymphoblastic Leukemia/Lymphoma: Is It Beneficial?.
Authors: Rassi Fuad El , Mitri Zahi , Heffner Leonard T , Langston Amelia , Waller Edmund K. , Winton Elliott F. , McLemore Morgan L. , Bernal Leon , Arellano Martha , Khoury H. Jean 
Published: October 2019

Abstract
Abstract 2576
Cerebrospinal fluid (CSF) involvement by leukemic blasts occurs in fewer than 10 % of adult patients with newly diagnosed acute lymphoblastic leukemia/lymphoma (ALL). Leukemic meningitis is diagnosed by microscopic detection of blasts in the CSF. Flow cytometry is a highly sensitive tool for detection of aberrant cells. We sought to analyze the additional benefit flow cytometry might provide for the diagnosis of leukemic meningitis. Between 11/2007 and 8/2011, 80 patients were diagnosed with ALL and treated at Emory University. 800 CSF samples were available for analysis 80 of which were collected from a diagnostic lumbar puncture (LP), 689 from follow-up LPs and 31 from LPs obtained at the time of relapse. As shown in the table, flow cytometry confirmed the presence of leukemic blasts in one, four and five samples diagnosed with leukemic meningitis by cytology at diagnosis, different stages of treatment and relapse, respectively. One and three samples were positive for leukemic blasts by cytology but negative by flow cytometry during different treatment stages and relapse respectively. We conclude that flow cytometry provided no additional benefit to cytology in the diagnosis of leukemic meningitis.
Table: CSF Cytology and Flow Cytometry in 80 Adult ALL patients: CSF samples New Diagnosis N=80 Induction/Consolidation/Intensification/Maintenance/Remission/Post-transplant N = 689 Systemic relapse N = 31 N Cytology N = 80 Flow cytometry N = 66 Cytology N = 689 Flow cytometry N = 188 Cytology N = 31 Flow cytometry N = 13 Negative 79/80 65/66 684/689 184/188 23/31 8/13 Positive 1/80 1/66∼ 5/689 4/188∼* 8/31 5/13∼** ∼ CSF samples positive by flow cytometry were also positive by cytology * One CSF sample was positive by cytology but negative by flow cytometry ** CSF flow cytometry was not done in 3/8 positive CSF samples by cytology

Disclosures:
No relevant conflicts of interest to declare.
Physicians Compliance During Maintenance Therapy in Children with Down Syndrome and Acute Lymphoblastic Leukemia.
Authors: Bohnstedt Cathrine , Levinsen Mette , Rosthøj Susanne , Zeller Bernward , Taskinen Mervi , Hafsteinsdottir Solveig , Björgvinsdóttir Helga , Heyman Mats , Schmiegelow Kjeld 
Published: October 2019

Abstract
Abstract 2577
Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have an inferior prognosis compared to non-DS ALL patients. We reviewed Methotrexate (MTX)/Mercaptopurine (6MP) maintenance therapy data for children with DS treated according to the NOPHO ALL92 or the NOPHO ALL2000 protocols between 1992 and 2007. The five year event-free survival (pEFS5y) for the DS patients was inferior to the non-DS patients (0.50 ± 0.07 vs 0.77 ± 0.01, p<0.001). The 48 DS patients in 1st remission at the beginning of maintenance therapy had pEFS10y below the 522 non-DS control patients (pEFS10y: 0.58, 95%-CI 0.43–0.77 vs. 0.83, 95%-CI 0.80–0.86, p<0.0001). The DS patients received lower median doses of MTX (Median: 11.8 vs 15.4, p<0.0001) and 6MP (median: 45.6 vs. 59.4, p<0.0001). In Cox regression analysis male gender, presence of DS, and high median maintenance therapy white blood cell levels (mWBC) were associated with increased risk for relapse. The mWBC hazard ratio for DS-ALL patients was 2.0, p<0.0005). This supports that DS children with ALL should be treated as vigorously as non-DS ALL patients. Obtaining WBC levels within target range could potentially increase their cure rates.
Figure 1: Kaplan-Meier curves for event free survival for DS and non-DS children. Figure 1:. Kaplan-Meier curves for event free survival for DS and non-DS children.
Non-DS 513 464 443 433 418 DS 47 25 19 12 6

Disclosures:
No relevant conflicts of interest to declare.
Addition of All-Trans Retinoic Acid (ATRA) to the Combination of Fludarabine, Cytarabine, Idarubicin, with or without GCSF in Older, Higher Risk Patients with AML and High-Risk MDS Does Not Improve the Outcome in Those with NPM1 Mutation.
Authors: Nazha Aziz , Bueso-Ramos Carlos E. , Faderl Stefan , Estey Elihu H. , O'Brien Susan M. , Farnandez Michael , Nguyen Martin , Koller Charles , Freireich Emil , Beran Miloslav , Pierce Sherry , Cortes Jorge E. , Kantarjian Hagop M. , Ravandi Farhad 
Published: October 2019

Abstract
Abstract 2616

Background:
Previous studies have been conflicting in their findings regarding whether NPM1 gene mutations may be a marker for response to all-trans retinoic acid (ATRA) given as an adjunct to intensive chemotherapy in patients with acute myeloid leukemia (AML) (Schlenk RF, Haematologica, 2009, 94, 54–60, Burnett AK, Blood, 2010, 115,948, and Schlenk RF, abstract #80, ASH 2011).

Patients and Methods:
we examined the impact of the addition of ATRA among patients with diploid cytogenetics treated on a randomized phase II study of fludarabine + cytarabine + idarubicine +/− GCSF +/− ATRA with available data on their NPM1 mutation status. Between September 1995 and November 1997, 215 patients with newly diagnosed AML (n=153) or high-risk MDS (RAEB or RAEB-T; n=62) were enrolled in the study. They had to have one of the unfavorable features of age > 71 years, antecedent hematological disorder (AHD), therapy- related disease, or high bilirubin (>2.9 mg/ml) or creatinine (>1.5 mg/ml) to be eligible to participate in the study (Estey E, Blood, 1999, 93, 2478). Among them 70 patients had diploid cytogenetic and are the subjects of this analysis.

Results:
The median age of the 70 patients was 66.5 (range, 23–87), 60% had AHD, 15.7% had therapy-related disease, and 40% were older than 71. Bone marrow samples were available for all patients for examination by immunohistochemistry (IHC) for the presence of cytoplasmic NPM (correlating to NPM1 mutation). Twenty (29%) of patients had NPM1 mutation. Among them 7 (35%) did and 13 (65%) did not receive ATRA in combination with chemotherapy. Complete remission (CR) was achieved in 5 (71.4%) of patients treated with ATRA as compared to 9 (69.2%) without ATRA (p=NS). The median event-free survival was 82 weeks vs. 56 weeks for patients receiving ATRA or not [(p=0.5), ranges, (10–173 weeks) and (1–646 weeks), respectively]. The median overall survival was 41 weeks vs. 60 weeks for patients receiving ATRA or not [(p=0.74), ranges, (3–452 weeks) and (0–735 weeks), respectively].

Conclusion:
There was no significant difference in CR rate, EFS, or OS in this higher risk population of patients with NPM1 mutated diploid AML or high-risk MDS receiving ATRA as an adjunct to chemotherapy.

Disclosures:
Kantarjian: Genzyme: Research Funding. Ravandi:genzyme: Research Funding.
Is Interim/Mid-Treatment PET (interim PET, i-PET) Scan Predictive of Outcome in Diffuse Large B-Cell Lymphoma?.
Authors: Verma Dushyant , Takalkar Amol , Shi Runhua , Mills Glenn M. , Paladugu Srikanth , Veillon Diana , Munker Reinhold , Hildebrandt Gerhard , Nair Binu S. , Koshy Nebu 
Published: October 2019

Abstract
Abstract 2675

Background:
Initial treatment of diffuse large B-cell lymphoma (DLBCL) involves 6–8 cycles of chemo-immunotherapy and may be curative in 60–65% of patients. However, in the remaining patients, subsequent therapies appear inadequate for long lasting remission. A strategy to improve patient outcomes could involve early identification of patients who do not respond to treatment as expected and then employing different/aggressive treatment modalities in these patients. PET scan done during mid-treatment (interim PET, i-PET) may help identify these patients early. However, the value of i-PET in DLBCL is not established as there is controversy about its prognostic value and studies are ongoing to evaluate its benefit.

Aims:
To determine predictive value of i-PET on progression-free survival (PFS), overall survival (OS) in DLBCL patients.

Methods:
We performed retrospective analysis of DLBCL patients treated at LSU Health Shreveport, LA, between Jan 2002 – July 2012. All patients were treated with R-CHOP chemotherapy. PET-CT was performed at baseline at time of diagnosis, after 2 to 4 courses (i-PET) and at the end of therapy (final PET, f-PET).

Results:
Forty-four patients were evaluable for analysis. The median age was 55 years (range 21–84), 32 (73%) were males. Ann-arbor staging showed 5 patients each in stage I and II, 11 patients in stage III, 23 in stage IV, and the median IPI score was 3. Median time to i-PET was after 3 cycles of chemotherapy, and median days to i-PET after chemotherapy were 16. The median follow-up duration from start of chemotherapy was 23 months (range 4 – 89). The PET results were as follows: i-PET negative 30 (68%), i-PET positive 14 (32%) patients. Final PET results were: f-PET negative 33 (75%), f-PET positive 11 (25%) patients. The 3-year PFS was 96.3% and 35.7% for i-PET negative versus positive patients respectively (p<0.001), and the 3-year PFS for f-PET negative versus positive patients was 78.9%% versus 30.0% respectively (p<0.001). The 3-year OS was 79.4% and 62.6% for i-PET negative versus positive patients respectively (p=0.3306). The 3-year OS was 79.9% and 58.7% for f-PET negative versus positive patients respectively (p=0.021).

Conclusion:
Interim/mid-treatment PET (i-PET) scan is predictive of progression free survival but not overall survival for DLBCL patients. A final PET (f-PET) scan is predictive of progression free survival as well as overall survival for DLBCL patients. Larger prospective studies are needed to confirm these findings and could also look into the biology of i-PET positive patients by gene expressing profiling (GEP) and evaluate the role of novel agents in modifying the disease course.

Disclosures:
No relevant conflicts of interest to declare.