bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-Wide Abnormality Patterns of B-Lineage Acute Lymphoblastic Leukemia in Adults in Comparison with Pediatric Cases
Authors: Wang Bai-Yan , Liu Yuan-Fang , Tang Jing-Yan , Gu Zhao-Hui , Zhang Wei-Na , Zhang Zi-Guan , Wang Qiang , Chen Bing , Wang Sheng-Yue , Zhu Yong-Mei , Li Jun-Min , Wang Jin , Bai Yun , Lu Gang , Yang Min-Jun , Zhang Jin-Li , Shi Jing-Yi , Wang Kan-Kan , Pan Chun-Ming , Lu Jing , Jiang Lu , Li Yang , Zhao Chun-Jun , Chen Jing , Gu Long-Jun , Mi Jian-Qing , Li Ben-Shang , Chen Zhu , Chen Sai-Juan 
Published: October 2019

Abstract
BACKGROUND
B-lineage acute lymphoblastic leukemia (B-ALL) represents the most common subtype in ALL. Genomic sequence information has been lacking in adult B-ALL, whose outcome remains dismal, while a comparison between genomic abnormalities in adult and pediatric groups is useful to further decipher disease mechanisms.
METHODS
We used whole exome sequencing (WES), copy number variation and molecular cytogenetics to catalog somatic mutations in 95 B-ALL patients (43 adults and 52 children).WES was conducted with appropriate depths for paired genomic DNA from bone marrow mononuclear cells at diagnosis and their matched peripheral blood samples during complete remission (CR) or saliva samples. Targeted deep sequencing (TDS) was performed in a validation cohort of 179 adult and 199 pediatric B-ALLs.
RESULTS
Eighty-four recurrent gene mutations were revealed by WES. Integrative analysis identified the involvement of 9 functional categories of genes: key fusions (KFs), epigenetic modifiers (EMs), signaling molecules (SMs), transcription factors (TFs), tumor suppressors (TSs), actin binding/cytoskeletons (ABCs), ion binding proteins (IBPs), trans-membrane proteins (TPs) and the others. Mutually cooperative or exclusive relationships were revealed among some of these categories. Genomic landscapes suggested two distinct mechanisms involved in the leukemogenesis: one is mainly driven by KFs together with mutations of TFs and TSs; the other results from the abnormalities of TFs and TSs, in cooperation with mutations of EMs, SMs, ABCs and IBPs recapitulating the role of KFs. A panel of histone/DNA methylation modifiers (HMMs) were revealed to bear potential value of relatively favorable prognosis in both adult and childhood patients.
CONCLUSIONS
We described the genome-wide abnormality patterns in adult B-ALL patients in comparison with those of pediatric cases, contributing to the understanding of leukemogenesis and the identification of potential new prognostic markers.

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Combined Transplants of Cord Blood Plus Peripheral Blood from an HLA Matched Sibling in Thalassemia Patients
Authors: He Yuelin , Li Changgang , Wu Xuedong , Liu Sixi , Feng Xiaoqin , Li Chunfu 
Published: October 2019

Abstract

Background Cord blood from HLA matched sibling was widely used as stem source in transplants in patients with thalassemia major (TM), but failure of engraftment is frequent.
Aim To improve engraftment of CB transplant in patients TM
Patients and method A combined transplants of CB and peripheral blood (PB) from same HLA matched sibling was conducted (i.e. CB and PB were harvested and infused on day 0) from June, 2010 to February, 2014. Total 24 patients were involved in the study. Donor-recipient pairs were matched at HLA-A, B and DRB1 (antigen level) in 23 but one with HLA mismatched at one loci (DRB1). The conditioning protocol included intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa. Prophylaxis of GVHD included Cyclosporine and short MTX. All donors (newborn) were sent into NICU for monitoring, and then, discharged after 3 days.
Results The median age at transplant was 4 years (range, 1.5-7 years), and the ratio of male-to-female patients was 16:8. The median follow-up time was 17 months (range, 5-49 months). The mean mononuclear cell (MNC) dose of CB was 5.67×107/kg body weight of the recipient (BWR; range, 2.1-8.75×107/kg BWR) while that of PB was 3.21×107/kg BWR (range, 0.47-7.31×107/kg BWR). The mean volume of infused CB was 91ml (range, 31-131ml) while that of PB was35ml (range, 10-71ml). The median ANC engraftment time was 28 days (range, 15-47days), while the median platelet engraftment time was 34.0 days (range, 0-128days). The estimated 4-year overall survival (OS) and TM-free survival (TFS) were both 100%. The cumulative incidences of graft rejection and grades II-IV acut egraft-versus-host disease (aGVHD) were both 0%. All donors are normal as peers with following up to date.
Conclusion These results suggest that patients with TM have excellent outcomes after CB plus PB combined transplant from an HLA matched sibling.

Disclosures
No relevant conflicts of interest to declare.
The Prevalence of Hereditary Hemoglobin Disorders and Its Implications for Newborn Screening in Germany
Authors: Grosse Regine , Schneppenheim Reinhard , Lukacs Zoltan , Oyen Florian , Muntau Birgit , Lukacs Paulina , Noack Bernd 
Published: October 2019

Abstract
Introduction: Hemoglobin disorders are among those hereditary diseases with evidence that an early diagnose and treatment improve the clinical outcome of affected children. So far hemoglobin disorders are not included in the German newborn screening program despite increased immigration from countries with populations at risk.
Methods: To determine the birth prevalence in a major German area we tested 16910 anonymized newborns from Hamburg. High pressure liquid chromatography (HPLC) and subsequent molecular-genetic testing were used for the detection and confirmation of sickle cell variant (HbS), of hemoglobin C (HbC) and of beta- and alpha-thalassemia variants.
Results: We found sickle cell disease (SCD) to be the most prevalent with a frequency of disease-consistent genotypes of 1 in 3382 newborns. The prevalence for sickle cell trait (SCT) was 1 in 301 births. Statistical analysis indicates with 96% probability a prevalence for SCD of at least 1 in 8455 births and for SCT of at least 1 in 393 births. Duffy-blood group typing showed evidence that affected children were likely of Sub-Saharan ancestry. More than 90% of the newborns found with SCD or SCT were of sub-Saharian ancestry, suggesting that in Hamburg mainly children from members of the African community are at risk for the hemoglobinopathy SCD. Our data indicate a 95% probability that the prevalence of SCD in Hamburg is at least 1,18/10.000 births.
Alpha Thalassemia trait had a prevalence of 1: 994, indicating with 97% probability a minimal prevalence of 1: 2114 births. In this study we did not find any child with beta-thalassemia major or HbH- disease, which indicates a birth prevalence of less than 1 in 16910 births during the study period.
32 chromatograms indicated heterozygosity for other hemoglobin variants and 1 pattern indicated homozygosity for HbCC.
Conclusion: Our study sustains the notion that newborn screening in areas that see significant immigration is necessary to provide early intervention with the framework of a public health initiative. As long as a nationwide screening in Germany is not yet implicated all high-risk infants (those of African, Mediterranean, Middle Eastern, Indian, Caribbean, and South and Central American ancestry) should receive a neonatal screening for SCD. Any high-risk infant not screened at birth, or for whom neonatal screening results cannot be documented, should be screened for hemoglobinopathies prior to 2 months of age.

Disclosures
Grosse: Novartis Oncology Germany: Research Funding.
Minimal Renal Toxicity after Rituximab DHAP with a Modified Cisplatin Application Scheme in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma
Authors: Lisenko Katharina , McClanahan Fabienne , Schöning Tilman , Schwarzbich Mark-Alexander , Cremer Martin , Dittrich Tobias , Ho Anthony D. , Witzens-Harig Mathias 
Published: October 2019

Abstract
BACKGROUND: Rituximab (R) in combination with DHAP is a widely accepted salvage regimen in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). DHAP combines cisplatin (100 mg/m2) typically administered intravenously (i. v.) by continuous infusion over 24 hours, followed on day 2 by cytarabine (2 g/m2) in a 3-hour infusion repeated after 12 hours, and oral administration of dexamethasone (40 mg/d) for 4 consecutive days. A common adverse effect of this protocol consists of renal toxicity which may result in dose reduction or treatment discontinuation. Therefore novel approaches to overcome renal toxicity of R-DHAP are urgently warranted. Assuming that a lower single dose of cisplatin over several days would reduce renal toxicity, our institution has chosen to administer cisplatin at a dosage of 25 mg/m2 per day as a 3-hour infusion over 4 consecutive days. In this study we systematically examine efficacy and renal toxicity of this modified R-DHAP regimen.
METHODS: We retrospectively analyzed data of 122 patients with relapsed/refractory DLBCL who were treated at our institution from July 2002 to July 2013. Patients were grouped according to the number of R-DHAP courses applied and renal function was evaluated in each subgroup. Creatinine serum levels before each R-DHAP cycle and two to three weeks after the last R-DHAP were assessed and GFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
RESULTS: Overall, 256 R-DHAP cycles were administered. 31 (25%), 61 (50%), 14 (12%) and 16 (13%) patients received one, two, three or four R-DHAP courses, respectively. Dose adjustments needed to be applied in only 5 (4%) patients who in total received 11 R-DHAP courses. A step-by-step evaluation of renal function after each R-DHAP course revealed that a GFR decrease can be observed after each chemotherapy cycle. However, in none of the subgroups GFR was lower than 60 ml/min/1.73 m2. In most patients, only renal impairment stage I and II was observed. Renal impairment stage III was observed in 12 patients (10%) and stage IV only in one patient (1%). The overall response rate of the modified R-DHAP protocol was 54% (CR 17%, CRu 5%, PR 32%, SD 15% and PD 29%, not known 4%).
CONCLUSION: A modified R-DHAP regimen with administration of cisplatin 25 mg/m2 over 4 consecutive days is effective and safe in relapsed/refractory DLBCL and leads only to minimal renal toxicity.

Disclosures
Witzens-Harig: Pfizer: Honoraria, Research Funding; Roche: Honoraria.
HLA-Mismatched Microtransplantation Vs HLA-Matched Nonmyeloablative Transplantation for Acute Myeloid Leukemia in Intermediate-Risk: Comparable Survival but Avoids of Gvhd
Authors: Guo Mei , Yu Chang-Lin , Dong Zheng , Hu Kaixun , SUN Qiyun , Qiao Jianhui , SUN Wanjun , Zuo Hongli , Huang Yajing , Qiao Junxiao , CAI Bo , LIU Zhiqing , Yao Bo , LIU Tieqiang , Zhao Hongxia , SUN Xuedong , Shen Xuliang , Zhan Xinrong , WANG Juan , Li Jianyong , HU Liangping , Zhou Qianqian , Ai Huisheng 
Published: October 2019

Abstract
The optimal therapy for intermediate-risk patients with acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Recent studies shown that microtransplantation (MST) can improve survival in AML-CR1 patients. However, a comparison study between the MST and nonmyeloablative stem cell transplantation (NST) is lacking. 156 intermediate-risk AML-CR1 patients aged 9 to 59 years were enrolled in this study. 57 patients who had a HLA-identical donors were assigned to receive NST therapy with graft-versus-host disease (GVHD) prophylaxis. The other 99 who had no HLA-identical donors including 86 family-related, 9 distantly related and 4 unrelated donor were assigned to receive MST therapy but without GVHD prophylaxis. The probabilities of 10-year overall survival and leukemia-free survival was comparable in the MST-group and NST-group (70.7% vs. 61.4% and 59.6% vs. 57.9%). The NST-group exhibited a higher full donor chimerism (96.5%) and higher GVHD (33.3%), whereas the MST-group produced a higher donor microchimerism (75%), slightly higher relapse (32.3% vs. 22.8%) and significantly lower non-relapse mortality (6.9% vs. 19.3%, P=0.021) but without GVHD. In the MST-group, the patients with increase of WT1+ CD8+ T cells exhibited significantly higher leukemia-free survival and lower relapse than those without (92.0% vs. 40.0%, P=0.003; 8.0% vs. 50%, P=0.009). These results indicate that, compared to NST, MST produced a comparable survival, less transplantation-related mortality, avoidance of clinical GVHD and overcome limitations of HLA-barrier, suggesting a much safe and effective therapy for intermediate-risk AML-CR1, particularly for those without a HLA-identical donor.

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (CML) Who Switch to Imatinib Following Optimal Response to Second Generation Tyrosine Kinase Inhibitors
Authors: Kota Vamsi K , Winton Elliott F. , Arellano Martha , Jillella Anand , McLemore Morgan L. , El Rassi Fuad , Khoury H Jean 
Published: October 2019

Abstract

The second-generation TKIs (2G-TKIs) Dasatinib (DAS) and Nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) CML as compared to Imatinib (IM) however, long-term safety of these agents is a growing concern.
We identified 10 patients with CP CML diagnosed between 08/2013 and 06/2015 who initiated 2G-TKIs and were then switched after optimal response at 3 months to IM. DAS was administered to 8 patients at 100 mg/d and NIL in two patients at 300 mg twice a day. Response to TKI was assessed by quantitative reverse transcriptase polymerase chain reaction (qPCR) for BCR-ABL1. Response to 2G-TKIs after 3 months was as follows: CHR (n=10), 1 log (<10%, n=10), 2 log (<1%, n=7), and 3 log (<0.1%, n=2) reduction of BCR-ABL1 transcripts. Median qPCR at 3 months was 0.77% by IS (range 0-7%).
NIL was discontinued due to grades 2-3 non-hematological toxicities in both patients. DAS was discontinued due to patient or physicians' preference or drug availability. Median time to discontinuation of 2G-TKIs and initiation of IM was 103 days (range, 92 - 120) from diagnosis. IM was started at 400 mg/d and was well tolerated except in 2 patients who required dose-reduction and discontinuation due to grade 2 skin rash (1) and grade 2 anxiety (1). Both patients switched back to DAS at 54 and 228 days after initiation of IM respectively. 9/10 patients that switched to IM were evaluable with a follow up of at least 3 months. These patients have shown a continuous response with 9/9(100%) achieving a 2 log reduction at 6 months. With a median follow-up from initiation of IM of 8 months (range 2-20 months), 5/9 (55.5%) evaluable patients achieved MMR at 6 months and 3/6 MR5 at 9 months from diagnosis.
In conclusion, this retrospective analysis shows that IM can be safely and effectively administered following optimal response to 2G-TKIs. Longer follow-up is needed, but with up to 20 months follow-up, all patients showed continuous decrease in their transcripts (Figure 1) and no losses of major molecular response or progression to blast phase were observed. A strategy of induction with 2G-TKIs followed by maintenance with IM is worth evaluating in a prospective trial.
Figure 1. BCR-ABL1 qPCR (IS value) at diagnosis and follow-up after a switch to IM at 3 months from 2G-TKIs. Figure 1. BCR-ABL1 qPCR (IS value) at diagnosis and follow-up after a switch to IM at 3 months from 2G-TKIs.

Disclosures
Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.
A Primary Study of the Gene Mutations in Predicting Treatment Response to Decitabine in Patients with MDS
Authors: Chang Chunkang , Zhao Youshan , Xu Feng , Li Xiao 
Published: October 2019

Abstract
Background
To analyze whether some distinct gene mutations could predict treatment response to Hypomethylation Agent---Decitabine.
Patients and Methods
Targeted next-generation sequencing was performed on reported 30 recurrently mutated genes for 106 MDS patients before they accepted Decitabine therapy. For those who presented satisfactory response (CR) or poor response (NR or PD), their gene sequencing were repeated after Decitabine therapy to analyze the alteration of the gene mutation.
Results
The overall response rate was 67.0%, with 26.4% patients (28 cases) achieving CR. The median survival of patients who achieved CR was longer than those who just achieved NR/PD (22 months VS 14 months, p =0.021). Among the 14 TP53 mutant patients, ten achieved CR (71.4%). Moreover, two of 3 BCOR mutant patients (66.7%) and three of 5 KIF20B mutant patient (60.0%) also achieved CR. Zero of the patients who were with IDH1/2(n=11), GATA2 (n=5), SETBP1 (n=5), EZH2 (n=3) or CEBPa (n=1) mutations could get CR response (Figure1). On the other hand, total five of the 8 PTPRD mutant patients (62.5%) and five of 11 ASXL1mutant patients did not responded to Decitabine. In addition, 16 among the 28 CR patients accepted the target sequencing after the stop of decitabine therapy. Ten of the 16 patients showed decreased number of mutant genes (Table1). Besides, the TP53 mutation was completely fade away in five of 7 patients after Decitabine treatment (Table 2). Finally, the TP53 mutant and wild type of MDS patients achieved comparable overall survival, suggesting decitabine treatment could significantly alter the prognostic impact of adverse genetic alterations.
Conclusion
Some gene mutation (specially TP53) seemed predictive for Decitabine response. Further studies with large samples are needed to identify it.
Table 1. The number of mutant genes on CR patients before and after Decitabie therapy Sample Number of mutations response Before After Sample 586 3 2 CR Sample 967 3 2 CR Sample 1761 4 2 CR Sample 1619 2 3 CR Sample 1864 7 4 CR Sample 1854 3 1 CR Sample 1818 3 2 CR Sample 1522 2 4 CR Sample 2038 2 2 CR Sample 2055 2 1 CR Sample 702 3 1 CR Sample 828 2 0 CR Sample 1361 0 0 CR Sample 1002 2 1 CR Sample 1917 1 2 CR Sample 1154 0 0 CR
Table 2. Status of TP53 mutation after hypomethylating agents in CR patients. Sample Before After response Sample 586 TP53/8/D242H TP53-WT CR Sample 967 TP53/6/R174L TP53-WT CR Sample 1864 TP53/8/R244H TP53/8/R244H CR Sample 1854 TP53/4/W91 TP53-WT CR Sample 2038 TP53/8/F231S TP53/8/F231S CR Sample 2055 TP53/6/R196* TP53-WT CR Sample 1002 TP53/8/R234H TP53-WT CR

Disclosures
No relevant conflicts of interest to declare.
Favorable Immune Signature in CLL Patients, Defined By Antigen-Specific T-Cell Responses, Might Prevent Secondary Skin Cancers
Authors: Stickel Juliane S , Kowalewski Daniel Johannes , Schuster Heiko , Kahn Stefan , Backert Linus , Kanz Lothar , Salih Helmut R , Rammensee Hans-Georg , Stevanovic Stefan 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The course of disease predisposes patients to the development of secondary malignancies, which might be due to a generalized immunosuppression induced by the disease and/or the therapies used for treatment. Skin cancer, including melanoma, is the most common secondary malignancy reported in these patients.
In a recent study we reported on spontaneous memory T cell responses against CLL-associated antigens defined by HLA ligandome analysis in CLL patients. Moreover, retrospective analysis suggests a significant survival benefit for CLL patients showing immune reactions to more than one of the tested antigens (Kowalewski et. al., PNAS 2015).
Here we analyzed our CLL patient cohort for the incidence of secondary malignancies, and in particular for skin cancers. A total of 15 CLL-associated HLA-peptides (6 A*02, 3 A*03, 6 B*07) were implemented for stimulation of HLA-matched PBMC obtained from CLL patients. 45 CLL patients (Binet A n=15, Binet B, n=15, Binet C n=15, median age, 33.3% (15/45) with prior CLL specific therapy) were analyzed for antigen-specific memory T-cell responses in IFNγ-ELISPOT assays. 13 patients (28.9%, response cohort) showed specific T cell response against > 1 antigen, while 32 patients (71.1%, negative cohort) showed none or only one immune response. The median age was 71 in the response cohort and 73 in the negative cohort. 40.0% (6/15) of CLL patients with Binet stage A and 33.3% (5/15) with stage B were classified as responders whereas only 13.3% (2/15) of patients with stage C showed >1 immune responses. Of the included CLL patients with prior therapy only one patient (8%) showed > 1 immune responses. In the analyzed CLL patient cohort 7 skin cancers (melanoma: n=2, squamous cell carcinoma: n=2, basal cell carcinoma: n=3), 3 precancerous skin lesions and 9 other secondary malignancies including renal cell carcinoma (n=2), colon (n=3), breast (n=2) and prostate cancer (n=2) were observed. In the negative cohort 34.4% (11/32) of the patients developed a secondary malignancy, while only 15.4% (2/13) in the immune response cohort presented with secondary neoplasms. Strikingly all skin cancers and precancerous skin lesions were observed in the non-immune responder cohort. Furthermore multiple secondary malignancies (e.g. squamous cell carcinoma and colon cancer) were only observed in the cohort that showed no immune response.
Taken together our data suggest that a favorable immune signature in CLL patients, i.e. the ability to mount T-cell responses against CLL-associated antigens not only is associated with improved overall survival but also might protect these patients from the development of secondary skin cancers.

Disclosures
No relevant conflicts of interest to declare.