bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Inhibition of Histone Deacetylases and Phosphoinositide 3-Kinase Enhances Therapeutic Activity Against B Cell Lymphoma
Authors: Mondello Patrizia , Derenzini Enrico , Asgari Zahra , Philip John , Brea Elliot J , Seshan Venkatraman E , Hendrickson Ronald , de Stanchina Elisa , Scheinberg David A , Younes Anas 
Published: October 2019

Abstract
Oncogenic co-operation between c-Myc and activated phosphoinositide 3-kinase (PI3K) signaling pathways is crucial in lymphomagenesis, providing an opportunity for developing mechanism-based therapy to disrupt this co-operative survival mechanism. Combining constitutive c-Myc expression with constitutive PI3K activity in mouse germinal center B (GCB) cells resulted in Burkitt lymphoma-like tumors. Furthermore, analysis of primary human Burkitt lymphoma (BL) tissue sections revealed that two-thirds of the cases expressed high levels of phosphorylated AKT and S6 proteins, indicative of PI3K and mTORC1 activation. Prior attempts to develop small molecule inhibitors that specifically and directly target c-Myc protein have been unsuccessful. However, c-Myc cellular protein abundance can be decreased by using epigenetic modifying drugs (HDAC inhibitors or bromodomain/BET inhibitors) that are known to inhibit c-Myc transcription. Several investigators attempted disrupting c-Myc and PI3K cooperation by combining HDAC inhibitors and PI3K pathway inhibitors and synergic activity was demonstrated in DLBCL irrespective of subtype. In this study, we assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with c-Myc and PI3K-dependent lymphomas.

Disclosures
No relevant conflicts of interest to declare.
A Common Signaling Node Constitute Non-Oncogene Addiction in Kinase Driven Leukemia:Mechanism of Oncogne Addiction in CML
Authors: Kesarwani Meenu , Kincaid Zachary , Gomma Ahmed Ramadan , Huber Erika , Rohrabaugh Sara , Grimes H. Leighton , Azam Mohammad 
Published: October 2019

Abstract

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions
Authors: Kong Jee Hyun , Khoury Hanna Jean , Winton Elliott F. , Heffner Leonard T. , Gaddh Manila , Arellano Martha , El-Rassi Fuad , Kim Audrey S , Jillella Anand , Bodó Imre , Kota Vamsi 
Published: October 2019

Abstract

Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation.
Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively .
Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3).
Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined.

Disclosures
Heffner: Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
The Novel Missense Mutation of GATA1 Caused Red Cell Adenosine Deaminase Overproduction Associated with Congenital Hemolytic Anemia
Authors: Ogura Hiromi , Yamamoto Toshiyuki , Utsugisawa Taiju , Aoki Takako , Iwasaki Takuya , Ondo Yumiko , Kawakami Takahiro , Nakagawa Shinichiro , Ozono Shuichi , Inada Hiroko , Kanno Hitoshi 
Published: October 2019

Abstract
Red cell adenosine deaminase (ADA) overproduction (OMIM 102730) is a rare form of congenital hemolytic anemia. To date, only four independent families have been reported. Recently, we examined the red cell enzyme activities of an 18-year-old male Japanese patient with congenital hemolytic anemia, and diagnosed a new case of ADA overproduction. His ADA activity was measured as 39.7 IU/gHb, representing an over 30-fold elevation of the normal mean value. The patient's mother also showed a high red cell ADA, 7.40 IU/gHb, and the father had normal ADA activity. To elucidate the molecular basis of the elevated ADA activity, we performed a target-captured sequencing focusing on the 67 congenital-anemia related genes. The results showed that there was no structural mutation of ADA gene, and that the proband had a novel missense mutation of GATA1, c.920G>A, p.R307H. The proband was hemizygous, and the mother was heterozygous for the mutation. Subsequently, we examined a previously reported case of ADA overproduction, and identified the identical missense mutation of GATA1. These two cases had clinical similarities, such as low birth weight with hypospadias, splenomegaly, and slightly decreased platelet counts, suggesting that these cases could be categorized as X-linked anemia with or without neutropenia and/or platelet abnormality (XLANP, OMIM#300835). The previous case showed a rare blood type, Lu(a-b-) and a low beta/alpha globin synthetic ratio, whereas the present case depicted abnormal red cell morphology, such as stomatocytosis and target cells. Taken together, the missense mutation of GATA1 might cause the aberrant expression of erythroid-genes, inducing a short life-span of red cells.

Disclosures
No relevant conflicts of interest to declare.
Treatment Outcomes and Prognostic Factors of Patients with Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Choi Yunsuk , Lee Jung-Hee , Lee Kyoo-Hyung , Park Han-Seung , Choi Eunji , Ko Sun-Hye , Seol Miee , Lee Young-Shin , Kang Young-Ah , Jeon Mijin , Lee Je-Hwan 
Published: October 2019

Abstract
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the curative option for treatment of acute myeloid leukemia (AML). Even after HSCT, the relapse rate of AML ranged from 20% to 55%. The prognosis of relapsed AML after HSCT is very poor. But, treatment guideline for relapsed AML after HSCT has not been defined. Thus, we aimed to investigate treatment outcomes and prognostic factors of patients with relapsed AML after allogeneic HSCT.
Patient and Method: Among 624 patients with AML who received HSCT in Asan Medical Center, Korea between 1995 and 2014, 219 patients who had a relapse of AML after HSCT were included in this retrospective study.
Results: Seventy-two patients (32.9%) reattained complete remission (CR). Refractory AML at the time of HSCT (odds ratio [OR], 0.199, P=0.001), high BMI (> 28) (OR, 0.88, P=0.032), graft source from peripheral blood (OR, 0.299, P=0.001) and shorter relapse free interval (< 6 months) (OR, 0.199, P=0.001) were significant negative predictors for CR achievement (Table1). Of included patients, survival after relapse was median 5.2 months (95% CI, 3.96-6.44, months). Leukemia free survival of patients reattaining CR after relapse was median 10.6 months (95% CI, 8.1-13.2 months). Twenty-seven patients received second HSCT following salvage chemotherapy. Patients who had underwent upfront HSCT without chemotherapy for AML and relapse before 6months after HSCT were significantly associated with worse survival after relapse (Hazard ratio [HR], 3.106, P=0.006 and HR, 2.018, P=<0.001, respectively). Donor lymphocyte infusion following salvage chemotherapy and second HSCT had a significant impact on better survival (HR, 0.131, P=0.002 and HR, 0.423, P=0.003, respectively). Male gender (Hazard ratio [HR] 2.465, P=0.012) and extramedullary relapse (HR, 4.215, P=0.001) were negative factors affecting shorter leukemia free survival after relapse.
Conclusion: Donor lymphocyte infusion following salvage chemotherapy and second HSCT can be beneficial option for relapsed AML patients after HSCT. But, novel treatment modalities need to be investigated for improving survivals of relapsed AML patients after HSCT.

Disclosures
No relevant conflicts of interest to declare.
Mechanism of IL-10 Protective Effect in Development of Childhood B Cell Acute Lymphoblastic Leukemia
Authors: Fitch Briana , Hermiston Michelle L. , Wiemels Joseph L. , Kogan Scott C. 
Published: October 2019

Abstract
B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. While significant progress has been made in the treatment of B-ALL, the factors that influence the development of B-ALL remain poorly understood. Epidemiological studies have established a role of early childhood infections in altering leukemia risk. The focus of these studies has been on documenting the number and timing of infectious exposures; however, the role of host immune response to infections in B-ALL development is largely unknown. Low birth levels of the immunomodulatory cytokine interleukin 10 (IL-10) are associated with a 25 fold increased risk of developing childhood B-ALL. Mechanistically, IL-10 plays a critical role in controlling the neonatal immune response to infections. Together, these findings suggest that IL-10, an important regulator of host immune responsiveness, protects against childhood B-ALL.
To establish whether loss of IL-10 has an impact on leukemogenesis, we crossed Il10 knockout mice to the TEL-AML1 (ETVX6-RUNX1I) Ckdn2anull mouse model of childhood B-ALL. ETV6-RUNX1 t(12;21) is the most frequent chromosomal translocation in childhood B-ALLand one-fourth of these leukemias are observed in combination with loss of the Cdkn2a locus. The leukemia incidence in TEL-AML1 Ckdn2anull mice is 60%, therefore this is a robust and clinically relevant mouse model of childhood B-ALL. We used this model to assess the role of IL-10 in leukemogenesis by following Il10 knockout TEL-AML1 Ckdn2anull mice for the development of disease in comparison with control IL-10 expressing TEL-AML1 Ckdn2anull mice.
We found that Il10 knockout accelerated leukemogenesis in the presence of TEL-AML1. The cancer free survival of the IL-10 expressing TEL-AML1 Ckdn2anull mice (n=74) was 227 days, whereas the survival of IL-10 knockout mice (n=40) was reduced to 180 days (p<0.0005). These data support a causal role of low levels of IL-10 in the development of B-ALL and raise the possibility of using an IL-10 receptor agonist for leukemia prevention in children with high risk of B-ALL.
Thus, IL-10 loss is a defect in the host immune system that accelerates childhood B-ALL development, potentially through modifying immune responses to infections. Studies to understand the mechanism of how low IL-10 levels interact with infections to influence leukemogenesis are underway.

Disclosures
No relevant conflicts of interest to declare.
Efficacy of Pegaspargase, Etoposide, Methotrexate and Dexamethasone (PEMD) in Newly-Diagnosed Advanced-Stage Extra-Nodal Natural Killer (NK)/T-Cell Lymphoma
Authors: Xu Wei , Liang Jin-Hua , Wang Li , Fan Lei , Zhu Hua-Yuan , Li Jian-Yong 
Published: October 2019

Abstract
Objective: Determine efficacy and safety of PEMD (pegaspargase, etoposide, methotrexate, dexamethasone) in persons with newly-diagnosed advanced-stage extra-nodal NK/T-cell lymphoma.
Subjects and methods: Twenty-seven consecutive subjects with newly-diagnosed advanced-stage (stage III-IV) extra-nodal NK/T-cell lymphoma were prospectively studied from July, 2010 to August, 2015. All subjects received PEMD (methotrexate, 3.0 g/m2 IV over 6 h on day 1, etoposide, 100 mg/m2 IV on days 2-4, dexamethasone, 40 mg IV on days 1-4 and pegaspargase, 2500 U/m2 IM on day 2). Courses were given every 3 week. Primary co-endpoints were response and survival. Secondary endpoints were proportion of subjects completing planned therapy (4 to 6 cycles of PEMD regimen) and frequencies of adverse events.
Results: Median age was 46 y (range, 17-73 y). There were 21 males (78%). Nine subjects (33%) had non-nasal NK/T-cell lymphoma including 5 of the skin involvement, 1 of the testis involvement, 1 of the muscle involvement and 2 of the gastrointestinal tract involvement. Thirteen subjects (48%) had elevated serum LDH levels. Eleven subjects (41%) had higher level of EBV-DNA in blood (>5000 copies/mL). Twenty-one subjects (78%) had B-symptoms and 13 (48%) had an IPI score of 3-5. Subjects received a median of 4 courses of PEMD (range, 1-6). Median follow-up is 48 mo (range, 13-74 mo). Three patients had early death (within 3 mo after the diagnosis). Overall response rate (ORR) was 74% (95%CI 54%-89%) in the 27 subjects with advanced-stage disease including complete response (CR)/unconfirmed CR (CRu) in 12 (44% [95%CI 26%-65%]) and a partial response (PR) in 8 (30% [95%CI 14%-50%]). Four-year progression-free survival (PFS) was 44% (95%CI 25%-63%) and overall survival (OS) 51% (95%CI 32%-70%) (Figure 1). PFS and OS were not correlated between nasal and non-nasal types of ENKTL. There was no treatment-related death or serious allergic reactions. The most common grade-3/-4 hematologic complication was neutropenia (37% [95%CI 19%-58%]). The most common non-hematologic complications were infection (16% [95%CI 4%-34%]) and hypo-fibrinogenemia (12% [95%CI 2%-29%]).
Conclusion: PEMD is effective and safe in persons with newly-diagnosed advanced-stage extra-nodal NK/T-cell lymphoma.
Figure 1. PFS and OS for all the patients (N=27). Figure 1. PFS and OS for all the patients (N=27).

Disclosures
No relevant conflicts of interest to declare.
Decitabine Priming Enhances Mucin 1 Inhibition Mediated Disruption of Redox Homeostasis in Cutaneous T-Cell Lymphoma
Authors: Jain Salvia , Washington Abigail J. , Leaf Rebecca Karp , Bhargava Parul , Clark Rachael , Kupper Thomas S. , Stroopinsky Dina , Pyzer Athalia Rachel , Cole Leandra , Nahas Myrna R. , Apel Arie , Rosenblatt Jacalyn , Arnason Jon , Kufe Donald , Avigan David E. 
Published: October 2019

Abstract
Background: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous neoplasm and patients with relapsed/refractory disease exhibit resistance to standard cytotoxic therapies. We have previously demonstrated that the MUC1-C oncoprotein plays a critical role in regulating apoptosis and protection from oxidative stress in CTCL. Targeting of MUC1-C with a pharmacologic inhibitor, GO-203, was associated with late apoptosis and early necrosis and slowing of tumor growth in in vitro and in vivo models of CTCL, respectively. However, disease responses following MUC1-C inhibition were incomplete underscoring the need for combinatorial strategies that could exploit the vulnerability of CTCL cells to oxidative signals. Decitabine is a DNA methyltransferase inhibitor, previously shown to modulate oxidative stress in acute myeloid leukemia models. We hypothesized that treatment with decitabine and GO-203 would present a potent novel therapeutic combination for patients with CTCL.
Method/Results: Our studies demonstrate that exposure of CTCL cells to decitabine in combination with GO-203, increased the generation of reactive oxygen species (ROS) and decreased levels of scavenger molecules, NADPH, glutathione (GSH), and TIGAR, a p53-inducible regulator of glycolysis and apoptosis, critical to intracellular redox homeostasis. This in turn led to marked increase in the ratio of stress activated proteins; phospho-p38 and phospho-JNK to Total-p38 and Total-JNK repectively. Further dual exposure to GO-203 and decitabine resulted in near abrogation of DNA methyl transferase 1 and 3b crucial for maintaining DNA methylation, demonstrating significant synergy of these agents for inducing hypomethylation. In concert with these findings, treatment with decitabine and GO-203 upregulated the ROS generating enzyme, NADPH oxidase 4 (Nox4) potentially due to their effect on epigenomic regulation of this protein. In concert with these findings, exposure to decitabine and GO-203 resulted in heightened apoptotic death of CTCL cell lines, primary patient derived samples and in a aggressive murine xenograft model.
Conclusion: These findings indicate that decitabine augments MUC1-C inhibition induced redox imbalance and provides a novel combination of targeted and epigenetic agents for treatment of patients with CTCL. Accordingly an early phase multi-institution clinical trial to to investigate this combinatorial strategy based on epigenetic modulation of redox homeostasis in patients with relapsed/refractory T cell lymphomas is being planned.

Disclosures
Rosenblatt: Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding. Arnason:Gilead: Consultancy. Kufe:Genus Oncology LLC: Consultancy, Equity Ownership.
Benefit of Consolidative Radiotherapy in Patients with Limited Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era
Authors: Nakamura Nobuhiko , Ikoma Yoshikazu , Shibata Yuhei , Matsumoto Takuro , Ninomiya Soranobu , Kitagawa Junichi , Shimizu Masahito , Hara Takeshi , Tsurumi Hisashi 
Published: October 2019

Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma and the most common lymphoid neoplasm in adults. In the pre rituximab era, the standard therapy for patients with limited stage DLBCL had been three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) followed by involved-field radiotherapy (IFRT). The addition of rituximab has revolutionized the treatment of DLBCL. Rituximab combined with CHOP (R-CHOP) has been established as the standard treatment for patients with DLBCL. However, the role of consolidative radiotherapy (RT) in the treatment of limited stage DLBCL in the rituximab era is controversial.
Patients and Methods: We retrospectively analyzed 108 patients with limited stage DLBCL who received R-CHOP or R-THP-COP (rituximab plus, cyclophosphamide, pirarubicin, vincristine and prednisone) regimen between June 2004 and August 2015. We compared overall survival (OS) and progression-free survival (PFS) according to the treatment. OS was calculated from the date of initiation of chemotherapy to the date of the last follow-up or death. PFS was calculated from the date of initiation of chemotherapy to the date of progression disease, death, or last contact, whichever occurred first. Survival was estimated from Kaplan-Meier curves and compared using the log-rank test. P < 0.05 was considered statistically significant. Weighted Cox proportional hazards regression modeling with the inverse probability weighted (IPW) estimators method adjusting to propensity for RT was used to account for differences in baseline characteristics.
Results: Median age at diagnosis was 66 years (19-88 years), with 61 males and 47 females. Forty-three patients (40%) had stage I, and 65 patients (60%) received consolidative RT after chemotherapy. Patients who received consolidative RT were significantly younger (65 vs 72, P < 0.01) and were more likely to have stage I disease (51% vs 23%, P < 0.01). The median number of chemotherapy cycles was 4 (range 3-8) in patients who received RT, and 6 (range 3-8) in patients who did not. Median follow-up was 4.3 years (0.3-10.9 years), and the 5-year OS (92% vs 63%, P < 0.01) and PFS (87% vs 65%, P < 0.01) were significantly higher for patients who received RT than those who did not. Using IPW adjustment, RT remained predictive of OS (HR 0.30, CI 0.13-0.72, P < 0.01) and PFS (HR 0.47, CI 0.22-0.99, P < 0.05).
Conclusion: Our results suggest that consolidative RT improves OS and PFS in patients with limited stage DLBCL in the rituximab era. Although consolidative RT seems to be gradually phased out by chemotherapy alone, it is still an important treatment strategy.

Disclosures
No relevant conflicts of interest to declare.