bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDKN2 Gene Deletion Impair Prognosis in Adult Ph+ Acute Lymphoblastic Leukemia Even in Tyrosine Kinase Inhibitors Era
Authors: Xu Na , Li Yuling , Zhou Xuan , Zhu Hongqian , Li Lin , Lu Qisi , Cao Rui , Li Huan , Liu Qifa , Xiaoli Liu 
Published: October 2019

Abstract
Background: Philadelphia chromosome-positive (BCR-ABL1+) ALLs benefit from the addition of a specific tyrosine kinase inhibitors (TKIs) to chemotherapy, However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The 9p21 locus, encoding important tumor suppressors (CDKN2A/B), is a major target of inactivation in the pathogenesis of many human tumors, but only few report investigated this deletion effect on clinical prognosis in Ph+ ALL.
Purpose: Many studies found that deletion of CDKN2 was associated with poor prognosis in ALL, and CDKN2 deletion also as a frequent cytogenetic aberration in Ph+ ALL patients. Here we study about the prognostic significance of the CDKN2 in Ph+ ALL in TKIs era.
Patients and Methods: To explore the frequency and size of alterations affecting this locus in adult BCR-ABL1-positive ALL and to investigate their prognostic value, 135 patients (98 denovo and 37 relapsed cases) were analyzed by Paired diagnosis-relapse samples were interphase fluorescence in situ hybridization(I-FISH).
Results: The prevalence of CDKN2 deletions in all study population was 27.4% (37/135). There is no difference between patients with CDKN2 deletion and wild-type patients in sex, age, white blood cells(WBC) count, BM blast percentage, and induction complete remission(CR) rate. Compared with patients with wild-type CDKN2, the patients with CDKN2 deletion had higher rates of hepatosplenomegaly, CD20 expression (p<0.05). Deletions of CDKN2 were significantly associated with poor outcomes including decreased overall survival (OS) (P<0.001), lower disease free-survival (DFS) (P<0.001), and increased cumulative incidence of relapse (P=0.003). In case of 37 patients with CDKN2 deletion, 20 patients treated with chemotherapy and Dasatinib followed by allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and another 13 patients treated with chemotherapy and Imatinb followed by Allo-HSCT,there were no difference associated with OS(P=0.813) and DFS(p=0.513) between the above groups.
Conclusions: Deletion of CDKN2 by I-FISH is a frequent event in Ph-positive ALL, and frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes even though treated by adding dasatinib. We also found CDKN2 deletion patients had higher CD20 expression, this group patients may be benefit from rituximab.

Disclosures
No relevant conflicts of interest to declare.
Increased Use of Allogeneic Transplant in CR2 Improves the Outcome for Children with Acute Myeloid Leukaemia
Authors: Vedi Aditi , Mitchell Richard , Oswald Cecelia , Marshall Glenn M , Trahair Toby , Ziegler David S. 
Published: October 2019

Abstract
Improvements in Outcome for Paediatric de novo Acute Myeloid Leukaemia Aditi Vedi1,2, Richard Mitchell1, Cecelia Oswald1, Glenn Marshall1,2, Toby Trahair1, David S Ziegler1,2 1Kids Cancer Centre, Sydney ChildrenÕs Hospital, Randwick, NSW, Australia, 2 School of Women and Children's Health, University of New South Wales, Randwick, NSW, Australia ABSTRACT The treatment for paediatric acute myeloid leukaemia (AML) has not changed significantly over the past 3 decades, yet outcomes have improved with cure rates increasing from 30% to over 50% of all newly diagnosed children over this period. This improvement in survival has been attributed to both treatment intensification and improved supportive care over the decades, although the precise impact of each remains unknown. Our group has retrospectively analysed a unique cohort of patients with de novo AML diagnosed in childhood (n=276), all treated with the same chemotherapy protocol over a 25-year period from 1986-2012. The contemporary cohort (2000-12), compared to historical cohorts (1986-99) had significantly improved overall survival (OS, 75% vs. 50%, p = 0.01), lower disease related mortality (38% vs. 19%, p = 0.02) and were significantly more likely to receive allogeneic transplant after relapse (SCT, 73% vs. 12%, p <0.0001). Allogeneic transplant post relapse was associated with a significantly improved survival across the entire cohort (OS 50% for allogeneic SCT vs. 12% for autologous or none, p<0.0001). There was no significant difference between the contemporary and historical cohorts in treatment related mortality (13% vs. 7%, p = 0.42) or relapse rates after induction (50% in older cohort vs. 40% in recent era, p=0.25), suggesting consistency of induction treatment efficacy and toxicity across the two periods. This data suggests improved survival in paediatric AML in the modern era has predominantly resulted from increased use of allogeneic SCT after relapse rather than from improved supportive care and is independent of chemotherapy intensification.

Disclosures
No relevant conflicts of interest to declare.
Drug Response Profiling to Identify Selective Pharmacological Activity in Drug Resistant ALL
Authors: Frismantas Viktoras , Dobay Maria Pamela , Rinaldi Anna , Joachim Kunz , Marovca Blerim , Horvath Peter , Delorenzi Mauro , Cario Gunnar , Schrappe Martin , Stanulla Martin , Kulozik Andreas E. , Muckenthaler Martina U. , Stackelberg Arend , Eckert Cornelia , Radimerski Thomas , Bornhauser Beat , Bourquin Jean-Pierre 
Published: October 2019

Abstract
With the rapid development of new therapeutic agents, better strategies are needed to select patients with high risk or relapsed acute lymphoblastic leukemia (ALL) for experimental therapy. We developed a large-scale drug response profiling platform that is based on an established ALL co-culture system on bone marrow stromal cells, with the advantage of standardized conditions in serum-free medium. Comparing the profiles of 61 ALL samples that were enriched for relapsed and refractory ALL, we identified informative patterns of drug sensitivity and resistance comparing between clinical and cytogenetic ALL subtypes. We detected strong and selective activity for therapeutic agents that could be used in the clinic. These include a BCP-ALL with particular sensitivity to SMAC mimetics and a T-cell ALL subsets with very high sensitivity to dasatinib or topotecan. Here we focus on identification of ALLs subtypes that are critically dependent on BCL2, based on their response patterns to the BCL2-specific BH3-mimetic venetoclax (ABT-199). A subset of BCP-ALL, including MLL-AF4 and TCF3-HLF positive ALL cases were highly sensitive to venetoclax. As reported by others recently, we also detected a smaller subgroup of T-ALL that were highly sensitive to BCL2 inhibition and confirm that these are not restricted to early thymic precursor ALL. Sensitivity to venetoclax in vitro correlated with anti-leukemic activity in ALL xenografts in vivo. Moreover combination testing on our platform indicated synergistic activity of venetoclax with conventional anti-leukemic agents such as dexamethasone and vincristine, and with the new class BRD4 inhibitors. In vivo, combination of venetoclax with dexamethasone and vincristine completely prevented disease progression of very aggressive TCF3-HLF ALL cases compared to a transient delay in disease progression that we observed in the control arms with single agent venetoclax or dexamethasone + vincristine treatment. Based on our results, we propose that drug activity profiling should be evaluated prospectively in clinical phase I and II settings as a tool to develop more personalized approaches for patients with resistant disease that are at urgent medical needs.

Disclosures
No relevant conflicts of interest to declare.
TCRab Deficient CAR T-Cells Targeting CD123: An Allogeneic Approach of Adoptive Immunotherapy for the Treatment of Acute Myeloid Leukemia (AML)
Authors: Galetto Roman , Lebuhotel Céline , Gouble Agnès , Mencia-Trinchant Nuria , Nicole Cruz M , Roboz Gail J. , Guzman Monica L. , Smith Julianne 
Published: October 2019

Abstract
The remissions achieved using autologous T-cells expressing chimeric antigen receptors (CARs) in patients with advanced B cell leukemia and lymphomas have encouraged the use of CAR technology to treat different types of cancers by targeting distinct tumor-specific antigens. Since the current autologous approach utilizes CAR T-cells manufactured on a "per patient" basis, we propose an alternative approach based on the use of a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" CAR T-cell-based frozen products.
In the present work we have adapted this allogeneic platform to the production of T-cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML).
Multiple antigen recognition domains were screened in the context of different CAR architectures to identify candidates displaying activity against cells expressing variable levels of the CD123 antigen. The three lead candidates were tested in an orthotopic human AML cell line xenograft mouse model. From the three candidates that displayed comparable activity in vitro, we found two candidates capable of eradicating tumor cells in vivo with high efficiency.
Subsequently, Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology was used to inactivate the TCRα constant (TRAC) gene, eliminating the potential for engineered T-cells to mediate Graft versus Host Disease (GvHD). Editing of the TRAC gene can be achieved at high frequencies, and allows efficient amplification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. In addition, we show that TCR-deficient T-cells display equivalent in vitro and in vivo activity to non-edited T-cells expressing the same CAR.
We have performed an initial evaluation of the expression of CD123 in AML patients and found an average cell surface expression of CD123 was of 67% in leukemic blasts (95% CI 48-82), 71% in CD34+CD38+ cells (95% CI 56-86), and 64% in CD34+CD38- (95% CI 41-87). Importantly, we have found that CD123 surface expression persists in CD34+CD38-CD90- cells after therapy in at least 20% of patients in remission (n=25), thus emphasizing the relevance of the target. Currently, the sensitivity of primary AML cells to CAR T-cells is being tested.
Finally, we will also present our large scale manufacturing process of allogeneic CD123 specific T-cells from healthy donors, showing the feasibility for this off-the-shelf T-cell product that could be available for administration to a large number of AML patients.

Disclosures
Galetto: Cellectis SA: Employment. Lebuhotel:Cellectis SA: Employment. Gouble:Cellectis SA: Employment. Smith:Cellectis: Employment, Patents & Royalties.
UCH-L1 Cooperates with BCL6 and Identifies Patients with Aggressive Germinal Center Diffuse Large B-Cell Lymphoma
Authors: Bedekovics Tibor , Hussain Sajjad , Feldman Andrew L , Galardy Paul J. 
Published: October 2019

Abstract
Gene expression profiling has identified two major subclasses of diffuse large B-cell lymphoma. Cases resembling germinal center B-cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-germinal center cells (ABC-DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here we show that UCH-L1 reflects germinal center lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in germinal center B-cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biologic diversity in this subset of disease. We also find that UCH-L1 synergizes with BCL6 in a mouse model of germinal center B-cell lymphoma, but not with the development of multiple myeloma derived from post-germinal center cells. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in germinal center B-cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL.

Disclosures
Galardy: Mission Therapeutics: Research Funding.
Intermediate Dose Methotrexate Improves Overall Survival and Progression-Free Survival of Patients with Diffuse Large B Cell Lymphoma Treated with the R-CHOP or CHOP Regimen
Authors: Dann Eldad J , Heffes Vered , Mashiach Tatiana , Benyamini Noam , Avivi Irit , Horowitz Netanel A 
Published: October 2019

Abstract
Introduction: Patients (pts) with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal localization are at a higher risk for relapse with central nervous system (CNS) involvement. The current policy at the Rambam Health Care Campus (Haifa, Israel) is to give DLBCL pts 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) together with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenous MTX (ID-MTX). The present study aimed to compare the outcome of DLBCL pts with risk factors for CNS relapse who did or did not receive prophylaxis with ID-MTX.
Methods: We retrospectively evaluated a cohort of DLBCL pts treated at Rambam between the years 1991 and 2012. Overall survival (OS), progression-free survival (PFS) and CNS involvement at relapse were estimated in 203 of 355 pts [96 females, 107 males; median age 59 (range18-90) years]. The study included all pts with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (5%), breast (2%), testicular (3%), orbital (1%) involvement, bone marrow involvement (25%), stage IV disease (63%), LDH > normal (68%), ≥1 extra-nodal site (26%), IPI ≥3 (41%). Ten percent of pts had stage I-IE disease, 15% - stage II-IIE, 12% - stage III, 63% - stage IV, 38% had B symptoms. Pts with CNS involvement at diagnosis were excluded from the study.
Results: One hundred and fifty patients (74%) were treated with R-CHOP. In this group, 40% of pts with IPI=0/1, 29% with IPI=2 and 47% with IPI ≥3 received ID-MTX prophylaxis. Sixty four pts received ID-MTX (32%), 14 pts (7%) received IT MTX only, 125 pts had no prophylaxis (62%). At a median follow-up of 92 months, 5% of pts had CNS relapse with no difference in incidence between the study groups. Pts with IPI≥3 treated with ID-MTX had a reduced overall relapse rate and significantly better PFS and OS (table 1).
Conclusion: The addition of 2 cycles of ID-MTX to the R-CHOP regimen improved both PFS and OS of DLBCL pts with IPI≥3. A randomized controlled study is warranted to provide stronger evidence.
Table 1. All patients Pts No. PFS % P *HR 95% CI P OS % #HR 95% CI ID-MTX 65 60 1 88 1 IT MTX 15 56 0.09 1.92 0.9-4.1 0.008 43 3.27 1.4-7.8 No prophylaxis 123 42 0.04 1.58 1.0-2.49 0.002 51 2.49 1.4-4.4 R-CHOP Data IPI≥3 no prophylaxis 35 20 1 26 1 IPI≥3 +ID-MTX 31 58 0.004 0.38 0.29-0.85 0.001 67 0.29 0.14-0.6 No.: number; *HR: hazard ratio for progression; #HR for mortality; CI: confidential interval

Disclosures
No relevant conflicts of interest to declare.
Chemotherapy Alone Is Effective to Treat Localized and Disseminated Ocular Adnexa Lymphomas
Authors: Ma Wei-Li 
Published: October 2019

Abstract
Background:
The treatment strategies for ocular adnexa lymphomas (OALs), including conjunctiva, orbital, and lacrimal gland lymphomas, remain controversial. In this study, we assessed the efficacies and outcomes of different modality treatment, including chemotherapy, radiotherapy, and surgery for OALs.
Methods and Materials:
Between Jan. 1990 to Dec. 2013, patients receiving first-line chemotherapy (oral alkylating agents, rituximab-based treatment, or CHOP [cyclophosphamide, doxorubicin, vincristine, and steroid]-like regimens), radiotherapy (30 to 50 Gy, in 1.8- to 2.0- Gy per daily fractions), and surgery for newly diagnosed OAL were included in this study. The clinicopathologic features, including patients' characteristics, primary lymphoma locations, pathology subtypes, treatment modality, event-free survival (EFS) following first-line therapy, and OS (OS) were analyzed.
Results:
There were 56 men and 37 women with median age of 58 years were included. Of them, 79 patients (85%) were diagnosed with low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, 5 (5%) with high-grade transformed MALT lymphoma, and 9 (10%) with diffuse large B cell lymphoma. Orbit was the most common involved location (45 patients, 48%), followed by conjunctiva (35 patients, 38%), and lacrimal gland (13 patients, 14%). Of 79 patients with stage I-IIE1 disease, 22 received chemotherapy, 34 with radiotherapy, and 23 patients with other modality treatments (18 with surgery, 4 with combined radiotherapy and chemotherapy, and 1 with intra-lesional injection of rituximab). The 5-year EFS for chemotherapy, radiotherapy, and other modality treatment was 89.2%, 89.7%, and 83.1%, respectively, whereas the 5-year OS for chemotherapy, radiotherapy, and other modality treatment was 100%, 90.4%, and 87.5%, respectively. Of 14 patients with stage IIE2 to IV disease, the 5-year EFS for chemotherapy alone (n=9) and combined radiotherapy and chemotherapy (n=5) were 68.6%, 80%, respectively, whereas the 5-year OS for both group was 80.0%. Among 42 patients receiving radiotherapy, 7 (16.7%) patients developed cataract, 4 (9.5%) patients with keratitis, and 2 (4.8%) patients with maculopathy. In multivariate analysis, high-grade transformation (P=0.049) was the significant factor for shorter EFS of 1st -line treatment. Old age (> 60 years) (p = 0.014), advanced stage (stages III and IV) (p = 0.03), and high-grade transformation (p = 0.018) were the prognostic factors of poor OS.
Conclusions:
In addition to radiotherapy, our data indicate that chemotherapy as first-line therapy provides good disease control and less radiotherapy-associated side effects for patients with stage I to IIE1 OALs. Old age, advanced stage, and high-grade histology subtype remain poor prognostic factors for OALs, and new treatment strategies for these patients are warranted.

Disclosures
No relevant conflicts of interest to declare.
JQ1, a Potent c-MYC Inhibitor Overcomes Rituximab-Chemotherapy Resistance in Lymphoma Pre-Clinical Models
Authors: Gu Juan J , Zhang Qunling , Mavis Cory , Czuczman Myron S. , Hernandez-Ilizaliturri Francisco J. 
Published: October 2019

Abstract
Background: The poor clinical outcomes of patients with aggressive B-cell lymphoma in the post-rituximab era, stress the need to identify and/or optimize novel targeted agents. Several retrospective and prospective clinical studies had demonstrated that C-myc expression correlates with a poor clinical outcome in patients with newly diagnosed or relapsed/refractory diffuse large B-cell lymphoma (DLBCL). To this end, we evaluated the therapeutic effects of targeting C-myc using JQ1, a novel bromodomain inhibitor in rituximab-sensitive or -resistant models.
Methods: A panel of rituximab-sensitive (RSCL) or rituximab-resistant (RSCL) cell lines was exposed to JQ1 (0-100 µM) for 24-72 hrs. Changes in cell viability and cell cycle distribution were evaluated using the Presto Blue assay and flow cytometry respectively. IC50 values were calculated using the GraphPad Prism6 software. Subsequently lymphoma cells were exposed to JQ1 or vehicle and various chemotherapy agents such as doxorubicin (0.5, 1, 2µM), dexamethasone (1µM), Ibrutinib (1µM), bortezomib (10-20nM) or carfilzomib (10nM) for 48 hours. Coefficient of synergy was calculated using the CalcuSyn software.
Results: In vitro exposure of RRCL and to a lesser degree RSCL to JQ1 resulted in a dose- and time-dependent cell death. Strong synergistic activity was observed when JQ1 was combined with doxorubicin, dexamethasone bortezomib or carfilzomib in vitro. Cell cycle analysis demonstrated that in vitro of RSCL or RRCL to JQ1 resulted in G1 cell cycle arrest.
Conclusions: In summary, our data suggests that targeting C-myc expression using JQ1 results in anti-tumor activity against RSCL and RRCL. In addition, JQ1 exhibited synergistic activity when combined with chemotherapy agents (doxorubicin or dexamethasone) or targeted agents (bortezomib or carfilzomib). On going studies are aimed to study the mechanisms by which c-myc inhibition results in cell death in RSCL and RRCL. JQ1 is a distinct targeted agent undergoing clinical evaluation in patients with relapsed/refractory lymphomas. Molecular studies dissecting the cellular pathways affected by JQ1 are important in order to further advance the clinical development of c-myc inhibitors in lymphoid malignancies. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute and The Eugene and Connie Corasanti Lymphoma Research Fund)

Disclosures
Czuczman: Boehringer-Ingelheim: Other: Advisory Board; Immunogen: Other: Advisory board; MorphoSys: Consultancy; Celgene: Employment.