bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imatinib Has a Negative Impact On Growth In Children With Previously Untreated Chronic Myeloid Leukaemia (CML) In Early Chronic Phase (CP): Results Of The French National Study
Authors: Millot Frédéric , Guilhot Joelle , Baruchel Andre , Petit Arnaud , Leblanc Thierry , Bertrand Yves , Mazingue Françoise , Lutz Patrick , Vérité Cécile , Berthou Christian , Galambrun Claire , Sirvent Nicolas , Yacouben Karima , Chastagner Pascal , Gandemer Virginie , Reguerre Yves , Couillaud Gérard , Cayuela Jean-Michel 
Published: October 2019

Abstract

Aims
The French pediatric CML working group conducted a retrospective study analysing the growth of patients under 18 years with CML treated with imatinib front-line.

Patients and Methods
Data from 78 patients receiving imatinib (260 mg/m2) for newly diagnosed CML in chronic phase between July 2001 and August 2012 were collected. Height was expressed as standard deviation score (SDS). Height SDS was calculated using French growth standard, as patient height minus mean height for age and sex, divided by standard deviation of height for age and sex. Pre-pubertal age was defined as being younger than 9 years for girls or 11 years for boys.

Results
A gradual decrease in the median of the height SDS score is observed over time since the start of imatinib. Sixty three patients were assessable for paired analysis at onset of imatinib and 12 months later. The median height-SDS in this group of patients was significantly lower (p < 10-4) 12 months after the start of imatinib. Variance analysis was performed in 36 children at onset of imatinib, 12 months and 24 months later. The median height-Z score in this group of patients was significantly lower 12 months and 24 months after the start of imatinib (p < 10-4) compared to initial diagnosis. The 63 patients assessable for paired data analysis at onset of imatinib and 12 months later were classified by sex and pubertal status. The median height Z score in boys and girls was significantly (p < 10-4) lower 12 months after the start of imatinib. When the patients were analysed according to the pubertal status at onset of imatinib, the median height SDS score was significantly (p < 10-4) lower 12 months after the start of imatinib in the prepurbertal group as well as in the postpubertal group. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prebubertal or postpubertal age. No significant difference was observed when the median M12 height SDS score in patients who started imatinib at a prepubertal stage or a pospubertal stage were compared. Moreover, no significant difference was observed when the median M12 height-Z score in boys and girls were compared.

Conclusion
This retrospective analysis revealed a statistically significant deceleration in growth during the first 2 years of imatinib treatment in children and adolescents with CML and an absence of influence of sex and pubertal status on the depth of growth deceleration.

Disclosures:
No relevant conflicts of interest to declare.
Rituximab and High-Dose Dexamethasone (R-dex) Is Effective In The Treatment Of Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Simkovic Martin , Belada David , Motyckova Monika , Smolej Lukas , Zak Pavel 
Published: October 2019

Abstract

Introduction
High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) but serious infections are frequent. Recently published data suggest that high-dose dexamethasone might be equally effective to HDMP despite lower cumulative dose.

Aims
To assess efficacy and safety of high-dose dexamethasone combined with rituximab (R-dex) in relapsed/refractory CLL.

Patients and Methods
A total of 60 pts (pts) with relapsed/refractory CLL treated at a single tertiary center between September 2008 and October 2012 were included in this retrospective analysis. Basic characteristics are summarized in Table 1. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13. Treatment was repeated every 3 weeks for a maximum of 8 cycles. All pts received antimicrobial prophylaxis with sulfamethoxazole/trimethoprim and aciclovir.

Results
Median number of administered R-dex cycles was 6 (range, 1-8). The overall response (ORR)/complete remissions (CR) were achieved in 75/3%. At the median follow-up of 9 months, median progression-free survival was 8 months and median overall survival 24 months. Significant predictors of short PFS in univariate analysis were bulky lymphadenopathy (p=0.023) and refractoriness to fludarabine (p=0.02). Interestingly, activity of R-dex in bulky fludarabine-refractory CLL was similar to ofatumumab (ORR 62 %, median PFS, 4 months, median OS, 12 months) (Wierda et al., 2010). R-dex was successfully used as a debulking regimen before allogeneic stem cell transplantation in 8 patients. Serious (CTCAE grade III/IV) infections occurred in 29% of patients; 19% pts developed steroid diabetes requiring temporary short-acting insulin.

Conclusions
Our data show that R-Dex is an active and feasible treatment for patients with relapsed/refractory CLL; however, major infections remain relatively frequent despite combined antimicrobial prophylaxis. In addition, durable responses are infrequent. Therefore, further optimization of this therapeutic approach is warranted. Updated results will be presented.

Disclosures:
No relevant conflicts of interest to declare.
TIM-3, a Leukemia Stem Cell Marker, Plays a Role In Leukemic Transformation Through Autocrine Stimulatory Signaling By Its Ligand, Galectin-9
Authors: Kikushige Yoshikane , Yuda Junichiro , Shima Takahiro , Miyamoto Toshihiro , Akashi Koichi 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We have reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML but not on normal hematopoietic stem cells (HSCs) (Kikushige et al, Cell Stem Cell, 2010). We extended the analysis of TIM-3 expression into various types of human hematological malignancies, and found that human TIM-3 is expressed in the vast majority of CD34+CD38- LSCs of human myeloid malignancies including chronic myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes (MDS). Although CD34+CD38- normal bone marrow stem cells do not express TIM-3, TIM-3 is expressed in the CD34+CD38- population in MDS, and is further up-regulated with progression into leukemia. The average percentages of TIM-3+ cells in the CD34+CD38- population was 7.8% in RCMD (n=10), 19.2% in RAEB-1 (n=10), 84.0% in RAEB-2 (n=10) and 92.2% in overt AML (n=10). The close association of TIM-3 expression with transformation into AML led us to hypothesize that TIM-3 itself has a function in AML stem cell development. TIM-3 is a type 1 cell-surface glycoprotein and has a structure that includes an N-terminal immunoglobulin variable domain followed by a mucin domain, a transmembrane domain and a cytoplasmic tail. Tyrosine residues are clustered in the cytoplasmic tail, suggesting that TIM-3 can induce signal transduction in TIM-3+ AML cells. To understand the function of TIM-3, we investigated the interaction between TIM-3 and its ligand galectin-9 in AML LSCs. We found that AML patients showed significantly higher serum galectin-9 concentration than healthy individuals (healthy controls: 18.3+4.3 pg/ml, AML patients: 139.1+33.4 pg/ml, P<0.05). Unexpectedly, we found that leukemic cells expressed a high level of galectin-9 protein, as compared to other hematopoietic cells including T cells, B cells and monocytes. Using KASUMI-3 (TIM-3+ AML cell line) and primary AML samples, we confirmed that AML cells could secrete galectin-9 after TLR stimulation in vitro. Furthermore, microarray analysis demonstrated that TIM-3 stimulation by the physiological concentration of galectin-9 induced significant gene expression changes toward pro-survival axis including up-regulation of MCL-1, the important survival factor for HSCs and LSCs. These results collectively suggest that AML cells can produce and secrete galectin-9, and galectin-9 can bind and stimulate TIM-3-expressing AML cells including LSCs in an autocrine manner to support their survival or leukemia progression.

Disclosures:
Miyamoto: Kyushu University Hospital: Employment.
Stem Cell and T-Cell Gene Therapy Using SIN-Lentiviral Vector In Type 3 Familial Hemophagocytic Lymphohistiocytosis
Authors: Rivière Julie , Soheili Tayebeh , Verhoeyen Els , Galy Anne , de Saint Basile Geneviève , Fischer Alain , Andre-Schmutz Isabelle , Cavazzana Marina 
Published: October 2019

Abstract
Familial hemophagocytic lymphohistiocytosis (FHL) is the genetic form of hemophagocytic lymphohistiocytosis with an autosomal recessive form of inheritance and early onset. FHL is characterized by prolonged fever, hepatosplenomegaly and pancytopenia. Type 3 of FHL (FHL3) which accounts for 30-35 % of all FHL patients, results from mutations in UNC13D gene encoding Munc13-4 protein. Munc13-4 controls fusion of lytic granules with the plasma membrane in cytotoxic lymphocytes and its defect leads to impaired cytotoxic activity in T and NK lymphocytes. The only curative method for FHL3 is allogenic hematopoietic stem cell (HSC) transplantation. For those patients without compatible bone marrow donor, gene therapy could represent a therapeutic option.
Our study is based on a comparative analysis to investigate the efficacy and safety of stem cell and T-cell gene therapy for FHL3. To this end we have generated SIN-lentiviral constructs expressing Munc13-4 and used them to produce either VSVG or T-cell specific pseudotyped lentiviral vectors. We also could obtain functionally mature T-cells in vitro, derived from umbilical cord blood HSCs which respond to TCR stimulation and show cytotoxic effect. Using these approaches, first we demonstrated that our SIN-lentiviral constructs are able to transduce efficiently human T-cells and HSCs. We used then these vectors to complement the FHL3 patient’s cells. Transduction of FHL3 CD8 effector cells restored their cytotoxic function that was comparable to that of control cells. In addition we noted that the overexpression of Munc 13-4 in normal human HSCs didn’t alter in vitro differentiation of these cells towards T-cells. The effect of this overexpression on B-cells and myeloid differentiation is currently under investigation.
These preliminary results will be followed by ex vivo gene transfer experiments in Munc13-4 deficient “Jinx” mice to further investigate the functional restoration as well as toxic effects. This strategy, if approved, could offer a safe therapeutic method not only for FHL3 patients but also for other genetic or acquired dysfunctions of T-lymphocytes.

Disclosures:
No relevant conflicts of interest to declare.
Preclinical Development Of a Nanomedicne Approach For Multiple Myeloma Targeting The Myc Oncoprotein
Authors: Soodgupta Deepti , Pan Dipanjan , Hu Grace , Senpan Angana , Yang Xiaoxia , Weilbaecher Katherine N , Prochownik Edward V. , Lanza Gregory M , Tomasson Michael H 
Published: October 2019

Abstract

Purpose
This study investigated alpha 4 beta 1/ Very Late Antigen-4 (α4β1/ VLA-4)-integrin targeted nanotherapy approach to deliver a new lipase-labile prodrug.

Experimental Design
A phospholipid-based MYC-MAX inhibitor prodrug (MI1-PD) was synthesized, and its inherent anti-proliferate potency was compared to the lipid-free compound (MI1) using mouse multiple myeloma (MM) cell line (5TGM1). VLA-4-targeted perfluorocarbon (PFC) nanoparticles binding to 5TGM1 cells was measured and compared to biomarker expression assessed with flow cytometry using antibodies. The efficacy of MI1-PD incorporated into non-targeted and VLA-4-targeted PFC NP exposed to 5TGM1 cells was assessed with MTT assays, Annexin V and cell cycle analysis.

Results
MI1-PD was more potent by several orders of magnitude than its free drug counterpart in culture. Targeted NP binding correlated well with biomarker expression assessment by flow cytometry in 5TGM1 cells. Non-targeted NPs had no appreciable binding to 5TGM1 cells. High anti-MM potency of MI1-PD was noted in VLA-4-targeted NPs compared to the non-targeted NPs demonstrating that the efficacy was dependent on expression of the targeted biomarker to afford particle-to-cell drug delivery.

Conclusions
These results suggest the feasibility of an improved integrin VLA-4- targeted nanotherapy approach to deliver a lipase- labile prodrug construct, MI1-PD.

Disclosures:
No relevant conflicts of interest to declare.
Tmem14c Plays An Essential Role In Mitochondrial Heme Metabolism
Authors: Paw Barry H. , Yien Yvette Y. , Robledo Raymond F , Schultz Iman J. , Takahashi-Makise Naoko , Philllips John , Miyata Non , Gwynn Babette , Dailey Tamara A. , Pierce Eric , Hildick-Smith Gordon J. , Cooney Jeffrey D. , Chen Wen , Shah Dhvanit I. , Hattangadi Shilpa M , Kingsley Paul D , Palis James , Cantor Alan B. , Koehler Carla M. , Lodish Harvey F. , Kaplan Jerry , Dailey Harry A. , McVey Ward Diane , Peters Luanne L. 
Published: October 2019

Abstract

Red cells synthesize large amounts of heme during terminal differentiation. Central to this process is the transport and trafficking of heme synthesis intermediates within the cell. Despite the importance of transport during heme synthesis, the molecules involved in this process are largely unknown. In a screen for genes that are upregulated during erythroid terminal differentiation, we identified Tmem14c, a predicted multi-pass transmembrane protein as an essential component of the porphyrin metabolism pathway.
Here, we report that Tmem14c facilitates the synthesis of mitochondrial protoporphyrin IX from coproporphyrinogen III and is thus required for heme synthesis. Tmem14c is a mitochondrial inner-membrane protein enriched in vertebrate hematopoietic tissues and is required for terminal erythropoiesis. Tmem14c gene-trap mouse embryos are severely anemic and mostly die by E13.5 (Fig. A). Fetal liver erythroid cells derived from gene-trap embryos experience maturation arrest. shRNA silencing of Tmem14c in Friend murine erythroleukemia (MEL) cells results in a significant decrease in de-novo heme synthesis. The biochemical defect is due to a decrease in mitochondrial protoporphyrin IX synthesis, while cytoplasmic porphyrin levels remain normal (Fig. B). The heme synthesis defect in Tmem14c-silenced MEL cells is complemented with a protoporphyrin IX analog. These data show the role of Tmem14c in regulating the terminal steps in mitochondrial porphyrin trafficking.
Our findings collectively demonstrate that Tmem14c is required for the transport of mitochondrial porphyrins in developing erythroid cells. Due to its inner-mitochondrial localization and its relative proximity to heme synthetic enzymes coproporphyrinogen oxidase and protoporphyrinogen oxidase (Rhee et al., 2013 Science), Tmem14c can function as a molecular adaptor that facilitates the interaction of proteins involved in porphyrin transport, or as a protoporphyrinogen IX transporter (Fig. C). The identification of Tmem14c as an essential regulator of porphyrin transport and heme synthesis provides a novel genetic tool for exploring erythropoiesis and disorders of heme synthesis such as porphyria and anemia.

Disclosures:
No relevant conflicts of interest to declare.
Whole Body PET-CT In Management Of Lymphoblastic Lymphomas In Adults: Does It Have a Prognostic Impact?
Authors: Sengar Manju , Jain Hasmukh , Menon Hari , Epari Sridhar , Agrawal Archi , Rangarajan Venkatesh , Shet Tanuja , Gujral Sumeet , Laskar Siddhartha 
Published: October 2019

Abstract

Introduction
The two relevant questions that emerge and remains unanswered in the management of adult lymphoblastic lymphomas (LBL) are- how to select patients for mediastinal radiation and whom to subject for autologous transplant. Mediastinal radiation or intensification of therapy may reduce the mediastinal recurrence- a common site for relapse. It is also understood that not all patients with residual mediastinal mass relapse. The inability of computed tomography to differentiate between necrotic and viable disease in a residual mediastinal mass post induction therapy led us to explore PET-CT as modality to differentiate the same. In a retrospective analysis we evaluated the role of post-induction chemotherapy PET-CT in predicting the risk of relapse or progression in adult LBL patients.

Methods
In a single centre retrospective analysis we included newly diagnosed LBL patients (>15 years) who were treated with ALL- like therapy between January 2010 and February 2013. All patients who underwent PET-CT after induction chemotherapy were analysed. SUVmax was used to assess the response. Details of demographic variables, diagnosis, subtype, baseline LDH, bone marrow involvement, cerebrospinal fluid analysis, chemotherapy, radiotherapy, responses, relapse/progression, death and its cause and last follow up date were taken from electronic medical records.

Results
Twenty-two patients (17 males and 5 females) with median age 24.5 years (range, 16-44 years) were analysed. All patients had T- LBL. Thirteen patients (13/22) had stage IV disease (Ann Arbor stage) and all had bulky mediastinal mass at diagnosis. None of the patient had CSF or bone marrow involvement. Raised LDH and low albumin were present in 80% and 60% of patients respectively. Median WBC was 10,200/cumm (range, 4400-15300/cumm). All but 4 patients received BFM-90 ALL protocol based therapy. After induction 19 patients achieved complete remission on PET-CT. Patients who had residual mediastinal masses on PET-CT relapsed during later phase of therapy (all within 6 months) in mediastinum and died subsequently. Mediastinal radiation was given to one of these patients but it did not prevent a subsequent relapse. One patient who achieved complete response had bone marrow relapse after 16 months of therapy. Three patients had treatment related death (sepsis). At median follow up of 14 months 1-year overall survival was 69% and progression free survival was 78%.

Conclusion
Post induction therapy PET-CT seems to have prognostic role and may predict relapse for patients with residual disease activity. Such patients should be considered for treatment intensification. However, the role and timing of mediastinal radiation in such patients remains investigational.

Disclosures:
No relevant conflicts of interest to declare.
Absence Of BRAF and KRAS Hotspot Mutations In Primary Mediastinal and Other Diffuse Large B-Cell Lymphoma
Authors: Nagel Philipp D , Feld Fenja M , Weissinger Stephanie E , Stenzinger Albrecht , Moeller Peter , Lennerz Jochen K 
Published: October 2019

Abstract
Recently whole-exome-sequencing has identified oncogenic BRAF and KRAS mutations as likely drivers in diffuse-large B-cell lymphoma (DLBCL). It is currently unclear whether primary mediastinal B-cell lymphoma (PMBL), a clinicopathologically distinct variant of diffuse-large B-cell lymphoma, harbors such mutations. Here, we screened 100 samples (84 primary tumors and 16 cell lines), composed of 52 PMBL and 48 DLBCL samples for BRAF (V600/601) and KRAS (G12-K16) hotspot mutations using a sensitive pyrosequencing approach. All 100 samples were BRAF and KRAS wild-type. When combining our results with those reported in the literature (Table 1), the overall mutation frequency in DLBCL for BRAF is ∼2.4% (n=13/541) and for KRAS is ∼1.6% (n=7/445). We demonstrate the absence of BRAF and KRAS hotspot mutations in PMBL. The overall prevalence of KRAS and BRAF mutations argues against hotspot genotyping as part of the diagnostic workup in PMBL/DLBCL.Table 1Summary of DLBCL genotyping resultsBRAFKRASMut./tested%Mut./tested%Lohr et al., 20112/554,12/554,1Pasqualucci et al., 20110/4800/480COSMIC*11/3383.25/2422,0Subtotal13/4413.07/3452.0Nagel et al., (here)0/10000/1000Summary13/5412,47/4451,6%*At time of review, COSMIC did not include the results from Lohr et al. and Pasqualucci et al.

Disclosures:
No relevant conflicts of interest to declare.
Role Of Aggressive Chemotherapeutic Regimens In Double Hit Lymphoma- Can Alternate Aggressive Induction Regimens Overcome The Poor Prognosis Of Diffuse Large B Cell Lymphoma?
Authors: Tsai Judy , Greer John P , Morgan David S. , Li Shaoying , Reddy Nishitha M. 
Published: October 2019

Abstract

Background
Double-hit (DH) diffuse large B cell lymphomas (DLBCL), characterized by concurrent translocations involving MYC and BCL2, or BCL6, portend to have an aggressive clinical course. Recent studies have highlighted the fact that DH lymphomas are resistant to standard R-CHOP or experience a short disease free interval. There is however limited data evaluating patient outcomes with alternative therapy that include aggressive regimens often used to treat high grade lymphoma.

Methods
Five hundred sixty patients (pts) diagnosed with DLBCL at a single institution between January 2004 and December 2012 were included in our analysis after obtaining IRB approval. Descriptive statistics, Wilcoxon signed rank sum test and Kaplan-Meier analysis were performed using SPSS.19 software.

Results
Of the 560 pts, 34 were confirmed as DH based on FISH analysis. The median age at diagnosis was 63 yrs (range 36-87). Twenty pts (59%) were male. Thirty-one pts (91%) were Caucasian. Fourteen pts (53%) had an Eastern Cooperative Oncology Group performance status of 2-3. Thirty pts (89%) had advanced stage disease (stages III and IV). Thirteen pts (38%) had bone marrow involvement, and twenty-six pts (76%) had more than one extranodal site. The majority of pts (70%) had high intermediate or high risk based on the International Prognostic Index (IPI). Of the 34 pts, 15 (46%) received R-CHOP, 6 (18%) received R-Hyper CVAD/Ara-C/MTX, 8 (24%) received DA-R-EPOCH and 2 (6%) received other aggressive forms of chemotherapy. Two pts died before any therapy was initiated. Ten pts (29%) received central nervous system prophylaxis. Five pts (15%) underwent stem cell transplant, 2 of which in CR1. Twenty-eight pts (82%) were alive at the time of analysis. At a median follow up of one year, the median overall survival (OS) of all pts was 12.2 months. The median OS was 16.8 months for pts who received R-CHOP and 12.2 months for pts receiving other aggressive chemotherapy (P=0.07) (figure 1). The progression free survival for pts who received R-CHOP was 32.6 months as compared with 7.6 months in pts treated with R-hyper CVAD/Ara-C/MTX or DA-R-EPOCH. This was not statistically significant (P=0.44) (figure 2). In addition, there was no significant difference in disease free interval between the two groups of patients.

Conclusion
Our data suggests that prognosis of patients with DH-DLBCL remains poor independently of the chemotherapy administered, whether conventional R-CHOP or more aggressive regimens such as R-HyperCVAD or DA-R-EPOCH. Durable long term remission with R-CHOP is still possible in a minority of patients. There is a need to modify and incorporate novel agents in the initial treatment strategy for DH-DLBCL.

Disclosures:
No relevant conflicts of interest to declare.