bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kruppel-Like Factor, Klf9, Promotes Proliferation of Notch-Independent Precursor T-Cell Lymphoblastic Lymphomas
Authors: Wong Peggy P. C. , Merico Daniele , Matei Irina , Ling Vicki , Bashir Shaheena , Chang Stephen G. , Cheung Queenie C. K. , Haw Robin A. , Stueker Oliver , Montpellier Bertrand , Bader Gary D. , Beyene Joseph , Danska Jayne S. , Guidos Cynthia J. 
Published: October 2019

Abstract
Abstract 3496
Notch1 signaling is required at multiple stages of normal T-lymphocyte development. Notch1 is a transmembrane receptor that is physiologically activated when Notch ligands induce conformational changes that allow Notch1 cleavage by the intramembranous γ-secretase complex, releasing active intracellular Notch1 (ICN1) fragment from the plasma membrane. Activating NOTCH1 mutations are very frequent in human and mouse T-cell lymphoblastic leukemia/lymphoma (T-LL). Typically, these mutations promote ligand-independent Notch1 cleavage by γ-secretase or increase ICN1 stability by truncating the C-terminal PEST domain. Understandably, much effort has focused on elucidating mechanisms of normal and oncogenic Notch1 signaling. However, some studies suggest that the absence of NOTCH1 mutations portends a worse prognosis for human T-LL. Therefore, we set out to define signals that promote proliferation and survival of T-LL cells lacking activated Notch1. We used Western blotting to detect γ-secretase cleaved ICN1 protein in a cohort of 35 primary T-LLs that developed spontaneously in mice lacking the Ataxia telangiectasia mutated (Atm) tumor suppressor. We identified 3 ICN1 subgroups: 63% expressed PEST-truncated ICN1 (T-ICN1); 17% expressed non-truncated ICN1 (NT-ICN1); and 20% had undetectable ICN1 (UD-ICN1), most lacked Notch1 mRNA. We confirmed the difference in Notch transcriptional activity and functional dependence between the UD-ICN1 and T-ICN1 subgroups and then compared their gene expression profiles to define pathways unique to the UD-ICN1 group. Gene set enrichment analyses revealed that UD-ICN1 T-LLs expressed higher levels of Klf9 and other transcription factors associated with a highly proliferative stage of normal T-cell development. siRNA knock-down studies demonstrated that Klf9 promoted proliferation of UD-ICN1 but not T-ICN1 T-LL cells. Collectively, these data demonstrate that Klf9 can regulate proliferation of Notch-independent T-LLs and suggest that Klf9 may provide a novel therapeutic target for human T-LLs lacking activating NOTCH1 mutations.

Disclosures:
No relevant conflicts of interest to declare.
Dietary Restriction and Weight Loss Improves the Outcome of Acute Lymphoblastic Leukemia in Diet-Induced Obesity
Authors: Alhushki Waseem , Mittelman Steven , Sheng Xia , Ehsanipour Ehsan 
Published: October 2019

Abstract
Abstract 3570

Background:
Obesity increases the mortality of numerous types of cancer. Furthermore, children over 10 years of age who are obese at diagnosis of acute lymphoblastic leukemia (ALL) have twice the risk of relapse. We have found that obese mice transplanted with leukemia are more likely to relapse after treatment with chemotherapy. We further found that adipose tissue can protect ALL cells from chemotherapy in culture. But it is unclear whether a weight loss intervention after leukemia diagnosis will improve outcome.

Hypothesis:
A weight loss intervention by dietary modification in diet induced obese mice will decrease the ability of their adipose tissue explants to protect ALL cells from chemotherapy.

Methods:
Diet-induced obese C57Bl/6 mice (n=7) were switched to a low-fat diet either 3 or 21 days prior to sacrifice at 20 weeks of age. Adipose tissue explants (100 ± 5 mg) from perirenal, visceral, and subcutaneous sites were collected and used in transwell co-cultures with 250 X103 8093 murine pre-B ALL cells. Explants from non-dieted obese mice and lean mice were used as controls. Viable ALL cells were quantified using trypan blue exclusion after a 3-day exposure to 15 nM daunorubicin or 5 nM of vincristine.

Results:
Dietary intervention significantly reduced body weights in the short (39.2 ± 2.4 grams; P= 0.014) and long (32 ± 2.9 grams; P=0.041) diet groups compared to obese mice (44.5 grams ± 2.6).
Leukemia cells were partially protected from daunorubicin by both visceral (21.5±15.7×103 viable cells, p=0.01) and perirenal (28.0±20.7×103, p=0.013) fat explants from obese mice, compared to cultures without adipose tissue (9.4±8.6×103). Fat explants from mice dieted for 3 days prior to collection showed similar protection of ALL cells from daunorubicin (not shown); however, fat explants from mice dieted for 21 days did not protect ALL cells from daunorubicin (visceral: 9.4±8.0×103, p=0.009; perirenal: 7.8±6.3×103, p=0.066 vs. obese).
Similar findings were obtained with vincristine. Leukemia cells were protected from vincristine significantly by visceral fat from obese mice (50.8±5.9×103, p=0.01) and marginally by perirenal and subcutaneous fat (93.8±139.1×103, p=0.06 and 113.4±143.7×103, p=0.07 respectively) compared to cultures without adipose tissue (12.4±11.7×103). While short dieting did not restore sensitivity to vincristine, long dieting of obese mice reduced explants leukemia protection to vincristine significantly in visceral (21.8±20.2×103, p=0.004) and marginally in perirenal (34.9±43.3×103, p=0.06) explants compared to the obese group.

Conclusions:
Dietary intervention and weight loss in diet induced obese mice decreases the ability of adipose tissue ex vivo to protect ALL cells from daunorubicin and vincristine. These results could support a potential role for dietary intervention in improving leukemia outcome in obese patients.

Disclosures:
No relevant conflicts of interest to declare.
High-Dose Cytarabine-Based Consolidation Shows Superior Results for Elderly AML Patients with Intermediate Risk Cytogenetics in First Complete Remission
Authors: Hassanein Mona Fawzy Ramadan , Atenafu Eshetu G , Gupta Vikas , Schuh Andre C. , Yee Karen , Minden Mark D. , Schimmer Aaron D , Brandwein Joseph M. 
Published: October 2019

Abstract
Abstract 3574

Introduction:
In elderly patients with acute myeloid leukemia (AML) treated intensively, the optimal post-remission strategy is unclear. High dose cytarabine (HiDAC) 3 g/m2 is the standard consolidation dose for younger adults with AML with favorable and intermediate risk disease, but is associated with high rates of severe toxicity and early death in older adults that counteract any improvement in efficacy when compared to standard dose cytarabine. We have used a modified high-dose cytarabine consolidation regimen, and compared this to a similar cohort receiving a conventional-dose regimen.

Methods:
164 patients with AML age 60 years and over, who achieved complete remission after standard induction therapy consisting of cytarabine 100 mg/m2/day continuous IV infusion × 7 days and dauorubicin 60 mg/m2 IV daily × 3 (7+3) from 1998 – 2008, received two different types of post-remission therapy in sequential cohorts. Group 1 (n=55), treated from 1998–2002, received 2 consolidation cycles, each consisting of cytarabine 1.5 g/m2 q12h × 6 doses + daunorubicin 45 mg/m2/day × 2, while group 2 (n=109), treated from 2003–2008, received a first consolidation using 7+3 followed by a second cycle consisting of mitoxantrone 10 mg/m2 IV daily × 5 plus etoposide 100 mg/m2 IV daily × 5 (NOVE).

Results:
The two groups did not differ with respect to median age (68 vs. 69 years), mean baseline WBC, gender, prior malignancy/AHD and proportion of patients undergoing allogeneic HSCT in CR-1 (9.1 vs.8.3%). 40 patients (72.7%) in the first group, and 86 patients (78.9%) in the second group received the intended consolidation regimen (p=0.38). Among the entire cohort (n=164), and in the subgroup with adverse risk cytogenetics, there was no significant difference in OS or DFS between the two groups. For patients with intermediate risk cytogenetics, on an intention-to-treat basis, the disease-free survival (DFS) was significantly higher for group 1 vs. group 2 (Table 1).

Conclusion:
Older patients with intermediate-risk cytogenetics, who received a modified high-dose cytarabine-based consolidation regimen combined with anthracycline, had a superior DFS and a trend toward superior OS, as compared to those who received conventional-dose consolidation therapy. These findings require further evaluation in a prospective randomized study but, if confirmed, suggest that older fit patients with intermediate risk cytogenetics should receive more intensified post-remission therapy with modified high-dose cytarabine.

Disclosures:
No relevant conflicts of interest to declare.
Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma
Authors: Palumbo Antonio , Larocca Alessandra , Montefusco Vittorio , Rossi Davide , Carella Angelo Michele , Mina Roberto , Crippa Claudia , Sciacca Mariella , Galli Monica , Scalabrini Delia Rota , Marcatti Magda , Guglielmelli Tommasina , Giuliani Nicola , La Verde Giacinto , Baldi Ileana , Muccio Vittorio Emanuele , Boccadoro Mario , Corradini Paolo 
Published: October 2019

Abstract
Abstract 446

Background:
The outcome of myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide or bortezomib is poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012). The newer immunomodulatory drug pomalidomide, has shown significant activity in these clinical conditions.

Aims:
We assessed dosing, efficacy and safety of pomalidomide-cyclophosphamide-prednisone (PCP) in MM patients relapsed/refractory to lenalidomide.

Methods:
Pomalidomide was administered in doses ranging from 1 to 2.5 mg/day on days 1–28, cyclophosphamide at 50 mg every other day on days 1–28 and prednisone at 50 mg every other day on days 1–28 for 6 cycles, followed by maintenance therapy with pomalidomide-prednisone. Thromboprophylaxis with aspirin 100 mg/day or low-molecular weight heparin was recommended at physician's discretion.

Results:
The maximum tolerated dose (MTD) of pomalidomide was defined as 2.5 mg/day. Fifty-two patients were enrolled at the MTD and evaluated after completing at least 1 PCP cycle. Median age was 69 years (range 41–83). The median time from diagnosis to enrolment was 55 months (range 15–203). Best responses to PCP included 6% of complete response (CR), 19% of at least very good partial response (VGPR), 54% of at least partial response (PR) and 75% of at least minimal response (MR). Time to PR was rapid (median 1.8 months). After a median follow-up of 11 months (range 1–18), 1-year progression-free survival (PFS) and OS rates were 52% and 78%, respectively. PFS was not significantly different in patients with high-risk cytogenetic compared with patients with standard-risk disease and in patients younger or older than 75 years.
Toxicities were primarily hematologic and included grade 4 neutropenia (13%) and thrombocytopenia (4%). At least grade 3 non-hematologic toxicities included infections (8%), rash (6%) and neurologic (6%). Thromboembolism occurred in 1 patient. Four patients discontinued treatment for toxicity (2 infections, 1 neurologic and 1 hepatic toxicity).

Conclusions:
PCP induced high response rates and prolonged PFS after prior exposure to lenalidomide and bortezomib (Table), without adding significant toxicity. PCP could be considered a valuable salvage option for pre-treated MM patients.

Disclosures:
Palumbo: Celgene: Consultancy, Honoraria. Larocca:Celgene: Honoraria. Sciacca:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Honoraria.
Functional Hyposplenism in Pediatric Chronic Graft-Versus-Host Disease
Authors: Rozmus Jacob , Ke Janny , Schultz Kirk R. 
Published: October 2019

Abstract
Abstract 4493

Introduction:
Functional hyposplenism is a well-recognized complication of chronic graft versus host disease (cGVHD). Whether the hyposplenism in cGVHD is transient and if there is any association between the severity of cGVHD and degree of hyposplenism are not well understood. The pitted red cell count has been shown to be a simple and reliable biomarker of splenic function that correlates well to other tests such as quantitative Howell-Jolly bodies and 99mTc sulfur-colloid liver-spleen scans. It measures the ability of the splenic red pulp to pinch off intracellular vesicles, or pits, from red blood cells as they pass through narrow adjustable slits in an endothelial lining.

Methods:
We hypothesized that functional hyposplenism correlates with the severity of cGVHD in pediatric BMT patients. We performed a single-center, retrospective review of pediatric allogeneic bone marrow transplant (BMT) patients who had more then one pit count performed post-BMT and clinical diagnosis of cGVHD based on NIH consensus criteria.

Results:
We identified 9 pediatric BMT recipients (3 males, 6 females; average age at BMT = 9.6 years) that met our criteria. Indications for BMT were AML (2), ALL (1), biphenotypic acute leukemia (1), CML (2) and thalassemia (3). All 9 had functional hyposplenism with active cGVHD as determined by a pit count > 2%. We identified two distinct groups. In 7 of the 9 BMT recipients, there was a return to normal splenic function that lagged between 12 and 18 months after clinical improvement/resolution of cGVHD symptoms and successful weaning of immunosuppressive therapy. In the other 2 patients there was no correlation between abnormal pit count and cGVHD symptoms.

Conclusions:
Our single-centre retrospective cohort study provides evidence that the functional hyposplenism associated with cGVHD is not permanent but improvement in cGVHD symptoms and successful weaning of immunosuppressive therapy should not be used as indicators of return to normal splenic function and reasons to stop Penicillin prophylaxis. We propose that all patients post-BMT should have serial pit counts performed, as resolution of cGVHD clinical symptoms does not ensure normal splenic function.

Disclosures:
No relevant conflicts of interest to declare.
Molecular Screening for Hepatitis B and Hepatitis C Viruses in Allogeneic Hematopoietic Stem Cell Transplantation– a Pilot Study
Authors: Sobczyk-Kruszelnicka Malgorzata , Markiewicz Miroslaw , Wieczorkiewicz-Kabut Agata , Wieclawek Agnieszka , Soja Anna , Dzierzak-Mietla Monika , Koclega Anna , Bialas Krzysztof , Kyrcz-Krzemien Slawomira 
Published: October 2019

Abstract
Abstract 4494

Introduction:
Viral hepatitis is, despite graft versus host disease (GVHD) and veno-occlusive disease (VOD), the third cause of hepatic complications after allogeneic hematopoietic stem cell transplantation (alloHSCT). The aim of this study was to analyze the effectiveness of molecular screening for hepatotropic viruses: hepatitis B virus (HBV) and hepatitis C virus (HCV), basing on a single centre experience.

Materials and methods:
We have evaluated 30 pts (15 women, 15 men), median age 33.5 years (18–61), who underwent alloHSCT from HLA-identical sibling (7) or unrelated donors (23) in years 2011–2012. The stem cell source was peripheral blood in all pts. Indication for allo-HSCT was: AML(11pts), ALL (10pts), OMF (4pts), SAA(2pts), PNH (2pt) and CML(1pt). Preparative regimen was myeloablative in 20pts (BuCy:10pts, Cy+TBI:10pts) and reduced in 10pts (Flu+Bu:5pts, Treo+Flu:3pts, Treo+Cy:1pt, Flu+Cy:1pt). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (in 28pts). Molecular quantitative polymerase chain reaction (QPCR) HBV-DNA and HCV-RNA tests and screening for serological markers of HBV (HBc-Ab, HBs-Ab, HBs-Ag, HBe-Ab, HBe-Ag) and HCV (HCV-Ab) infection were performed at four time-points (before the start of conditioning treatment and on days +28, +100 and +180 post-transplant).

Results:
HBc-Ab was initially positive in 2 pts, who presented negative results of other serological markers and molecular tests. In remaining 28 pts all serological and molecular markers were negative. No pt developed hepatitis infection and/or reactivated virus replication. Both pts who were initially HBc-positive did not develop any markers of HBV reactivation after one year observation, despite the intensive immunosuppression.

Summary:
Outcomes of our pilot study do not justify the routine molecular screening of hepatotropic viruses in patients undergoing alloHSCT, despite the profound immunosuppression. The routine molecular screening should be reserved only for patients with positive serological markers or/and those with symptoms of hepatitis.

Disclosures:
No relevant conflicts of interest to declare.
Clofarabine As the Element of Conditioning Regimen in Matched Related Allogeneic Transplantation – Single Center Experience
Authors: Mensah-Glanowska Patrycja , Piatkowska-Jakubas Beata , Skotnicki Aleksander 
Published: October 2019

Abstract
Abstract 4516
Since June 2010 to July 2012 since in Department of Hematology of the University Hospital in Krakow five patients with advanced hematological malignancies have been subjected to allogeneic transplantation from matched related donors with clofarabine as a part of conditioning regimen.
Indications for transplantation were relapsed/refractory acute myeloid leukemia in four patients and CML lymphoblastic crisis in relapse after RIC alloPBSCT in one patient. In a case of three patients conditioning regimen consisted of two phases. First phase: cytoreduction with clofarabine 20mg/m2/day + ARA-C 2000 mg/day for 4 days in 2 patients with refractory AML and Clofarabine 20mg/m2/day + Cyclophosphamide 400mg/day for 4 days in one (CML lymphoblastic crisis). Second phase: Busilvex + Fludarabine (Bu4Flu). Two later patients were treated without cytoreduction. One patient with extramedullary AML in second CR was treated with Clofarabine 30mg/m2 for 4 days + TBI. Last patient with early AML relapse was conditioned with Clofarabine30mg/m2 for 5 days+ Busilvex (BuClo). G-CSF mobilized peripheral blood was used as a source of stem cells in all the patients.

Results:
One patient died during conditioning regimen after cytoreduction (Clofarabine + Cyclophosphamide). It was the patient with CML lymphoblastic crisis relapse after RIC allogeneic transplantation. The other patients treatment toxicity was moderate (mucositis garde I-III). Aplastic period was complicated in one patient with septic infection. One patient relapsed 5 months after transplantation. He was diagnosed with AML secondary to MDN/MPD with very high cytogenetics (t(3;3) with 7 monosomy) Three of patient series remain in complete remission. All of them were diagnosed with relapse/refractory AML with CR duration 6 months to 26 months.

Conclusions:
Use of clofarabine as a part of conditioning regimen is valuable therapeutic option especially in the group of patients with relapsed/refractory AML.

Disclosures:
No relevant conflicts of interest to declare.
Fractionated Stem Cell Infusions for Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant
Authors: Wood Kevin , Giralt Sergio A , Koehne Guenther , Chung David , Lendvai Nikoletta , Hassoun Hani , Lesokhin Alex , Hoover Elizabeth , Devlin Sean , Landau Heather 
Published: October 2019

Abstract
Abstract 4550

Background:
High dose therapy with autologous stem cell transplant (SCT) is an established therapeutic modality for multiple myeloma (MM). Although effective, it is associated with significant symptom burden due to the obligate period of neutropenia in addition to an increased risk of infectious complications. In animal models, infusing stem cells over a period of days enhances immune reconstitution (Felfly H, et al. Br J Haematol. 2009; 148: 646–658). We hypothesized that multiple stem cell infusions could reduce the period of neutropenia and enhance immune recovery resulting in a better tolerated procedure.

Methods:
We are conducting a phase II trial of multiple fractionated autologous stem cell infusions after high-dose Melphalan. We compared initial engraftment kinetics of the first 14 patients to receive multiple infusions (Days 0, +2, +4, +6) after high-dose Melphalan (study group) to 23 patients receiving high-dose Melphalan followed by the standard single stem cell infusion (Day 0) (standard group). Pegfilgrastim was given to all patients on Day +1. All patients underwent SCT between October 2011 and July 2012.

Results:
Results are shown in Table 1. Similar numbers of stem cells were collected in the study and standard groups. The total number of stem cells infused was 9.7 × 10∧6 CD34+ cells/kg in the study patients compared to 5.0 × 10∧6 CD34+ cells/kg in the standard patients. To date, the median duration of neutropenia (days of ANC < 500) and lymphopenia (days of ALC < 500) as well as the days to neutrophil, lymphocyte and platelet engraftment are similar. There are no significant differences in the number of red cell or platelet transfusions, days of fever, diarrhea, empiric antibiotics or documented infections. Despite receiving multiple infusions, none of the patients in the study group experienced an infusion reaction. Engraftment syndrome occurred in 3/14 (21%) of the study patients. The median duration of hospitalization was 15 days in the study cohort versus 17 days in the concurrent control group (P = 0.01).

Conclusion:
Multiple stem cell infusions following high dose Melphalan in patients with MM were not associated with a higher incidence of adverse side effects from DMSO nor unexpected frequency of engraftment syndrome. Fractionating stem cells over a period of days may result in less antibiotic use, reduced frequency of infection and was associated with shorter hospitalizations. We continue to collect patient reported symptom scores in order to determine if we can improve patient experience during SCT.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Study of Allogenetic Hematopoietic Stem Cell Transplantation for Three Cases of Leukodystrophy
Authors: Feng Xiaoqin , Li Chunfu , Li Na , Wu Xuedong 
Published: October 2019

Abstract
Abstract 4559

Objective:
Allogenetic hematopoietic stem cell transplantation (Allo-HSCT) can be used to cure some genetic leukodystrophy patients in current. This clinical study is to investigate efficacy and practicability of Allo-HSCT in treatment of genetic leukodystrophy in China.

Methods:
Three boy diagnosed genetic leukodystrophy (2 cases of metachromatic leukodystrophy, 1 case of X□|linked adrenoleukodystrophy) had undergone allogeneic Stem cell Transplantation. A 32 month old boy accepted HLA 8/10 high-resolution matched unrelated umbilical cord blood as graft, which contained nucleated cells 13.5×107/kg. A 2 year-old boy accepted HLA high-resolution 10/10 matched unrelated peripheral blood stem cells (PBSC) as graft which contained mononuclear cells 8 ×108/kg. The conditioning regimen consisted of cyclophosphamide (60–100 mg/kg), fludarabine (150–200mg/kg), TT (5mg/kg) and busulfan (12–13.2 mg/kg). A 12 year-old boy accepted sibling HLA low resolution 6/6 (A, B, DRB1) matched bone marrow as graft which contained mononuclear cells 1.23 ×108/kg. The conditioning regimen consisted of busulfan (16mg/kg) and cyclophosphamide (200mg/kg). Cyclosporine A and mycophenolate mofetil were used to prevent graft versus host disease (GVHD). ATG-Fresenius (15 mg/kg) and low dose of methotrexate were added for prophylaxis of GVHD in unrelated PBSC transplantation. XY chromosome by the FISH method or quantitative PCR for short tandem repeat (STR) were used to identify the chimerism. ASA level in peripheral blood leukocytes and C26:0 plasma level were monitored after transplantation respectively.

Results:

Conclusion:
Allogenetic hematopoetic stem cell transplantation is effective and feasible in the treatment of some childhood genetic leukodystrophy patients. These patients should accept allo-HSCT in the early stage of disease in order to get good survival.

Disclosures:
No relevant conflicts of interest to declare.