bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful Mobilization with the Combination of Plerixafor and G-CSF in Korean Pediatric Patients Who Failed in Previous Chemomobilization with G-CSF Alone
Authors: Kang Hyoung Jin , Hong Kyung Taek , Kim Nam Hee , Kim Min Sun , Lee Ji Won , Kim Hyery , Park Kyung Duk , Shin Hee Young , Ahn Hyo Seop 
Published: October 2019

Abstract
Abstract 4397

Introduction:
The classical peripheral blood stem cell mobilization (PBSCM) relies on granulocyte colony-stimulating factor (G-CSF) either as a single agent or in conjunction with chemotherapeutic agents (chemomobilization). This method however, sometimes fails in patients who have previously been heavily treated with chemotherapy or radiotherapy. PBSCM with plerixafor (AMD3100), a newly developed specific inhibitor of the CXCR4 receptor, in combination with G-CSF has been shown to enhance stem cell mobilization in adult patients, but pediatric data is scarce. We document our experiences with this drug in five pediatric patients.

Patients & Methods:
Five patients (three males, two females) with a median age of 9.6 years (range 6–11 years) who have failed in chemomobilization with G-CSF alone, received plerixafor. The diagnosis of patients was medulloblastoma in 2, osteosarcoma in 2, and neuroblastoma in 1. All the patients had previously been heavily treated with chemotherapy (median 15.4 months) and two of them with medulloblastoma underwent craniospinal irradiation. Patients received G-CSF (10mcg/kg) for 4 days at 10 AM before the first plerixafor (240ug/kg) administration, which was given subcutaneously 10 hours before apheresis. Apheresis was performed thereafter on the fifth day of G-CSF administration. Patients received G-CSF at 8AM and apheresis was started at 10AM. Each apheresis was performed with plerixafor and G-CSF in the same manner.

Results:
All the patients mobilized targeted numbers of CD34+ cells (median 12.86×10^6/kg, range 6.34–28.97×10^6/kg) successfully with two to three cycles of apheresis, without complications (Per each apheresis: median 3.8×10^6/kg, range 1.55–14.49×10^6/kg). A total of four autologous transplantations were performed in 3 patients including one tandem transplantation in a neuroblastoma patient. Neutrophil and platelet were successfully engrafted in four transplantations within a median of 9.7 days (range 9–10 days) and 68.3 days (range 15–197 days), respectively.

Conclusion:
Our study suggests that mobilization with plerixafor is safe and effective in Korean pediatric patients who have previously been heavily treated and have failed PBSC mobilization with classical chemomobilization with G-CSF. This is the first results of PBSCM with plerixafor in Asian pediatric patients.

Disclosures:
No relevant conflicts of interest to declare.
Single-Agent Bruton's Tyrosine Kinase (Btk) Inhibitor and Single-Agent Carfilzomib Induce Cell Apoptosis, Arrest Cell Growth and Downregulate NF-Kb Activity In Mantle Cell Lymphoma
Authors: Ou Zhishuo , Pham Lan V , Zhang Liang , Tamayo Archito T. , Lee John , Zhang Kejie , Wang Jacqueline , Phan James , Li Changping , Sun Luhong , Ford Richard J. , Wang Michael 
Published: October 2019

Abstract
Abstract 4971
Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma with poor prognoses. Discovery of less-toxic and better therapeutic agents is an ongoing challenge. Bruton tyrosine kinase (BTK), is identified as an essential kinase for B-cell survival, activated through the B-cell receptor (BCR) pathway. Recent studies have indicated that BTK mediates NF-kB activation. The potential therapeutic agent PCI-32765, a novel BTK inhibitor (Pharmacyclics, Sunnyvale, CA) have shown effective preliminary targeting of these pathways in MCL. Carfilzomib, a 2nd generation proteasome inhibitor (Onyx Pharm. Inc., Emeryville, CA) proven effective in myeloma in clinical trial is also effective in MCL in vitro and in vivo in pre-clinical studies. The objective of our study was to evaluate the therapeutic efficacy of PCI-32765 and carfilzomib in MCL, and elucidate the mechanisms of their actions. We initially screened 12 MCL cell lines and discovered that Btk is constitutively phosphorylated in all MCL cells. Representative MCL cell lines, both classic and blastoid variant, were utilized for in vitro studies. PCI-32765 effectively inhibited phospho-BTK, leading to reduced MCL cell growth with IC:50 values range from 10–50 uM. PCI-32765 also induced MCL cell apoptosis in both dose- and time-dependent manner as well as carfilzomib. Using luciferase pGL3 reporter plasmid (6xNF-kB-CD40L/TKm), we demonstrated that both PCI-32765 and carfilzomib down-regulated the reporter with a dosage dependent manner. Our data suggest that strategic targeting of growth/survival pathways with novel therapeutic agents PCI-32765 and carfilzomib should provide a novel therapy regimen for patients with relapsed/refractory MCL.

Disclosures:
Wang: Onyx Pharmaceuticals: Research Funding.
Adeno-Associated Viral Vector Mediated Gene Transfer for Hemophilia B
Authors: Nathwani Amit C , Tuddenham Edward GD , Rangarajan Savita , Rosales Cecilia , McIntosh Jenny H , Linch David C , Chowdary Pratima , Griffioen Anja , Riddell Anne , Pie Jun , Harrington Chris , O’Beirne James , Smith Keith , Pasi John , Glader Bertil , Rustagi Pradip , Ng Catherine , Kay Mark , Zhou Junfang , Spence Yunyu , Morton Christopher , Allay James , Coleman John , Sleep Susan , Cunningham John M , Basner-Tschakarjan Etiena , Mingozzi Federico , High Katherine A. , Gray John T. , Reiss Ulrike M. , Nienhuis Arthur W. , Davidoff Andrew 
Published: October 2019

Abstract
Abstract 5

Background:
Hemophilia B (HB), an X-linked bleeding disorder, is ideally suited for gene therapy. We investigated a novel approach using peripheral vein infusion of a single dose of a serotype-8 pseudotyped self-complementary adeno-associated virus (AAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco).

Methods:
Six severe HB subjects (FIX ≤1%) were enrolled sequentially into one of three dose cohorts with two subjects in each group. Vector was administered without immunosuppression. The subjects were followed for 6–16 months post treatment.

Results:
AAV-mediated expression of FIX at 2–11% of normal was observed in all subjects. Four of the six have discontinued prophylaxis and remain free of spontaneous hemorrhage. The other two have increased the interval between FIX prophylaxes. A high-dose subject developed asymptomatic, transient elevation of serum transaminases associated with detection of AAV8 capsid specific T cells in peripheral blood. The second high-dose subject experienced a slight increase of liver enzymes, of less clear etiology. Treatment of each with a short course of steroids led to rapid normalization of the transaminases and maintenance of FIX levels in the 3–11% range.

Conclusion:
Peripheral vein administration of scAAV2/8-LP1-hFIXco was well tolerated and resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype. Immune-mediated clearance of AAV-transduced hepatocytes remains a concern but our data suggest that this process may be controlled with a short course of steroids without loss of transgene expression. Hence, our novel approach shows promise for gene therapy of HB and other protein deficiencies. (ClinicalTrials.gov number, NCT00979238)

Disclosures:
Nathwani: Amsterdam Molecular Therapeutics: Patents & Royalties. Gray:Amsterdam Molecular Therapeutics: Patents & Royalties. Davidoff:Amsterdam Molecular Therapeutics: Patents & Royalties.
Rescue of Doxorubicin-Induced Chemoresistance by API 31510 in Chloroleukemia
Authors: Narain Niven R , Wu Shuohan , McCook John P , Sarangajan Rangaprasad R , Alshaji Jasem M , Castillo Maite , Mauro Lucia M , Jimenez Joaquin J 
Published: October 2019

Abstract
Abstract 5016
Cancer resistance to single or multiple chemotherapy regimens continues to be a major problem in achieving complete remission. Fundamental knowledge of the mechanistic aspects underlying chemoresistance has yet to yield a practice changing answer to the problem. Thus, models of chemoresistance are necessary to shed light into molecular pathways and translational aspects of chemotherapy induced resistance. A classical example of chemotherapy to which resistance is developed is with use of doxorubicin. Several molecular and cellular aspects of doxorubicin resistance have been elucidated; however overcoming resistance remains elusive, thereby rendering animal models of doxorubicin to test novel drugs vital in solving this problem. In the present study we have used a well-established model of rat chloroleukemia (Science. 1987; 238:1278-80) to study resistance to doxorubicin. As an extension of this study, we derived a novel clone of the parent chloroleukemic cell resistant to doxorubicin. We proceeded to test this clone on the development of chloroleukemia in rats and to compare the cure rates of the parent (doxorubicin sensitive) cell line versus the doxorubicin resistant clone. Animals injected with the parent clone were treated with 1 mg/kg doxorubicin for 3 days. This regimen resulted in a cure rate of 35 percent. In sharp contrast, 100% of the animals injected with the doxorubicin resistant clone did not respond to doxorubicin therapy. Conversely, treatment of animals injected with the parent and doxorubicin-resistant clones exhibited a 50% cure rate when treated with ubidecarenone (API31510) (p<0.01). In vitro investigations revealed that API 31510 induced apoptosis in both chloroleukemic cell lines. The molecular pathways regulating API 31510- induced reversal of doxorubicin resistance were characterized, and shown to be independent from doxorubicin effect on the induction of resistance. The data herein strongly demonstrate that resistance to doxorubicin can be overcome by co-administration with API 31510.

Disclosures:
Narain: Berg Biosystems, LLC: Director, stock ownership, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Berg Therapeutics, LLC: Director, stock ownership, Equity Ownership. McCook:Berg Therapeutics, LLC: Director, stock ownership. Sarangajan:Berg Therapeutics, LLC: Director, stock ownership; Berg Biosystems, LLC: Director, stock ownership.
A Phase I Study of the Combination of Decitabine with Lenalidomide for Patients with High Risk (IPSS Int-2 or High) Myelodysplastic Syndrome
Authors: de Castro Carlos Manuel , Adams Donna , Rao Arati V , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , Beaven Anne W , Warzecho Julie , Rizzieri David A. 
Published: October 2019

Abstract
Abstract 5029

Background:
Decitabine and lenalidomide have demonstrated single agent activity in patients with myelodysplastic syndromes (MDS). The addition of lenalidomide to decitabine in patients with high risk MDS may improve responses through distinct mechanisms. A phase I study of azacytidine and lenalidomide has previously demonstrated the feasibility of the combination of a hypomethylating agent with lenalidomide and did suggest higher response rates. (Sekeres M, et al. JCO 2010)

Methods:
We conducted a 3×3 cohort design. Patients with high risk MDS who had received prior hypomethylating agent were eligible for the study. Patients were treated with decitabine 20mg/m2 IV over 1 hour daily on days 1–5. Lenalidomide was escalated in each cohort using a dose of 5 mg po daily for 21 days in cohort 1 and 10 mg po daily for 21 days in cohort 2. Additional cohorts using 15 mg and 25 mg of lenalidomide are planned but have not yet been entered. Cycles were repeated every 28 days if count recovery was adequate. Toxicity was assessed by NCI CTCAE v3.0 criteria. Responses (a secondary objective) were assessed using IWSG criteria.

Results:
Seven patients have been entered into this study and are evaluable for toxicity and response. Median age is 74 years (69–77). Because of 1 death in cohort 1 (felt to be due to respiratory failure in a patient with severe COPD and not related to study drugs), the cohort was expanded to 6 patients. No other deaths occurred on study. One patient has been entered on cohort 2. No grade 3 or 4 toxicities were seen in the other 6 patients. Myelosuppression is common but does not appear to be worse than decitabine alone. In the 6 patients in which response could be assessed, there were 2 complete responses (CRs) and 3 partial responses (PRs). One patient progressed to AML after one cycle. Responses were seen in the 3 patients that had received prior treatment with hypomethylating agents (1 CR, 2 PR). Duration of responses ranged from 4 months to 16 months.

Conclusion:
The combination of decitabine and lenalidomide has been well tolerated in patients with high-risk MDS. The maximum tolerate dose has not been reached, although myelosupression is common. Good responses have been seen even in patients with prior treatment with a hypomethylating agent.

Disclosures:
Off Label Use: Decitabine in combination with lenalidomide for high risk myelodysplastic syndrome. Rizzieri:Celgene: Speakers Bureau.
Registry of Patiens with Myelodysplastic Syndrome (MyDyS) in Slovakia
Authors: Mistrik Martin , Richterova Katarina , Tothova Elena , Markuljak Imrich , Valekova L'ubica , Palasthy Stanislav , Brabec Petr 
Published: October 2019

Abstract
Abstract 5051
While clinical studies and guidelines provide important data regarding the safety and efficacy of new drugs, their application to daily practice can be limited by the inclusion of selected patient populations. Population-based studies can provide additional insight into the complex process of implementing treatment guidelines in daily practice. The objective of the MyDyS registry was to collect and analyze data regarding the diagnosis and management of patients with myelodysplastic syndrome (MDS) in Slovakia.

Material and methods:
five clinical centers collected data regarding demographics, staging, history and cytopathology from newly diagnosed patients (pts) with MDS from 2009 to 2011. Patients were classified according to the French American British (FAB) and World Health Organization (WHO) systems and the International Prognostic Scoring System (IPSS). The database allowed online pts registration.

Results:
one hundred thirty pts were registered to MyDyS in the yrs 2009–2011 and data from 128 pts were analyzed. Male/ female: 53,1%/ 46.9%; average age 64,8 yrs (range 22–89 yrs). The most frequent diagnosis according to FAB classification was RA (53.9%) and RAEB (21.9%), and according to WHO classification RCMD (27,3%) and RAEB II (22,7%). IPSS Low risk was in 16,4% pts, INT-1 in 43%, INT-2 in 19,5% and High risk in 11,7%. The majority of pts were de novo (89,8%). Patients with secondary MDS (10,2%) had a history of malignancy (breast cancer, 23,1%; hematologic malignancy, 2,6% only) and history of combination chemo and radiation therapy in 61,5%. In these pts, bone marrow (BM) was hypercellular in 49,2%, hypocellular in 24,2% of patients. Number of blasts less than 5% in 60,2% patients. Erythroid dysplasia was observed in 88,3%, myeloid dysplasia in 56,3% and dysplasia of megakaryocytes in 71,9% of patients. BM biopsy was performed at diagnosis in 87,5% and reported as hypercellular in 56,6%, with fibrosis in 62,8% and abnormal localization of precursors (ALIP) in 8%. Peripheral cytopenia in 2–3 lineages was observed in 67,2% pts. Growth factor therapy was given to 63 pts and red blood cell transfusions (average 20,7; range 2–80 RBC units) were given to 35 patients. Deferasirox (mostly 1500mg/ d) was given to 25 patients, and serum ferritin level decreased after 8 months in 27,3% pts, after 12 months in 57,4% pts. Chelation therapy was associated with gastrointestinal intolerance in 1 case, and skin reaction in 2 patients.

Conclusion:
The presented data document the first steps in the complex process of improvement of management of MDS in daily clinical practice in Slovakia. Expansion of the registry is necessary for determination of best practices for discussion with health care authorities and health insurance institutions.

Disclosures:
No relevant conflicts of interest to declare.
Decitabine Treatment in Higher Risk MDS, CMML and AML Post-MDS Who Failed Azacitidine
Authors: Sanna Alessandro , Gozzini Antonella , Sassolini Francesca , Bosi Alberto , Santini Valeria 
Published: October 2019

Abstract
Abstract 5052

Background:
5-azacytidine (Vidaza, AZA) and 5-aza-2'-deoxycytidine (Decitabine, DAC) are active in therapy of myelodysplastic syndromes (MDS) probably with different mechanisms of action. Azacitidine is approved by FDA and EMEA and is routinely used in therapy of higher risk MDS in Europe and in the US. Decitabine is a demethylating agent approved for treatment of IPSS INT-2 and high risk MDS by FDA but not yet from EMEA and it seems particularly active in Chronic myelomonocytic leukemia (CMML) and AML of the elderly. Difference in mechanisms of action of these 2 agents have been determined in vitro, involving nuclear acid incorporation, cell cycle and apoptosis, gene and protein expression.

Patients:
Nine patients (4 RAEB 2, 4 AML, 1 CMML-1) were treated with decitabine 20mg/m2 × 5 days every 28 days as single agent or in association with Gemtuzumab ozogamicin 3 mg/m2 in day 5 and 9. IPSS score at diagnosis was: 1 low, 4 intermediate 1, 4 intermediate 2. All patients received at least 4 cycles of azacitidine 75 mg/mq per seven days every 28, 44% of them reached at least Hematological improvement and received DAC as second line after relapse. Median age was 70 (62–84) and 8/9 were male.

Methods:
Medical records of 14 patients who received decitabine treatment were reviewed and survival was calculated by the Kaplan Meier method and differences in survival calculated by the log-rank test using SPSS software. Complete remission was defined by normo-cellular bone marrow with <5% blasts and normal Hgb, WBC, and platelet counts, and PR required 50% decrease in blast count, increases in Hgb by >1.5 mmol/L, WBC count by >1000, and platelet count by >50,000. Results: Median overall survival (OS) was 121 days, range 27–586 days. Overall response rate (CR+PR+HI) was 33.3% with mean duration of response was 3.33 months. Mean number of cycles was 4 (range 1–20). Median OS of responder patients was 12 months vs 1 month of non responder patients. OS of patients treated with DAC after AZA-resistance was 2 months vs 4 months of patients relapsed, but who reached at least HI with AZA (p>0.05). Longer history of MDS disease seemed not relevant for outcome. Therapy was well tolerated and only two patients required a long hospitalization (42 and 77 days) for sepsis due to relevant myelosuppression.

Conclusions:
Decitabine treatment has some activity in MDS, CMML and AML patients refractory to AZA or who relapsed after initial response to AZA, suggesting that the two supposed hypomethylating agents act via partially different molecular mechanisms.

Disclosures:
No relevant conflicts of interest to declare.
Incidence of Bone Marrow (BM) Fibrosis in Multiple Myeloma (MM) Patients and Its Relationship to Cytogenetic (CG) Abnormalities in a Minority Population
Authors: Sidhu Gurinder , Latif Rabia , Liu Jinli , Axiotis Constantine , Khillan Ratesh , Braverman Albert S. 
Published: October 2019

Abstract
Abstract 5077

Background:
The incidence of BM fibrosis in MM is low and uncertain, and its causes are not known. Cytogenetic and fluorescence in situ hybridization (FISH) in some MM patients reveals prognostically significant anomalies.

Methods:
Records of patients with MM seen at Kings County Hospital from 2004 through 2010 were reviewed, the histological sections of patients reported to have fibrosis we re-examined. The degree of fibrosis was graded according to the World Health Organization system.

Results:
Records of 113 patients were reviewed, 110 (97%) were African American (AA). Of these, 62 (55%) were female and 51 (45%) male. Their age ranged (median 65) from 38 to 89 years. Cytogenetic data (CGD) was available in 46 patients; and abnormal in 10 (22%) and normal in 36 (78%) of those. All patients with abnormalities of chromosomal number were hyperdiploid.
Of 113 patients, 62 (55%) were female, 110 were African American. Ages ranged from 38–89 (median 65) years. Cytogenetic data was available for 46 patients and abnormal in 10 (22%). All patients with abnormal chromosome numbers were hyperdiploid. FISH studies to detect abnormalities in chromosomes 13, 14 and 17 were available in 25 and abnormal in 2 (8%).
BM fibrosis had been initially noted in 27 of 113 patients (24%), and confirmed by another hematopathologist; 17 (63%) were women. The ages of the patients with fibrosis ranged from 4–79 years: median age was 67, 67 for the women and 62 for the men. Focal and grades 1, 2 and 3 fibrosis were noted in 2 (7%), 12 (44%), 7 (26%) and 6 (22%) of patients. Grade 3 fibrosis was found in 24% of the women and 20% of the men with fibrosis.
CG data was available for 17 fibrosis patients and abnormal (hyperdipliod) in 2 (18%). FISH studies for chromosomes 13, 14 and 17 were normal in the 7 patients studied. CGD for all 8 of the female fibrosis patients studied were normal, and abnormal in 2 of the 9 men (22%).

Conclusions:
Of our 113 AA myeloma patients 25% had detectable BM fibrosis, but it was grade 3 in only 5%. Female preponderance was more marked in the patients with fibrosis than in the whole MM group. CG and FISH data did not distinguish patients with and without fibrosis.

Disclosures:
No relevant conflicts of interest to declare.