bluuebunny/crossref_metadata_2025_split huggingface dataset:
AML1/RUNX1 Mutations in 470 Adult Patients with De Novo Acute Myeloid Leukemia: Prognostic Implication and Interaction with Other Gene Alterations.
Authors: Hou Hsin An , Tang Jih-Luh , Lin Liang-In , Chen Chien-Yuan , Chou Wen-Chien , Tseng Mei-Hsuan , Huang Chi-Fei , Lee Fen-Yu , Liu Ming-Chih , Yao Ming , Huang Shang-Yi , Ko Bo-Sheng , Hsu Szu-Chun , Wu Shang-Ju , Tsai Woei , Chen Yao-Chang , Tien Hwei-Fang 
Published: October 2019

Abstract
Abstract 1564
Poster Board I-587
Somatic mutation of AML1/RUNX1 (RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 individuals (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male gender, older age, lower LDH value, FAB M0/M1 subtypes and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19 and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD (P=0.0061), but negatively associated with CEBPA (P=0.0057) and NPM1 mutations (P=0.0001). AML patients with RUNX1 mutations had a significantly lower complete remission rate, shorter disease-free and overall survival than those without the mutation (P=0.0087, P<0.0001 and P=0.012, respectively). Subgroup analysis of patients with normal karyotype showed that RUNX1-mutation was also closely associated with worse OS and DFS (P= 0.001 and P=0.001, respectively). Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival (hazard ratio 1.874, 95% CI, 1.101- 3.189, P=0.021). Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidences that RUNX1 mutations are associated with distinct biological and clinical characteristics and poor prognosis in patients with de novo AML.

Disclosures
No relevant conflicts of interest to declare.
Hypoxia-Inducible Factor-1 in Multiple Myeloma Progression.
Authors: Ria Roberto , Reale Antonia , Berardi Simona , Piccoli Claudia , Pietro Giulia Di , Basile Antonio , Capitanio Nazareno , Vacca Angelo 
Published: October 2019

Abstract
Abstract 1812
Poster Board I-838
Multiple Myeloma (MM) is a malignancy of immunoglobulin (Ig)-synthesizing plasma cells, that home to and expand in the bone marrow. Similarly to other tumours its development is correlated to the formation of regions of hypoxia, which may be a prognostic indicator and determinant of malignant progression. It is known how in solid tumours the degree of intra-tumoral hypoxia is positively correlated with the expression of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 is composed of HIF-1á and HIF-1β subunits and its production has been identified as a key element in allowing cells to adapt and survive in a hostile hypoxic environment via a variety of pathways. In hypoxia conditions, the HIF-1á subunit becomes stable and regulates the expression of target genes. When activated HIF-1á also targets those genes which are required for angiogenesis, the development of new blood vessels from an existing vascular network. Angiogenesis represents a constant hallmark of MM progression. In response to hypoxia plasma cells and stromal cells (endothelial cells [ECs], macrophages, mast cells) within the tumour express Vascular Endothelial Growth Factor (VEGF), a mitogen and survival factor specific for endothelial cells. VEGF is the major regulator of tumor-associated angiogenesis. HIF-1á directly activates transcription of the VEGF gene and this leads to autocrine signal transduction that is critical for angiogenesis.
In this study we demonstrate the role of HIF-1á in MM angiogenesis. The constitutive stabilization of HIF-1á contributes to increase angiogenesis in MM. Our data show that HIF-1á is stabilized in the nucleus of MM endothelial cells (MMECs) but not in ECs of Monoclonal Gammopathies of Undetermined Significance (MGECs) and in Human Umbilical Vein ECs (HUVECs) used as controls. Western Blot and Enzyme-Linked Immunosorbent Assay (ELISA) analyses show the overexpression of HIF-1á and the proteic products of its target genes VEGF and VEGF Receptor (VEGFR)-1, in patients with relapsed disease and in MM progression but not in patients with nonactive MM (avascular phase). Moreover, immunofluorescent staining confirm the nuclear stabilization of HIF-1á in MMECs.
At mRNA level all ECs express same quantity of HIF-1á mRNA, as confirmed by RT-PCR and Real-time RT-PCR, indicating that in MMECs the post-trascriptional control is affected. Finally, we show that the inhibition of HIF-1á by siRNA suppresses vessel formation in vitro and promote ECs apoptosis. Our findings indicate that HIF-1á plays an important role in MM progression and that it is correlated to the angiogenic switch from nonactive MM to active MM. Furthermore these data suggest that HIF-1á may represent a target for the MM antiangiogenic treatment.

Disclosures
No relevant conflicts of interest to declare.
Deletion of the 17p Chromosomal Region Is Associated with a Very Poor Outcome in Multiple Myeloma Independently of the Type of Treatment.
Authors: Avet-Loiseau Hervé , Leleu Xavier , Roussel Murielle , Mathiot Claire , Caillot Denis , Hulin Cyrille , Marit Gerald , Facon Thierry , Attal Michel , Harousseau Jean-Luc , Minvielle Stéphane , Campion Loic , Moreau Philippe 
Published: October 2019

Abstract
Abstract 1817
Poster Board I-843
Deletion of the short arm of chromosome 17 [del(17p)] is known to confer a poor prognosis in multiple myeloma (MM). However, no large study has been specifically dedicated to this purpose, especially in the novel drug era. We analyzed a series of 1324 patients with MM at diagnosis, treated within or according to IFM trials, and analyzed for del(17p). Most of the patients were under 65 years of age (1122 of the 1324 patients), and were treates either with a VAD-based induction or a Velcade®/Dexamethasone-based induction, followed by one or two courses of high-dose melphalan. Del(17p) was correlated to the major other prognostic parameters, both for event free survival and overall survival. Del(13) was observed in 71% of the patients with del(17p). A significant association was observed with anemia < 10g/dl (p=.05), with thrombocytopenia < 130 G/l (p<.0001), with hypercalcemia (p=.001), and b2-microglobulin>3.5 mg/l (p=.006). No specific association was observed with t(4;14) (17% of the del(17p)-positive patients displayed t(4;14)). Del(17p) was observed in 10% of the patients. Del(17p) was associated with a very poor outcome, both in young and elderly patients. Actually, the prognostic value was observed only in patients displaying del(17p) in at least 70% of their plasma cells. The median EFS and OS were 18 and 28 months respectively, versus 30 and 69 months for patients lacking the del(17p). A particularly poor outcome was observed in patients presenting both del17p and t(4;14), with a median EFS of 4.5 months and a median OS of 12 months. Of particular importance, none of the treatment modality (high-dose melphalan, thalidomide, bortezomib) overcame the poor prognosis associated with del(17p), although patients lacking del(17p) displayed a better outcome when treated with Vel/Dex or MP-Thalidomide. In conclusion, del(17p) is associated with an especially poor outcome, independently of the type of treatment, including novel drugs.

Disclosures
No relevant conflicts of interest to declare.
Mtor and PI3K Inhibitors Block Myeloma Cell Growth in a Synergistic Manner.
Authors: Guenther Andreas , Burger Renate , Klapper Wolfram , Tiemann Markus , Bakker Frank , Brocke-Heidrich Katja , Horn Friedemann , Gramatzki Martin 
Published: October 2019

Abstract
Abstract 1843
Poster Board I-869
Introduction: The mammalian target of rapamycin (mToR) plays a crucial role in cell growth due to its role as nutrient dependent regulator of important cytokine signaling pathways. In multiple myeloma, mToR is involved in the phosphoinositide-3-kinase (PI3K)-AKT pathway which can be activated by the loss of the tumor suppressor phosphatase and tensin homolog (PTEN) or by stimulation with growth and survival factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1). Inhibitors of the mToR pathway (sirolimus/rapamycin, everolimus and temsirolimus) are approved for immunosuppression and/or cancer treatment. However, the clinical activity of mToR inhibitors may be limited by the fact that, after inhibition of the rapamycin-sensitive mToR-Raptor complex, AKT is activated by the rapamycin-insensitive mToR-Rictor complex. In this regard, the inhibitory effect of mToR inhibitors was evaluated in combination with PI3K inhibitors in vitro and in vivo. Results: Rapamycin and everolimus induced a dose-dependent growth inhibition in six human malignant plasma cell lines. Growth inhibition was mediated by G1 cell cycle arrest and in a subset of cell lines by induction of apoptosis. Overexpression of Bcl-XL or Mcl-1 proteins did not prevent from apoptosis induction by mToR inhibitors, nor did sensitivity to rapamycin-induced apoptosis correlate with the p53 mutation status. In the INA-6 SCID mouse xenograft model, treatment with rapamycin resulted in a significant survival benefit compared to untreated mice. Six out of 14 rapamycin treated mice did not develop plasmacytomas during the observation period of 149 days. Remarkably, short term treatment of plasmacytoma bearing mice led to a significant shrinkage of the plasma cell tumor. Explanted tissue showed apoptotic plasma cells, a finding confirmed by immunohistological staining using an antibody specific for the human cleaved form of poly (ADP-ribose) polymerase (PARP). The combination of rapamycin and the PI3K inhibitor Ly294002 led to an increase of growth inhibition in all tested plasma cell lines. The additional growth inhibition by Ly294002 appeared to be due to AKT activation upon mToR inhibition by the rapamycin-insensitive Rictor complex, indicated by increased AKT phosphorylation at Ser473 as determined by Western blot analysis. Conclusion: Clinical trials currently evaluate mToR inhibitors for their potential to expand treatment options for myeloma patients. The data presented here suggest that a combination of mToR inhibitors with PI3K inhibitors may lead to additive therapeutic chances.

Disclosures:
Guenther: Novartis: Consultancy, Research Funding. Gramatzki:Novartis: Consultancy, Research Funding, Speakers Bureau.
Low Dose Subcutaneous Alemtuzumab and Prophylactic Donor Lymphocyte Infusion Results in Favorable Outcomes for High Risk Recipients of Unrelated Donor Allogeneic Transplants.
Authors: Solomon Scott R. , Bashey Asad , Morris Lawrence E. , Manion Karen L , Holland H. Kent 
Published: October 2019

Abstract
Abstract 2272
Poster Board II-249
Non-relapse mortality (NRM) remains a major obstacle to success of unrelated donor (UD) allogeneic transplantation, mostly due to the increased morbidity from graft-versus-host disease (GVHD). Unfortunately, efforts to reduce GVHD mortality with ex vivo or in vivo T cell depletion techniques have often been associated with increased risk of relapse and infectious complications. We hypothesized that pre-transplant low-dose Alemtuzumab would reduce early NRM following UD transplantation, coupled with the early use of donor lymphocyte infusion (DLI) to correct incomplete donor chimerism (DC) to improve disease control. We targeted a high risk patient population (age>40 years or prior transplant) to test this hypothesis. Twenty-seven patients (median age 56 years) received PBSC (n=25) or BM (n=2) allografts from matched (n=25) or one-antigen mismatched (n=2) unrelated donors for high-risk hematologic malignancies (CIBMTR disease risk high [n=14], intermediate [n=6], low [n=7]). Conditioning included Fludarabine and Busulfan (myeloid) or Cyclophosphamide ± Rituximab (lymphoid). Subcutaneous Alemtuzumab was administered at a dose of 43mg over 3 days, day -11, -10, and -9. Twenty-six patients (96%) achieved sustained engraftment. With a median follow-up of 1.6 years, the estimated 2-year overall survival is 73.5%. NRM at 100 days and 2 years is 0% and 4.2%, respectively. Twenty-two patients received early prophylactic DLI for incomplete DC, while 7 received ≥2 DLI. Risk of Grade II-IV and III-IV acute GVHD is estimated to be 48% and 11%, respectively, with chronic GVHD occurring in 78%. Relapse/progression was documented in 41.9% of patients with current disease-free survival (DFS) estimated to be 65.2%. Compared to contemporaneously treated UD transplant recipients not receiving pre-transplant Alemtuzumab, study patients demonstrated delayed achievement of complete DC (median 148 vs. 61 days, p=0.002), delayed acute GVHD onset (median 113 vs. 30 days, p=001), and increased requirement for DLI (81% vs. 10%, p<0.001). Overall rates of acute and chronic GVHD were similar. Despite being a decade older in age (median 56 vs. 44 years), study patients had comparable outcomes with a non-significant trend to lower 2-year NRM (4.2 vs. 21.5%) and higher current DFS (65.2 vs. 46.8%) (see figure). Low dose subcutaneous Alemtuzumab with prophylactic DLI results in favorable transplant outcomes and modest rates of NRM in an older patient population with high-risk hematologic malignancies receiving UD transplantation.

Disclosures:
Off Label Use: Alemtuzumab is being used off-label as part of the preparative regimen for unrelated donor allogeneic transplantation..
Visualizing the Molecular and Cellular Basis of Heparin Induced Thrombocytopenia.
Authors: Rauova Lubica , Hirsch Jessica , Greene Teshell , Nagaswami Chandrasekaran , Cines Douglas B. , Weisel John W. , Poncz Mortimer 
Published: October 2019

Abstract
Abstract 228
Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication of heparin therapy caused by antibodies that recognize the platelet chemokine, Platelet Factor 4 (PF4), complexed to heparin or to cellular glycosaminoglycans (GAG). The origin of the sentinel feature of HIT - high propensity for thrombosis in the setting of mild thrombocytopenia - remains undefined. We have shown previously that monocytes are particularly susceptible to activation by HIT antibody because unlike platelets, whose surface glycosaminoglycans (GAGs) consist almost entirely of chondroitin sulfates (CS), monocytes express heparan and dermatan sulfates that bind to PF4 with greater affinity. Therefore, antigenic complexes form at lower concentrations of PF4 on monocytes than on platelets and are more resistant to removal by exogenous heparin. We now provide 2 lines of visual evidence in support of this model of the prothrombotic state in HIT: 1) We demonstrate by scanning electron microscopy that spheroidal particles indicative of PF4/GAG complexes are present on the surface of human monocytes upon addition of PF4. 2) Thrombus formation has been visualized in a previously described murine HIT model involving the infusion of the HIT-like monoclonal antibody KKO into mice double-transgenic for human PF4 (hPF4+) and FcγRIIA receptor (FcγRIIA+) on their platelets. After KKO infusion, hPF4+/FcγRIIA+ mice developed vigorous and concurrent accumulation of HIT antigenic complexes and fibrin at sites of laser-induced endothelial injury, not present in similarly treated single transgenic mice. Accumulation of PF4 and fibrin at sites of injury was not increased by a polyclonal anti-hPF4 antibody that does not induce thrombocytopenia in hPF4+/FcγRIIA+ mice. Monocytes and/or monocyte microparticles accumulated at sites of laser-induced injury in KKO-infused hPF4+/FcγRIIA+ mice, but not in KKO-infused single transgenic mice or hPF4+/FcγRIIA+ mice infused with an isotype control, beginning 2.5 min after formation of HIT antigenic complexes and fibrin deposition, accumulating preferentially at the upstream end of developing thrombi. These results provide new insights into the potential role of monocytes in the prothrombotic sequelae of HIT. Antigenic complexes form on monocytes exposed to PF4 and accumulate in HIT antibody-induced thrombi. Monocytes appear to reinforce thrombus formation initiated by injured endothelial cells and activated platelets.

Disclosures:
Poncz: Diagnostica Stago: Patents & Royalties.
Non T-Depleted Bone Marrow Transplantation From Haploidentical Related Donor in Hematological Malignancies.
Authors: Santarone Stella , De Angelis Gottardo , Di Bartolomeo Erminia , Bavaro Pasqua , Montanari Mauro , Leoni Pietro , Cerretti Raffaella , Di Bartolomeo Paolo , Arcese William 
Published: October 2019

Abstract
Abstract 2291
Poster Board II-268
Haploidentical bone marrow transplantation (BMT) is an alternative treatment to patients with high-risk hematologic malignancy lacking a HLA-matched donor and those urgently need transplantation. We used a haploidentical-BMT protocol without ex vivo T cell depleted based on the knowledge that marrow grafts have 10 times fewer lymphocytes compared to peripheral blood stem cell grafts and granulocyte colony-stimulating factor (G-CSF) donor priming reduce the incidence of acute GvHD.

Materials and Methods:
40 patients (median age of 32, 12-63) with advanced disease or leukemia with poor prognostic features underwent unmanipulated haplo-BMT: 22 with AML, 9 with ALL, 3 with CML, 3 with Hodgkin lymphoma and 3 with plasmacell leukemia. Status at disease: 22 early (first or second comple! te remission), 18 advanced (progressive or refractory disease). All pairs of donors and recipients were identical for one HLA haplotype and incompatible at 2 or 3 loci.The myeloablative conditioning regimens used were different; antithymocyte globuline, cyclosporine, metotrexate, mycophenolate mofetil and basiliximab were used for GvHD prophylaxis. Donors were primed with filgrastim at 4 micrograms/Kg/d for 7 consecutive days. Bone marrow cells were harvest on the 8 day and were infused unmanipulated.

Results:
the median dose of total nucleated, CD34+ and CD3+cells was 7×10e8/Kg (1.01-28.7), 2.3×10e6/Kg (1.17-6.0) and 23.3×10e6/Kg (9.7-66.6) respectively. 1 patients had a primary graft failure and 5 patients died early prior to engraftment. In the remaining 34 patients, engraftment was seen with median time to granulocyte and platelet recovery of 22 and 27 days respectively; acute GvHD was grade 0 in 17 patients (50%), grade I in 9 (26%), grade II in 7 (20%) and grade IV in 1 (3%). In 29 evaluable patients, chronic GvHD was limited in 3 (10%) and extensive in 1 (3%). Transplant-related mortality at 6 months for early and advantage stage was 22% and 35% respectively. After a median follow up of 18 (3-42) months, 8 patients relapsed; 11 patients (50%) in the early stage and 4 (22%) in advanced phase are now living in haematological remission. The 1-year Kaplan-Meyer probability of disease-free survival is 45% for all patients.

Conclusion:
the high engraftment rate, low incidence of grade II-IV acute GvHD and an acceptable TRM suggest that G-CSF-primed marrow grafting along with sequential immunosuppression could provide an excellent alternative for patients who lack matched donors.

Disclosures:
No relevant conflicts of interest to declare.
A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma.
Authors: Sharma Manish , Thall Peter , Wang Xuemei , Hosing Chitra , Mendoza Floralyn L , Han Eric , Wang Michael , Weber Donna , Shah Jatin , Alousi Amin , Anderlini Paolo , Kebriaei Partow , Khouri Issa F , Popat Uday , de Lima Marcos , Champlin Richard E , Giralt Sergio , Qazilbash Muzaffar 
Published: October 2019

Abstract
Abstract 2309
Poster Board II-286

Background
There is a role for novel preparative regimens in multiple myeloma to improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto HCT). Bortezomib is an active agent in newly diagnosed or relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized phase II trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan.

Methods
auto HCT, with preparative regimen melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3(arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Primary endpoints were complete response (CR), NCI grade 4 toxicity, and overall survival (OS).

Results
In arms 1, 2 and 3, median intervals between diagnosis and auto HCT were 12.2, 9.6 and 8.8 months; median follow up in all surviving patients was 20 months (range 10 to 31). CR+near CR rates in arms 1, 2 and 3 were 35%, 30% and 25%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84%, 70% and 95% of patients in arms 1, 2 and 3. Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Median OS has not been reached in any of the 3 arms. Median progression-free survival (PFS) times were18.6, 13.2 and 17.5 months. OS was significantly shorter in patients with relapsed disease (0.00001) and cytogenetic abnormalities at auto HCT (0.0002).

Conclusions
Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant impact of adding bortezomib at either dose on the CR rate, grade 3-4 toxicity or OS.

Disclosures:
Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Cephalon: Speakers Bureau.