bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).
Authors: García-Gutiérrez J. Valentin , Herrera Pilar , Jimenez-Rolando Marta , Tenorio María , Calbacho María , Blanchard M. Jesús , Rey Maria Dolores , Ramos Paloma , Ramos ML , Lopez Javier 
Published: October 2019

Abstract
Abstract 3435

Background:
Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients.

Aims:
To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR).

Study Group and Methods:
We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients.

Results:
22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1).

Conclusions:
In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR.

Disclosures:
No relevant conflicts of interest to declare.
Stem Cell Transplant without Growth Factor In Multiple Myeloma: Engraftment Kinetics, Bacteremia, and Hospitalization.
Authors: Gertz Morie Abraham , Gastineau Dennis , Lacy Martha , Dispenzieri Angela , Hayman Suzanne R. , Kumar Shaji , Dingli David , Leung Nelson , Wolf Robert , Hogan William J , Buadi Francis 
Published: October 2019

Abstract
Abstract 3469

Introduction:
Stem cell transplantation is important in the management of multiple myeloma. In the United States, the standard of care is administration of growth factors to accelerate neutrophil recovery after stem cell transplant. The need for growth factors after transplant has not been investigated recently.

Patients:
We analyzed a cohort of 166 patients at our institution who underwent autologous transplant for multiple myeloma without receiving growth factors after transplant and compared them with 498 patients who received standard filgrastim beginning on posttransplant day 5. TABLE

Results:
A neutrophil count of 500/μL was achieved in a median of 12.5 days in patients receiving growth factor, compared with 13.5 days in those not receiving growth factor (P<.001) Fig 1. Platelet engraftment was identical (median, 14.5 days; P=.12) in both groups, despite a lower median number of CD34+ cells infused in patients who did not receive growth factors. Incidence of nonstaphylococcal bacteremia was identical in both groups. The median hospital stay was 3.5 days shorter in the group not receiving growth factor. Bacteremia impacted platelet but not neutrophil engraftment. Figure 2

Conclusion:
It is feasible and reasonable to perform autologous stem cell transplant for multiple myeloma without administering growth factors. Estimated savings would be $4,600 for each transplanted patient. Growth factor administration is not required for a safe outcome and decreases the number and severity of some of the fluid-related complications after transplant such as acute respiratory distress syndrome, allergic reactions, alveolar hemorrhage, and rarely splenic rupture.

Disclosures:
Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.
Clinical Significance of Polymorphisms During Hepatopoietic Stem Cell Transplantation.
Authors: Ahn Jae-Sook , Kim Hee Nam , Kim Nan Young , Li Yu– , Lee Il-Kwon , Kim Yeo-Kyeoung , Bae Soo-Young , Yang Deok-Hwan , Lee Je-Jung , Kim Hyeoung Joon 
Published: October 2019

Abstract
Abstract 3497
Conidtioning plays an important part in hematopoietic stem cell transplantation (HSCT) and is a major cause of early mortality. Most of conditioning regimens include the ionizing radiation and alkylating agent. The tissue damage made by chemotherapy or radiation is the major cause of acute toxicity and the development of graft versus host disease (GvHD). DNA repair and drug metabolism gene polymorphisms influence the transplantation associated mortality and GvHD by causing incomplete DNA repair and interference with metabolism of drugs. To explore whether these polymorphisms influence clinical implication and the adverse outcomes related to chemo-radiotherapy, we analyzed total 12 polymorphisms in DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XRCC4, XPC, MGMT and OGG1) and drug metabolizing pathway (GST T1, GST P1, CYP1A1 rs1048943 and CYP1A1 rs4646903).
The total 175 patients were assessed from a HLA identical sibling (n=122, 69.7%) and unrelated donors (n=53, 30.3%). Patients have either acute leukemia (n=123, 70.3%), MDS (n=18, 10.3%), CML (n=15, 8.6%) or others (n=19, 10.8%). We evaluated the association between SNPs with adverse effects such as venoocclusive disease (VOD), mucositis, treatment related mortality and acute/chronic GvHD. Multivariate analysis was performed adjusting for clinical factors; recipient age, donor type, diagnosis, disease status, gender mismatch, HLA mismatch, stem cell source, conditioning regimen and GvHD prophylaxis. Three SNPs were associated with clinical significance. XRCC4 (rs1056503) was associated with increased risk of acute gut GvHD (RR:6.84, 95% CI:1.69-28.2, p=0.007), CYP1A1 (rs1048943) with mucositis (RR:3.12, 95% CI:1.22-7.96, p=0.017) and XPC (rs2228001) with VOD (RR:38.23, 95% CI:2.08-702.18, p=0.014).
Our findings show that the acute adverse events after allogeneic HSCT were correlated DNA repair and drug metabolism gene polymorphisms and these findings suggest that XRCC4, CYP1A1 and XPC might provide useful information for the risk stratification of HSCT

Disclosures:
No relevant conflicts of interest to declare.
Reduced Intensity Versus Myeloablative Conditioning in Adults with Acute Myeloid Leukemia Transplanted with Umbilical Cord Blood
Authors: Oran Betul , Wagner John E. , Defor Todd , Weisdorf Daniel J. , Brunstein Claudio 
Published: October 2019

Abstract
Abstract 3531

Background:
Reduced intensity conditioning (RIC) umbilical cord blood (UCB) transplantation is increasingly used in hematopoietic stem cell transplantation (HCT) for older and medically unfit patients. Data on the efficacy of HCT after RIC relative to myeloablative conditioning (MAC) are limited. We compared the outcomes of acute myeloid leukemia (AML) patients > 18 yrs who received UCB grafts after either RIC or MAC.

Methods:
One hundred nineteen adult patients with AML in complete remission (CR) underwent an UCB transplant after RIC (n=74, 62%) or MAC (n=45, 38%) between January 2001 and December 2009. Conditioning was either reduced intensity and consisted of cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2 and total body irradiation (TBI) 200 cGy or myelablative and consisted for cyclophosphamide 120 mg/kg, fludarabine 75mg/m2 and TBI 1200–1320cGy. All patients received cyclosporine (day -3 to day +180) and mycophenolate mofetil (day -3 to day +45) post-HCT immunosuppression and hematopoietic growth factor. Use of RIC was reserved for patients >45 years (n=37, 82%) or pre-existing severe co-morbidities (n=8, 18%). The two groups were similar except RIC had more preceding myelodysplastic syndrome (RIC=28% vs. MAC=4%, p<0.01) and older age (median, RIC=55yrs vs. MAC=33yrs; p<0.01). Remission status (CR1; RIC=65% vs. MAC=56%, p=0.9), CR1 duration ≥ 1 yr for CR2 HCT (RIC=46% vs. MAC=45% p=0.9) and the HCT-comorbidity index were similar (score >2; RIC=50% vs. MAC=40%, p=0.1). Furthermore, most patients received double UCB graft (RIC=85% vs. MAC=89%, p=0.5) with a maximum HLA disparity of 4/6 and 5/6 in 52% and 34% of RIC recipients vs. 62% and 29% of MAC recipients (p=0.5).

Results:
Median follow-up for survivors was 4.2 (RIC) and 3.5 years (MAC). The 3-year leukemia-free survival (LFS) was 31% vs. 55% (p=0.02) and 3-year relapse incidence was 43% vs. 9% (p<0.01) in recipients of RIC and MAC, respectively (Figure). One-year transplant related mortality (TRM) was similar (RIC=16% vs. MAC=24%; p=0.55). In multivariate analysis (Table), RIC recipients and those in CR2 with short CR1 duration had higher risk of relapse and poorer LFS. No factors predicted TRM.

Conclusion:
UCB with RIC extends the use of allogeneic HCT for older and less fit patients with limited TRM. However, the increased relapse risk and poorer LFS in the RIC setting indicates the need for novel strategies to improve leukemia control post-transplantation, especially in CR2 patients with short CR1 duration.

Disclosures:
Wagner: CORD:USE: Membership on an entity's Board of Directors or advisory committees; VidaCord: Membership on an entity's Board of Directors or advisory committees. Weisdorf:Genzyme: Research Funding; Hospira.
Outcomes In Patients with Multiple Myeloma Following Autologous Stem Cell Transplantation Using Intravenous Busulfan and Melphalan: A Matched Comparison to a Double Autologous Transplant Strategy
Authors: Blanes Margarita , De La Rubia Javier , Lahuerta Juan-Jose , Gonzalez José David , Ribas Paz , Solano Carlos , Sanz Miguel Angel 
Published: October 2019

Abstract
Abstract 3560

Background:
We have previously reported a high response rate with a conditioning regimen consisting of intravenous busulfan (ivBu) and melphalan (Mel) in patients with multiple myeloma (MM) undergoing autologous stem cell transplant (ASCT) (Blanes M et al, Leuk Lymphoma 2009). In this case-matched study, we analyze the efficacy and toxicity of ivBuMel as conditioning regimen before ASCT in 51 patients with newly diagnosed MM. Their clinical outcome was compared with that of a control group of 102 pair mates included in the Spanish PETHEMA/GEM2000 study of tandem transplant (control group).

Patients and Methods:
Patients in the control group were transplanted between 2002 and 2005, while patients in the ivBuMel group underwent ASCT between 2005 and 2009. Controls were matched with respect to sex, age, Durie-Salmon and ISS stage at diagnosis, and disease status at transplant. The conditioning regimen comprised iv Bu (3.2 mg/kg in a single daily dose, days -5 to -3) and Mel (140 mg/m2, day -2). Patients in the control group underwent a first ASCT after Mel 200 mg/m2 (Mel 200) in a single dose on day -2 followed in patients failing to achieve a complete response (CR) by a second autologous transplant. The conditioning regimen administered in the second transplant was either Mel 200 or a combination of cyclophosphamide, carmustine, and etoposide.

Results:
There were no differences in the hematopoietic recovery and mild or moderate mucositis was the toxicity most frequently observed in both groups of patients. Two (4%) patients died due to transplant-related complications in the ivBuMel group and 5 (5%) in the control group. The CR/near CR (nCR) rate was 51 % in both groups. After median follow-up of 32 and 40.5 months in the ivBuMel and control group, respectively, median progression free survival (PFS) was 37.6 for patients who received ivBuMel and 26.5 months for those in the control group. At 4 years, overall survival and PFS was 65±10% and 42±9% in the ivBuMel and 62±5% and 32± 5% in the control group, respectively (P = NS). For patients achieving CR/nCR after ASCT, the 4-years PFS rate was 52±14% and 40±8% in ivBuMel and control group, respectively (P = 0.3). Finally, in patients achieving partial response or less after transplant, the 4-years PFS rate was 33±12% and 23±6% in ivBuMel and tandem transplant group, respectively (P = 0.3).

Conclusion:
Results of this case-matched study suggest that the use of ivBuMel conditioning regimen before ASCT in patients with newly diagnosed MM is associated with low transplant-related morbidity and mortality and a high anti myeloma efficacy that compares favourably with a tandem transplant strategy.

Disclosures:
No relevant conflicts of interest to declare.
RelB, Together with Rela, Maintains the Cellular Survival In Chronic Lymphocytic Leukemia
Authors: Feng Guo , Xu Jinjin , Wang Wenjuan , Ma Liang , Zhou Peng , Zhou Jun , Shen Yayin 
Published: October 2019

Abstract
Abstract 3583
RelA, a classical NF-κB subunit, has been shown to function critically in cellular survival and drug-resistance of B-cell chronic lymphocytic leukemia (B-CLL). The significance of RelB, contributing to the alternative NF-κB activity, has not been addressed in B-CLL yet. The protein expression levels of NF-κB subunits in 60 B-CLL samples were examined in this study. According to the RelA and RelB expression status in the nuclear extracts of peripheral blood and bone marrow, the B-CLL samples were classified as RelA+/RelB−, RelA+/RelB+, and RelA−/RelB− subgroups. The frequencies of the individual group were 30%, 30%, and 40%. In RelA+/RelB+ subgroup, both the RelA DNA-binding complex and the RelB DNA-binding complex were further detected in the nuclear extracts of B-CLL cells by electrophoretic mobility super-shift assay. Fresh CD19+ B-CLL cells from different subgroups were cultured for 48 hours ex vivo, the spontaneous apoptosis were quantified by Annexin-V/PI staining and the frequencies of apoptosis were 48±4.5% (RelA+/RelB−), 24±8.6% (RelA+/RelB+), and 65±5.0% (RelA−/RelB−) individually. In addition, when fresh B-CLL cells were incubated with MG-132, a proteosome inhibitor, a significant reduction of cellular survival in RelA+/RelB− and RelA+/RelB+ group was observed in a dose and time-dependent manner. B-CLL cells from RelA+/RelB+ group were cultured for 0, 6 and 24 hours in the presence of CD40L (250μ g/ml), the cellular survival was not affected and the protein expression levels of NF-κB family members stayed unchanged. While the CD19+ B-CLL cells from RelA+/RelB− group were cultured with CD40L, a modest decrease in apoptosis and a slightly increased RelB expression in cytoplasm and nucleus after 24-hour treatment were identified. The induction of RelA and RelB expression, companied by an evident decrease in apoptosis, was detected in cells from RelA−/RelB− group. The alternative NF-κB signaling pathway, in terms of RelB/p52 nuclear translocation, functions specifically in lymphoid organogenesis and B-cell development. In this study, we show that RelB expression is detected in B-CLL cells and partially maintain the basal survival. CD40L triggers the expression of RelB, correlating with the enhanced survival. Taken together, not only RelA but also RelB subunit of NF-κB family plays an important role in the cellular behavior of B-CLL cells.

Disclosures:
No relevant conflicts of interest to declare.
Autocrine IL6/STAT3 Signaling Enhances Survival of Chronic Lymphocytic Leukaemia Cells
Authors: Liu Fengting , Jia Li , Farren Timothy , Gribben John G. , Agrawal Samir 
Published: October 2019

Abstract
Abstract 3598
Signal transducer and activator of transcription 3 (STAT3) proteins have been found to play an important role in cancer cell survival and proliferation. The activation of STAT3 signalling pathways require interleukin-6 (IL6) and tyrosine kinase (JAK2) phosphorylation. Previous studies have shown that in patients with CLL elevated levels of serum IL6 correlate with adverse disease features and shorter survival.

Methods:
We investigated the relationship of CLL cell autocrine IL6 production, STAT3 activation and apoptosis resistance. Thirty-six CLL patients with high lymphocyte counts were investigated. Westen blot, flow cytometry, gene transfection and fluorescent microscopy techniques were used.

Results:
Autocrine IL6 production in CLL cells cultured for 24 hours was higher in Binet stage B/C patients (61pg/ml, range 1.4–297pg/ml) as compared with stage A patients (6.1pg/ml, range 0–23pg/ml) (p=0.02). Patients with high autocrine IL6 production had a higher ratio of phosphorylated STAT3/ total STAT3, indicating a high level of STAT3 activation and apoptosis resistance. Activation of the IL6/JAK2/STAT3 pathway by exogenous IL6 led to increased expression of anti-apoptotic proteins Mcl-1 and Bcl-xl. STAT3 activation by exogenous IL6 led to increased resistance of CLL cells to spontaneous in vitro apoptosis (mean increase in viable cells over control: 15%, range 2–36%; p=0.00008). This was associated with preservation of mitochondrial function: decreased cytochrome C release (p=0.004), mitochondrial membrane potential collapse (p=0.0004) and ROS generation (p=0.0007). This study demonstrates that higher autocrine IL6 production by CLL correlates with STAT3 activation and apoptosis resistance in CLL. The IL6/JAK2/STAT3 signal pathway may reveal new therapeutic targets.

Disclosures:
Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.
The Role of Reactive Oxygen Species In Apoptosis Induction of Mantle Cell Lymphoma (MCL); Inhibition of NADPH Oxidase 2 Induces Apoptosis In MCL
Authors: Miura Yuji , Miwa Hiroshi , Ohno Toshihito , Haneda Miyako , Hosokawa Yoshitaka , Nitta Masakazu , Daibata Masanori 
Published: October 2019

Abstract
Abstract 3616
Mantle cell lymphoma (MCL) is an aggressive tumor and is characterized by deregulated growth and resistance to apoptosis. Reactive oxygen species (ROS) are important signal transduction molecules in regulation of cell growth, differentiation and apoptosis. Some of the ROS-generating NADPH oxidase (Nox) family enzymes are involved in neoplastic proliferation. We hypothesized that Nox-mediated generation of intracellular ROS conferred antiapoptotic activity and thus a growth advantage to MCL cells. (1) To investigate whether Nox gene expression might be specific, this study measured the expression levels of Nox genes 1–5 and dual oxidase 1 and 2 in two MCL cell lines (SP49 and SP53) and peripheral blood leukemic cells from a patient with MCL by quantitative, real-time RT-PCR. (2) Effects of antioxidants or small inhibitory RNA (siRNA) on viability of MCL cells were examined by Calcein or MTT assay. (3) Generation of intracellular ROS were measured by FACS analysis after cells were labeled by dichlorofluorescin (DCF). (4) Apoptosis was evaluated by Annexin V assay. (5) Signal transduction was estimated by Western immunoblots. MCL cell viability decreased in dose-dependent manner when cells were exposed to a dietary antioxidant, an inhibitor of flavoprotein-dependent oxidase, diphenylene iodonium (DPI) and vitamin E. RT–PCR analysis revealed that high level Nox2 mRNA expression was observed in all MCL cells, whereas little or no Nox1, Nox3-5 and Duox1-2 mRNAs was detected. Moreover, Nox2 expression in CD19+ leukemic MCL cells was significantly higher than normal CD19+ B cells (5.1-fold). SiRNA knockdown of Nox2 in these cell lines results in 27% reduction in intracellular ROS as measured by a fluorescent DCF assay, and 22% reduction in cell viability. SiNox2-RNAs inhibited superoxide production in MCL cells, and depletion of ROS by DPI or siNox2-RNAs induced apoptosis (28% or 11%, respectively). DPI treatment and siNox4RNA transfection blocked activation of the cell survival kinase AKT by attenuating phosphorylation of AKT. AKT phosphorylation of apoptosis signal-regulating kinase 1 (ASK1) was reduced by DPI and siNox2-RNAs. Collectively, these findings suggest that ROS generated by Nox2, at least in part, transmits cell survival signals through the AKT- ASK1 pathway in MCL cells and their depletion leads to apoptosis.

Disclosures:
No relevant conflicts of interest to declare.
Regulation of Genes of the Circadian Clock In Human Chronic Myeloid Leukemia: Abolished Daily Oscillation of PER1, PER2, PER3 and CRY2.
Authors: Yang Ming-Yu , Yang Wen-Chi , Lin Pai-Mei , Hsu Jui-Feng , Hsiao Hui-Hua , Liu Yi-Chang , Tsai Hui-Jen , Chang Chao-Sung , Lin Sheng-Fung 
Published: October 2019

Abstract
Abstract 3633
Circadian rhythm is present in human and all eukaryotes with a 24-hour cycle. Circadian genes use transcriptional-translational feedback loops to control circadian rhythms. Therefore, the marked characteristic of circadian systems is the strong daily cycling of clock gene mRNA, clock protein, and clock-controlled gene RNA and protein. Recent studies have demonstrated that expression of some of the circadian genes display daily oscillation in peripheral tissues including liver, eye, lung, heart, spleen, kidney, peripheral blood and bone marrow. Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. In this study the expression profiles of the 9 circadian genes (hPER1, hPER2, hPER3, hCRY1, hCRY2, hCLOCK, hBMAL1, hCK1e and hTIM) in peripheral blood (PB) total leukocytes from 95 chronic myeloid leukemia (CML) and 54 healthy volunteers were investigated. For comparison of circadian gene expression between PB mononuclear cells (PBMCs) and polymorphonuclear cells (PMNLs), another group of 10 healthy volunteers were also investigated. Collection of PB was carried out at four time points: 20:00, 02:00, 08:00, and 14:00, respectively. In healthy individuals, the daily oscillation was shown for hPER1, hPER2, hPER3, and hCRY2 with peak expression levels at 8:00AM, and the expression of the nine genes displayed similar profile both in PBMCs and in PMNs. In contrast, oscillations of these four genes were abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients and partial recoveries of oscillations were observed in CML patients with complete cytogenetic response and major molecular response. In some serial monitored individual patients, the recoveries of oscillations of circadian gene expression accompanied with the disappearance of BCR-ABL transcripts were also noted. Expression of hCRY1, hCLOCK, hBMAL1, hCK1e and hTIM did not oscillate both in healthy individuals and CML patients. Updated results on more healthy volunteers and serial monitored CML patients will be presented at the meeting.

Disclosures:
No relevant conflicts of interest to declare.