bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.
Authors: Castillo Santiago del , Delgado Regina Garcia , Entrena Laura , Hernandez Agustin M , Campos Arturo , Duarte Jose , Gallardo Ana I , Sanchez Guacimara , Cerda Maria , Ramirez Gema 
Published: October 2019

Abstract
Abstract 4499

INTRODUCTION:
The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation.

MATERIAL:
Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low.
Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22).
Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly.

RESULTS:
All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment.

CONCLUSION:
Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior.

Disclosures:
No relevant conflicts of interest to declare.
Treatment of Red Cell Hypoplasia Following Fully Ablative Matched Related Allogeneic Transplant with Stem Cell Boost.
Authors: Essell James , Tierney Catherine , Alliston Mary , Broun Edward R. 
Published: October 2019

Abstract
Abstract 4530
We present the case of a 34 year old African American male with T-cell non-Hodgkin's Lymphoma who received a matched related allogeneic transplant using a preparative regimen of cyclophosphamide and TBI from his brother on 11/4/09. The patient's blood type was O+ and the donor's blood type was B+. The cell dose was 10.3 × 106 CD34/kg. His post transplant course was generally uncomplicated. Although he recovered his ANC on D+18 and he was platelet transfusion independent by D+28, he never became red cell transfusion independent. A bone marrow biopsy on day 33 showed no evidence of disease with minimal erythroid recovery. His engraftment studies were all 100% donor cells. His reticulocyte counts are detailed in the table below. On day 126 he had a positive qualitative PCR for parvovirus. He received IVIG (400 mg/kg) for 5 consecutive days beginning 3/15/10. Weekly surveillance for CMV by PCR remained non-detectable.
Repeat bone marrow biopsies on day 63 and 88 continued to show neutrophil engraftment, hypoplastic megakaryocytes and aplasia of red cells. His immune suppression was discontinued on day 99. A fourth bone marrow biopsy on day 155 again showed erythroid hypoplasia with neutrophil and megakaryocyte hypoplasia.
He received a second infusion of PBSC without a conditioning regimen. He received 2.5 × 106 G-CSF mobilized HPC-A from the original donor on day 205 post transplant. Tacrolimus was reinitiated on day 203. As noted in the table below, his reticulocyte count normalized three weeks post infusion. His last RBC transfusion was given two days prior to the stem cell infusion and he remains transfusion independent today. He continues on tapering doses of tacrolimus and has not experienced any graft versus disease.DateT+WBCHgbPLTANCreticParvo PCR12/7/09336.68.8632.412/9/09356.17.8692.50.68%negative2/25/101131.98.8691.10.10%3/10/101262.18.50.4positive3/25/101423.59.1732.20.10%negative4/1/101492.48.0491.2negative5/25/102032.77.0871.50.10%6/18/10227/233.18.31131.96.10%6/25/10234/303.68.41172.25.20%

Disclosures:
No relevant conflicts of interest to declare.
Incidence and Outcome of Auto/Alloimmune Hepatitis with Hepatic Graft-Versus-Host Disease After Hematopoietic Stem Cell Transplantation.
Authors: Koldehoff Michael , Elmaagacli Ahmet H , Klein Reinhild , Beelen Dietrich 
Published: October 2019

Abstract
Abstract 4534
Auto/alloimmune hepatitis (AIH) is an inflammatory liver disease characterized histological by a dense mononuclear cell infiltrate in the portal tract and serological by the presence of non-organ and liver-specific antibodies, high transaminases and increased levels of IgG. The relation between allogeneic hematopoietic stem cell transplantation (HSCT) and auto/alloimmune disease is complex. To examine this association, we retrospectively studied 1,636 allogeneic patients (median age 43, range 18–73 years) between May 1996 and December 2008. Among these patients, 311 (19%) developed hepatic graft-versus-host disease (GvHD) (162 pts had a hepatic GvHD of grade > II). We followed 25 patients (11 male, 14 female) in whom GvHD of the liver presented with marked elevation of serum aminotransferases, clinically resembling acute hepatitis and auto/antibodies characteristics for AIH. The median age at transplant was 35 (range, 18–54) years. Onset of liver dysfunction was at 286 days (range, 55–2766) after HSCT. Median peak serum was 312 (range 105–1750) U/L for alanine aminotransferase, 629 (133-2410) U/L for gamma-glutamyl transferase and 1.74 (0.5-23.4) mg/dl for bilirubin. The autoantibody profiles of AIH were 60% for anti-nuclear antibody, 44% for antibodies to liver-kidney microsomes, 24% for antibodies to smooth-muscle antigens, 28% for anti-mitochondrial antibody, 16% for antibodies to actin, 8% for antibodies to nucleoli, and 4% for other autoantibodies. AIH had a higher prevalence in younger and in female patients. AIH occurred in 92% in patients, who were transplanted with G-CSF mobilized and peripherally collected stem cells (PSC), but in only 8% in patients with bone marrow (BM) source (p<0.02), comparing all transplanted patients (1326 PSC, 310 BM). Stem cell grafts from matched sibling donor or matched unrelated donor were similar in the two groups. Acute GvHD of grade> II occurred more frequently in the groups with AIH (15/25 vs. 649/1636, p<0.002), and chronic GvHD (11 limited, 14 extensive) was ascertained in all AIH patients vs. 49.8% in all transplanted patients (p<0.0001). Three patients with AIH died from pulmonary bleeding, chronic GvHD, and relapse, whereas 22 patients with AIH are still alive (88%) at a median survival time of 2570 days. In conclusion, our evaluation confirms a strong association between G-CSF mobilized PSC, chronic GvHD and the development of AIH.

Disclosures:
No relevant conflicts of interest to declare.
Etanercept for Steroid-Refractory Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Park Joon Seong , Jeong Seong Hyun 
Published: October 2019

Abstract
Abstract 4548

Background:
Treatment strategy for steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to be standardized. We report our clinical experience of Etanercept, recombinant human soluble tumor necrosis factor receptor fusion protein, on steroid-refractory aGvHD, retrospectively.

Method:
A total of 18 patients who received allo-HSCT and presented with steroid-refractory aGvHD in Ajou University Hospital were studied retrospectively. Twenty five miligram of Etanercept was given subcutaneously twice weekly for 4 weeks. Clinical responses were checked with regard to the severity of aGvHD.

Results:
Median age was 43.5 years. Patients with AML, myeloma, ALL, aplastic anemia, myelodysplastic syndrome and idiopathic myelofibrosis were studied. The engraftment kinetics was adequate and no one failed to engraft. Before Etanercept, grade 4, grade 3, grade 2 and grade 1 of aGvHD occurred in 7, 6, 5, and zero patients, respectively however the number of patients were changed to 4, 5, 5, and 4 after Etanercept, respectively (p = .005). Eighty percent of grade II and 57% of grade IV patients showed partial response, so did in 14% of grade III patients. Skin and gut aGvHD was well controlled with Etanercept, whereas hepatic GvHD was not. Three patients died of severe infection. There was no factor affecting clinical outcome of Etanercept. All the non-responders died but 56.6% of the responders survived (p = 0.003).

Conclusion:
Etanercept can be one of the effective anti-aGvHD drugs for steroid-refractory cases after allo-HSCT considering tolerable side effects and tolerable cost.

Disclosures:
No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation (allo-SCT) for Isolated and Leukemic Myeloid Sarcoma (GS): a Survey on Behalf of the Acute Leukemia Working Party (ALWP) of EBMT.
Authors: Chevallier Patrice , Labopin Myriam , Cornelissen Jan J. , Socié Gérard , Ljungman Per T. , Lioure Bruno , Tilly Herve , Gratwohl Alois , Milpied Noel , Yakoub-Agha Ibrahim , Volin Liisa , Vernant Jean-Paul , Bay Jacques-Olivier , Michallet Mauricette , Buzyn Agnès , Samey Benedicte , Mohty Mohamad , Rocha Vanderson 
Published: October 2019

Abstract
Abstract 4558
Myeloid Sarcoma (MS) is a rare malignant disorder usually presenting as an extramedullary myeloid cell tumor proliferation. MS can be observed in 3 to 7% of AML cases (called “leukemic” MS, LMS hereinafter). MS prognosis is rather poor with overall survival (OS) not exceeding 2 years. We have previously shown, that allo-SCT following an AML-like chemotherapy is likely the best available therapeutic option for patients with LMS (J Clin Oncol 2008). However, it is still unclear whether allo-SCT is a valid therapeutic option for patients with isolated MS (IMS). The aim of this analysis was to assess the role of allo-SCT in patients with IMS as compared to patients with LMS.
We retrospectively analysed the outcome of 99 MS patients with a median age of 40 years (range: 18–70), including 30 cases of IMS and 69 cases of LMS, reported to the EBMT registry between January 1991 and June 2009. The majority of patients were in complete remission (CR) at time of transplant (IMS: first CR n=14, second CR or beyond n=7 vs. LMS: first CR n=38, second CR or beyond n=21, P=0.20). In this series, patients received either a standard (IMS, n=24 vs. LMS, n=55, P=NS) or a reduced-intensity conditioning regimen (IMS, n=6 vs. LMS, n=14, P=NS) prior to allo-SCT from a matched-related (IMS n=21 vs. LMS, n=48, P=NS) or unrelated donor (IMS, n=9 vs. LMS, n=21, P=NS).
After allo-SCT, engraftment was observed in all patients. The incidences of grade 2–4 and grade 3–4 acute GVHD were 32% and 9%, respectively. The incidence of chronic GVHD at 2 years was 45%. With a median follow-up of 48 (range: 6–213) months, the 5-years OS, and leukaemia-free survival (LFS), and the cumulative incidences of relapse (RI), and non-relapse mortality (NRM) were 48%, 36%, 40% and 19%, respectively. When comparing the two sub-groups (IMS vs. LMS), there were no significant differences in term of outcomes: neutrophils recovery (15 vs 18.5 days), grade 2–4 acute GVHD (27% vs 35%), chronic GVHD (54% vs 41% at 2 years), 5-year OS (33% vs. 48%), 5-year LFS (30% vs. 38%), 5-year RI (45% vs. 38%) and 5-year NRM (19% vs. 17%).
In all, we conclude that allo-SCT is an effective treatment for patients with MS. The current data suggest that patients with isolated or leukemic MS have similar outcome after allo-SCT. Therefore, allo-SCT is likely to be considered as the optimal therapy for both isolated and leukemic MS.

Disclosures:
Tilly: Amgen: Honoraria.
Haploidentical Stem Cell Transplantation for Children with High-Risk Leukemia In Chile: Report of the First 15 Cases.
Authors: Palma Julia I , Salas Lucia , Carrion Flavio , Sotomayor Cristián , Catalán Paula , Handgretinger Rupert , Rivera Gaston 
Published: October 2019

Abstract
Abstract 4581
The Chilean population is ethnically diverse, and more than 50% of the children referred for hematopoietic stem cell transplantation lack a suitable donor. To expand the donor pool we assessed the feasibility, tolerance, and efficacy of using a parental haploidentical (HI) donor and a reduced-intensity conditioning regimen for patients with high-risk leukemia; this study was preceded by 2 years of technology transfer from St. Jude Children's Research Hospital. Between March 2006 and November 2009 fifteen patients (median age, 9.6 years) received T cell-depleted grafts at Calvo Mackenna Hospital, from peripheral stem cells mobilized with G-CSF from parental donors. N° aphaeresis/patient = one; 6/15 products required a second depletion, final Log of depletion= 3, 11 (5, 05-1, 64). Median cell doses were CD34+: 9.5 × 106 cells/kg (range, 2.13 – 20.0), CD3+: 1.0 ×105cells/kg (0.11 – 1.59), and CD56+: 67, 9 × 106cells/kg (7, 6–131, 8). 14/15 patients engrafted one1ry primary engraftment failure and in 2 cases a 2ry engraftment failure (CMV and Toxoplasmosis treatment). Eight remain alive and clinically well at a median follow up of 12.4 months post-transplant (7.2 – 52.2). Four patients died after bone marrow relapse, while only one died of transplant-related causes. Virus reactivation was the main post-transplant complication: 9/15 had positive CMV PCR but none had CMV disease. One patient developed acute GvHD > grade II and one had chronic GvHD. In this setting, HI transplantation offers a rational option for children who lack suitable stem cell donors. This information is especially relevant for populations that are poorly represented in international donor registries. On the other hand HISCT with RIC with ATG and TNI permits a good OS and EFS in this especially high risk population low TRM. This approach is associated with low incidence of GvHD and high viral reactivation incidence but no lethal infection even without CD3+ lymphocyte recovery due probably to pre-emptive treatment and fast NK cell recovery.

Disclosures:
No relevant conflicts of interest to declare.
Faisability and Results of Autologous Stem Cell Transplantation In Lymphoma Patients Over 65 Years Old.
Authors: Tempescul Adrian , Ianotto Jean-Christophe , Eveillard Jean-Richard , Guillerm Gaelle , Bijou Fontanet Delices , Berthou Christian 
Published: October 2019

Abstract
Abstract 4593

Introduction:
The incidence of lymphoma is increasing in the western population. Autologous stem cell transplantation (ASCT) is the standard consolidation procedure in patients with lymphoma expressing bad features at the time of diagnosis or in patients relapsing after a first line of chemotherapy (or radiotherapy). It has already been proven that ASCT improves the overall survival and the disease free survival in younger patients. No data are available for the feasibility and the results of ABSCT in elderly patients (OMS defines elderly as age superior to 65 years).

Purpose:
We performed a retrospective study in our centre, comparing the feasibility and the results of ABSCT in elderly patients with lymphoma compare to patients younger than 65 years old.

Patients and Methods:
We identified 147 patients who underwent ASCT transplantation in Brest Transplantation Centre. Ninety-four patients were younger than 65 (mean51.44years) and 53 patients were older (mean 67.86 years).

Results:
Transplantation related mortality (TRM) (up to 100 days post ASCT) was similar for the two populations. There was no statistically significant difference between the two populations regarding the number of units of RBC and platelets transfused, the number of CD 34 reinjected and infectious complications. There was a statistically significant difference between the two populations regarding the duration of aplasia: 11.21 days in younger patients and 11.89 days in elderly population.
There was no statistically significant difference between the two populations regarding the overall survival (OS) and the disease free survival (DFS).

Conclusion:
Our retrospective, monocentric, comparative study showed that ACST could be performed in selected elderly patients (over 65 years old) with no significant difference regarding TRM, DFS and OS but a little bit longer period of aplasia: 11.21 days for young patients and 11.89 in elderly (p-0.0005).

Disclosures:
No relevant conflicts of interest to declare.
Nicotinamide Promotes Apoptosis In Chronic Lymphocytic Leukemia through Activation of the p53/Mir-34a/SIRT1 Tumor Suppressor Network
Authors: Audrito Valentina , Vaisitti Tiziana , Serra Sara , Rossi Davide , Gottardi Daniela , D’Arena Giovanni , Gaidano Gianluca , Malavasi Fabio , Deaglio Silvia 
Published: October 2019

Abstract
Abstract 4627
Nicotinamide (Nam), is the main precursor of nicotinamide adenine dinucleotide (NAD+). It regulates intracellular levels of NAD+ and consequently activities of four classes of NAD+-consuming enzymes, including NADases, mono-ADP-ribosyl transferases (ARTs), poly-ADP-ribose polymerases (PARPs) and sirtuins.
Pharmacological doses of Nam inhibit the physiological activation and proliferation of mouse B lymphocytes, suggesting that this agent might affect also human B cell homeostasis. We approaches this issue by comparing the effects of Nam on normal vs. leukemic B lymphocytes. Chronic lymphocytic leukemia (CLL) was selected as disease model, for testing in vitro the therapeutic potential of Nam, due its intrinsic resistance to apoptosis, mediated by an imbalance in the mechanisms regulating cell death, mainly regulated through the activities of NAD+-dependent enzymes.
This study shows that pharmacological doses of Nam (5-10 mM) significantly inhibit proliferation and induce apoptosis of CLL cells. At earlier time points, Nam markedly reduces phosphorylation of multiple intracellular substrates, including ERK1/2. Normal B lymphocytes, used as control, were significantly less sensitive to the action of Nam. We hypothesized that these effects could be explained at least in part as a consequence of the inhibitory effects of Nam on NAD+-consuming enzymes. Attention was focused on SIRT1, a deacetylase that plays a critical role in cancer and that acts as a longevity factor. The results demonstrate that Nam exposure inhibits the activity, and also the expression of SIRT1. This effect is apparent only in leukemic cells, where SIRT1 protein levels are significantly higher than in normal B lymphocytes, obtained from spleen or tonsils, markedly less sensitive to Nam effects. The functional block of SIRT1 induced by Nam is followed by activation of p53, transcription of miR-34a and translational repression of SIRT1 mRNA (p53/miR-34a/SIRT1 functional loop). The endpoint is the activation of apoptosis. The same loop is the target of conventional DNA-damaging drugs, such as etoposide. Thus, addition of Nam to conventional DNA-damaging chemotherapeutics agents, leads to an inhibition of SIRT1 through two independent and synergic pathways, resulting in additive effects on apoptosis.
In conclusion this work suggests that Nam represents a potentially useful non-chemotherapeutic agent, characterized by a known and established safety profile, to be associated to conventional cytotoxic drugs in the treatment of selected forms of CLL.

Disclosures:
No relevant conflicts of interest to declare.
DNA Methylation Profiling of Childhood Acute Lymphoblastic Leukaemia Using Illumina Infinium DNA Methylation27 Bead Arrays Identifies a Distinct DNA Methylation Signature Associated with Leukaemogenesis
Authors: Wong Nicholas C. , Chatterton Zac , Bell Katrina , Kowalcyk Adam , Bedo Justin , Wang Qiao , Haviv Izhak , Algar Elizabeth , Ashley David , Craig Jeff , Saffery Richard 
Published: October 2019

Abstract
Abstract 4650
Acute Lymphoblastic Leukaemia (ALL) is the most common form of cancer in children. Although up to 80% of cases can be characterised by either abnormal chromosome number (hyper- or hypo-diploidy) or a specific chromosome translocation, a significant proportion of cases do no exhibit any major chromosome abnormality. Indeed, no common gene mutation has been found to be associated with childhood leukaemia. This suggests that epigenetic modifications, in particular DNA methylation, may also play a significant role in ALL pathogenesis. Understanding the specific epigenetic changes associated with this disease is therefore of paramount importance for predicting onset and disease outcome and understanding disease aetiology.
From our cohort of over 450 cases of childhood leukaemia we analysed 12 cases of childhood ALL that carried the TEL/AML1 (RUNX1/ETV6) chromosome translocation using Illumina Infinium Human Methylation27K bead chip arrays. These interrogate 27,578 CpG methylation sites across the human genome covering 14,495 RefSeq gene promoters. We analysed matching leukaemia and remission bone marrow with the aim of identifying DNA methylation signatures associated with this leukaemia subtype.
We used a number of computational methods to determine the DNA methylation signatures associated with childhood ALL including LIMMA, Centroid Analysis and Support Vector Machine Modelling. This identified 16 probes sufficient to define a leukaemia sample from a remission sample based on methylation level.
We are currently validating our results using high throughput SEQUENOM and performing gene pathway and network analyses to look for commonly affected genes associated with leukaemia. These methylation changes we have identified may help refine the diagnosis of childhood ALL and identify cellular pathways subject to epigenetic disruption in ALL.

Disclosures:
No relevant conflicts of interest to declare.