bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Characterization of a Novel Chromosomal Translocation t(12;14)(q23;q11.2) in T-Lymphoblastic Lymphoma Between the T Cell Receptor Delta Deleting Elements (TRDREC and TRAJ61) and the Hypothetical Gene C12orf42.
Authors: Przybylski Grzegorz K , Dittmann Kathleen , Grabarczyk Piotr , Dölken Gottfried , Busemann Christoph , Gesk Stefan , Harder Lana , Landmann Eva , Siebert Reiner , Schmidt Christian A. 
Published: October 2019

Abstract
Abstract 4239
Chromosomal aberrations have diagnostic, prognostic and therapeutic consequences in haematological malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR) we established a fast and robust approach to precisely characterize chromosomal breakpoints. Using this approach we characterized at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma occurring during the deletional rearrangement of the T cell receptor delta gene (TRD). Normally, this transient rearrangement is a pivotal step in T cell differentiation towards the alpha/beta versus the gamma/delta lineage and generates the T cell receptor excision circles (TREC), which are quantitated to determine the proliferative history of T cells. We found that the rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 (ASCL1) gene into proximity to the TRA enhancer, which is encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors and is overexpressed in medullary thyroid cancer and small cell lung cancer.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Significance of Circulating Ki-67 Protein and Caspase-3 Activity Levels in Chronic Myeloid Leukemia.
Authors: Bruey Jean-Marie , Kantarjian Hagop M. , Estrov Zeev , Ma Wanlong , Yeh Chen-Hsiung , Sferruzza Anthony , Albitar Maher 
Published: October 2019

Abstract
Abstract 4249
Ki-67 and caspase-3 are widely accepted as proliferation and apoptosis markers. We recently reported that Ki-67 can be detected as a circulating protein (cKi-67) in the plasma of patients with acute lymphoblastic leukemia (ALL), and that higher levels correlated with more aggressive disease. Here we investigated the levels of cKi-67 in patients with chronic myeloid leukemia (CML). We also evaluated the level of apoptosis in CML as determined by plasma levels of caspase-3 activity. The study included 127 CML patients: 81 in chronic phase and 46 in accelerated phase/blast crisis. cKi-67 levels were determined with an electro-chemiluminescence-based immunoassay. Apoptosis was determined by measuring caspase-3 activity (DEVD) in the plasma using a standard enzymatic fluorogenic assay. Patients with CML had significantly (P<0.0001) higher levels of cKi-67 and caspase-3 activity than normal control (n = 96). However, median (range) cKi-67 levels did not differ significantly between CML patients in chronic phase (523 [73-5857] ng/mL) and those in accelerated/blast crisis phase (710 [100-3530] ng/mL), nor did caspase-3 activity: 12.2 (6.1-29.1) pmol/min the chronic phase group and 12.2 (range=6.6-17.9) pmol/min in the accelerated/blast crisis group. The median of cKi-67 and caspase-3 in the healthy control group was 353.06 and 8.19, respectively and range 35.76-2830.65 ng/ul and 4.54-34.30 pmol/min, respectively. Neither cKi-67 level nor caspase-3 activity correlated with white cell count or blast count in the chronic phase or in the accelerated/blast crisis phase. There was no correlation between cKi-67 or caspase-3 levels and response to imatinib therapy. However, patients in the chronic phase with high levels of cKi-67 (>354 ng/mL) had significantly longer survival than did those with lower levels (P=0.003); cKi-67 levels were not associated with outcome in accelerated/blast phase CML. Caspase-3 activity did not correlate with outcome in chronic or accelerated/blast phase patients. In conclusion, cell proliferation and apoptosis as determined by plasma cKi-67 level and caspase-3 activity are elevated in CML, but higher levels of cKi-67 unexpectedly correlated with longer survival in chronic phase CML. Although the cause for this is unknown, it is possible that higher levels of cKi-67 reflect that more stem cells are in cell cycle, and this may make them more susceptible to therapy.

Disclosures:
No relevant conflicts of interest to declare.
Soluble IL2R (CD25), IL10 and PDL1 May Control T Cell Activation in Chronic Myeloid Leukemia.
Authors: Christiansson Lisa , Lindqvist Camilla , Tötterman Thomas H , Simonsson Bengt , Olsson-Strömberg Ulla , Loskog Angelica 
Published: October 2019

Abstract
Abstract 4252
Cancer patients are known to have an impaired anti-tumor immune response because of various immune escape mechanisms exerted by the tumor cells. These mechanisms involve release of soluble molecules and expression of membrane-bound proteins inhibiting different arms of the anti-tumor immune responses. The immune escape mechanisms seen in cancer patients complicate the use of immunotherapy, such as tumor vaccines and adoptive T cell transfer. The aim of our study was to investigate the presence of IL10, soluble IL2R (sIL2R; CD25) and programmed death receptor ligand 1 (PDL1) in patients with chronic myeloid leukemia (CML) and to study their role as T cell inhibitors. IL10, sIL2R and PDL1 are all known immune inhibitory molecules. IL10 is a secreted molecule that has various suppressive effects on many different immune cells. sIL2R binds IL2 efficiently and may thereby prevent the binding of IL2 to IL2R on T cells, an interaction that is necessary for proliferation and maintenance of tumor-specific T cells. PDL1-expressing tumor cells can bind programmed death receptor 1 (PD1) on T cells. This interaction can induce apoptosis in the T cells. In this study, we used cytometric bead array, ELISA and multicolor flow cytometry to screen CML patients and healthy controls for the presence of IL10, sIL2R and PDL1 in blood. Further, Alamar Blue TM assay and IFNγ detection by flow cytometry were used to investigate T cell proliferation and activation in the presence of the inhibitors. We found that the levels of IL10 and sIL2R were increased in CML patient plasma compared to the levels in healthy control subjects. The level of sIL2R in a subgroup of patients was four-fold higher than the mean level of healthy controls. Patient T cells stimulated with various strong T cell stimuli including CML-specific peptides failed to respond to stimuli as measured by flow cytometric detection of the cytotoxic T cell activation marker IFNγ, indicating that these T cells might be anergic. In vitro studies on T cells from healthy donors showed that both IL10 and sIL2R have the ability to inhibit T cell proliferation. Half of the CML patients had a PDL1 expression on the CD34 cell population raging from 1-36%. PDL1 may, hence, be involved in T cell control in CML. Taken together, our results show that T cells from CML patients fail to respond to stimuli and that these T cells may be controlled by the high levels of IL10, sIL2R and PDL1 seen in the patients. Screening for these inhibitors may aid selection of patients considered for immunotherapy.

Disclosures:
Simonsson: Novartis: Consultancy, Honoraria, Research Funding, Sponsor; BMS: Consultancy, Honoraria, Research Funding, Sponsor; SCHERING-PLOUGH: Sponsor. Olsson-Strömberg:BMS: Honoraria.
Long-Term Follow-up of Patients with Chronic Myeloid Leukemia Having Received Autologous Stem Cell Transplantation.
Authors: Hackanson Bjorn W. , Waller Cornelius F 
Published: October 2019

Abstract
Abstract 4268
Before the introduction of imatinib mesylate, the median survival of chronic myeloid leukemia (CML) patients was approximately 60 months and the standard treatment with interferon-alpha (IFN-α) resulted in major cytogenetic responses of 20-25 %. As an alternative treatment approach at that time, intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) was investigated with the rational of debulking disease burden and mobilisation and transplantation of Philadelphia chromosome-negative (Ph-) stem cells. In the era of tyrosine kinase inhibitors (TKIs) as state-of-the-art therapy for CML, the concept of autoHSCT has attracted only little interest and long-term follow-up and outcome data after autoHSCT in CML patients is scarce.
In this long-term analysis, we report on 21 CML patients, mobilized in early chronic phase (ECP) and transplanted with largely Ph- grafts, who received interferon alpha (IFNα) as maintenance. Imatinib mesylate was given upon cytogenetic relapse or disease progression after IFN-α. The 10-year survival was 61% and 11 patients (52%) were alive at a median follow-up of 12.5 years (range 0.3 - 13.8) with 8 patients in complete hematologic remission (CHR) and 3 of 8 in major molecular remission (MMR). While all patients in MMR and 2 of 5 patients in CHR received imatinib, it is noteworthy that three patients remaining in CHR only received IFN-α maintenance after autoHSCT.
With the limitations of a small patient population, this is the longest follow-up analysis demonstrating that autoHSCT in CML is very efficient to debulk the disease and able to induce major and sustained molecular responses in the majority of patients with substantial long-term survival rates.

Disclosures:
Waller: Hospira UK Ltd: Consultancy.
Detection of BCR-ABL Mutations in Patients with Chronic Myeloid Leukemia Treated with Imatinib. Experience of One Centre.
Authors: Gutierrez J. Valentin Garcia , Odriozola Jesùs , Lopez Javier , Herrera Pilar , Calbacho Maria , Jimenez-Rolando Marta , Tenorio Maria , Chinea Anabelle , Garcia-Laraña Jose 
Published: October 2019

Abstract
Abstract 4280

Introduction
Imatinib (Imatinib) offers outstanding results in the treatment of chronic phase of chronic myeloid leukaemia (CML). However, there are still some patients who do not achieve an optimal response. There are several possible mechanisms both for primary refractoriness and for acquired resistance, but very often the blame falls in the appearance of ABL-kinase-domain (KD) mutations. Different mutations are related to variable degrees of resistance, ranging from the extreme refractoriness of the mutation T315I down to some which appear to have no clinical significance.

Aims
To define the clinical characteristics and outcome of patients treated in our centre, in which ABL-kinase-domain mutations through direct DNA sequencing have been analysed.

Results
In 24 of a total 86 patients, KD mutations were looked for. Screening for mutations was undertaken for one of three reasons: at diagnosis in 6 patients, suboptimal response (Leukemia-Net criteria) in 10 cases and Treatment-Failure (LN criteria) in 8 cases. Median time from diagnosis to ABL mutation detection was 38 months. No risk factors at diagnosis for the appearance of KD mutations have been found. Of the 7 mutations, 5 cases corresponded to treatment failures and 2 to patients in so-called suboptimal responses. One patient, after achieving a complete response to Imatinib, developed a T315I KD mutation and died due to blastic crisis despite having received second generation TKI. Another patient in failure (mutation G250E) achieved a molecular response with dasatinib. No mutations were found in 6 patients checked before treatment, but one of these developed a mutation G250E after 18 months, along with the criteria of a suboptimal response and achieved a mayor molecular response with dasatinib.

Conclusions
KD mutations are found in a proportion of patients in the situation of suboptimal response or failure to IM, more frequently in the latter in our experience, but the clinical significance of some of them is still unclear. On the contrary, DNA sequencing for screening at the moment of diagnosis offers little relevance in chronic phase CML.

Disclosures:
No relevant conflicts of interest to declare.
Anti-CD25 instead of ATG for the Conditioning of HLA-Mismtched Hematopoietic Stem Cell Transplantation.
Authors: Wang Jun , Meng Qingxiang , Guo Nailan 
Published: October 2019

Abstract
Abstract 4315

Purpose
To analysis the effect of Anti-CD25 instead of ATG for the conditioning of HLA-mismatched hematopoietic stem cell transplantation (HSCT).

Methods
21 cases underwent HLA-mismatched HSCT in our hospital from Mar. 2006 to May 2009. Diagnosis included ANLL(n=9)(2 in CR,7 in Relapse)?ALL(n=2), AHL(n=2), CML(n=4), MDS (n=2) and SAA (n=1), HLA Typing : All patients receive transplants from HLA-mismatched related donors. Among whom, 1,2 and 3 antigen mismatched were 11,8 and 2 cases respectively. Conditioning regimen consisted of modified BU/CY (n=12), BU/CY (n=6), FLU/BU (n=2) and CY/ATG for SAA(n=1). In addition, ATG(Thymoglobuline, 5-7.5mg/Kg, iv, divided into three days, -8∼-6d) was given for 8 patients. Anti-CD25 was given for 13 patients, including Daclizumab (50mg/d, -1?,03?,+4?,+11d) for 7 patients and Basiliximab (20mg/d, -1?,02?,+2?,+7d) for 6 patients. GVHD prophylaxis consisted of CSA and short course of MTX. In addition, MMF was given in all patients at the dosage 1.0 g/d for one month. The donors were given granulocyte colony-stimulating factor (G-CSF) at a dosage of 5 μg/Kg.d subcutaneously for 5 days, bone marrow was collected on day 3, peripheral blood stem cells were collected at day 4 and 5.

Results
Engraftment was obtained in all 21 patients, the median time to WBC >0.5×109/L and BPC>20×109/L in ATG and Anti-CD25 group were 14, 13d and 13, 12d, respectively (p>0.05), I∼II aGVHD accurred in 3 cases(37.5%) in ATG group and 5 cases(23.1%) in Anti-CD25 group,III∼IV aGVHD was observed in 1 case (12.5%) in ATG group and 2 cases (15.3%) in Anti-CD25 group. cGVHD was evaluable in 14 patients who survived after day +100, Extensive cGVHD developed in 1 (20%) of 5 patients in ATG group, and in 4 (44%) of 9 patients in Anti-CD25 group. Daclizumab and Basiliximab were not cause any infusion-related toxicity. Up to now, 13 patients survived in complete remission follow up 3-59 months, 4 cases (50%) died (3 in TRM and 1 in relapse) in ATG group, 4 cases (30.7%) died (1 in TRM and 3 in relapse) in Anti-CD25 group.

Conclusion
The replacement of ATG with Anti-CD25 seems to be more safety and effective for the conditioning of HLA –mismatched HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.
Authors: Benakli Malek , Ahmed nacer Redhouane , Talbi Amina , Belhadj Rachida , Mehdid Farih , Rahmoune Nadia , Harieche Farida , Abderahmani Soumeya , Saidani Keltoum , Akhrouf Sabrina , Boumansour Faiza , Zerhouni Fatiha , Hamladji Rose-Marie 
Published: October 2019

Abstract
Abstract 4326

Background
Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT.

Patients and methods
Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6).

Results
Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively.

Conclusion
This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions.

Disclosures:
No relevant conflicts of interest to declare.
Sirolimus for Graft-Versus-Host-Diseases Prophylaxis in Non-Myeloablative Matched Related Transplantation: Safety and Efficacy.
Authors: Zheng Hong , Carraher Michelle , Schaefer Eric , Talamo Giampaolo , Ehmann W. Christopher , Rybka Witold , Claxton David F. 
Published: October 2019

Abstract
Abstract 4329
The use of sirolimus (rapamycin) as an immunosuppressive agent after allogeneic hematopoietic transplantation is appealing given its antitumor and tolerance-inducing properties. Its safety and efficacy have been studied but are not completely understood in this patient population. We have compared GVHD prophylaxis with sirolimus together with early withdrawal of concomitant tacrolimus to standard tacrolimus in 49 patients receiving non-myeloablative transplant from matched related donors. All patients received identical conditioning with Cyclophosphamide 1g/m2 days –7 and –6 and Fludarabine 25mg/m2 days –7 through –3. Twenty-three patients received standard GVHD prophylaxis with methotrexate and tacrolimus. Twenty-six patients received methotrexate, sirolimus, with tacrolimus tapering over 15 days beginning day 20 or 30. Overall survival (OS) was similar in sirolimus and no sirolimus groups (median 526 vs 723 days, p=0.77). Similarly progression-free survival (PFS) was comparable (median 300 vs 382days p=0.78). Full chimerism was achieved in 73% patients received sirolimus vs. 58%patients received no sirolimus by day 100 (p=0.46). Chimerism was similar in the two groups at all time points examined. Toxicities including microangiopathy (MA), hypertriglyceremia and nephrotoxicity were analyzed. In patients receiving sirolimus MA developed in 2/26(8%) vs. in 1/23(4%) patients receiving no sirolimus (p=0.28). Creatinine >3mg/dl was seen in 6/26 (23%) patients receiving sirolimus vs. 6/23 (26%) patients receiving no sirolimus (p=0.47). In contrast the incidence of hypertriglyceremia (>500mg/dl) was significantly higher in the sirolimus group (10/26, 38% vs 2/23, 9% p<0.01). Hypertriglyceremia was however easily treated with anti-lipid agents, and no patient developed significant pancreatitis or other complications. The incidence of grade II-IV acute Graft versus host disease (GVHD) was modestly higher in the sirolimus (9/26, 35%) vs no sirolimus group (2/23, 9%), (p=0.0418). This acute GVHD occurred late at 60-100 days, more than 2 weeks after discontinuation of tacrolimus. Chronic GVHD was similar between patients receiving sirolimus and no sirolimus (15/26, 58%, vs. 9/23, 39%; p=0.25), as was transplant related mortality (3/26, 12%, vs. 4/23, 17%; p=0.69). Although sample size is limited, our data suggest that replacing tacrolimus early with continued sirolimus may be associated with modest increases in aGVHD. In our patients there is however little to suggest a negative impact on survival and engraftment. Other toxicities of sirolimus are minimal. Whether the early substitution of sirolimus for tacrolimus post transplant yields improved tumor control must await results of larger studies in specific tumor types.

Disclosures:
Off Label Use: Sirolimus for GVHD prophyllaxis.
Long Term Results of High-Dose Melphalan and Autologous Stem Cell Transplantation in Non-Amyloid Monoclonal Immunoglobulin Deposition Disorders.
Authors: Girnius Saulius , Seldin David C. , Quillen Karen , Finn Kathleen T. , Andrea Nancy T. , Sloan John Mark , Sanchorawala Vaishali 
Published: October 2019

Abstract
Abstract 4356
Monoclonal Immunoglobulin Deposition Disorder (MIDD) is a plasma cell dyscrasia in which whole immunoglobulins or heavy or light chain subunits form non-fibrillar deposits in various tissues, causing organ dysfunction. Several studies have previously reported that high dose melphalan and autologous stem cell transplantation (HDM/SCT) is safe and effective at achieving a complete hematologic response in this disease, but long term data is sparse. Hematological complete response is defined as normalization of serum free light chain ratio and concentration, bone marrow exam with less than 5% plasma cells, and absence of monoclonal gammopathy in serum and urine by immunofixation electrophoresis. Between 2003 and 2008, ten patients with MIDD were treated with HDM/SCT at a dose of 200mg/m2 (n=6) or 100-140 mg/m2 (n=4) depending upon age and clinical status and were assessed for hematologic responses and improvements in organ function at 3-6 and 12 months, and annually thereafter. The median age was 45 years (range, 34 to 70); all but one patient were male. Six patients had kappa clonal predominance and four patients had lambda clonal predominance. All ten patients had renal involvement, two were on dialysis and one had undergone a renal transplant. Two patients also had extrarenal manifestations with cardiac involvement. The median creatinine clearance was 26 mL/min (range 20 to 100) and the median 24 hour urine total protein excretion was 4,037 mg (range, 458 to 15,632). Peripheral blood stem cells were collected after GCSF mobilization and a median of 6.9 ×106 CD34cells/kg were collected. There was no treatment related mortality within 100 days of SCT. One patient developed end stage renal disease during the peri-transplant period. Of the seven patients who have had follow-up of at least a year, five (71%) achieved a complete hematological response (CR) and two (29%) had a partial hematological response. One patient died six months after HDM/SCT due to progressive disease. Clinical and organ responses were also evident after HDM/SCT in 5 out of 7 patients. The median creatinine clearance was 42 mL/min (range, 38-55) and the median 24 hour urine total protein excretion was 179 mg (range, 150 to 349) at 2 years after treatment. Of the five patients with hematologic CR, 3 (60%) have relapsed at a median of 3 years (range, 2-3). Two of the 5 patients continue to have hematologic CRs at four and six years after HDM/SCT. In summary, HDM/SCT in MIDD often results in hematological CRs, as well as an improvement in renal function. However, the 5-year relapse rate is high. This group of patients may benefit from maintenance anti-plasma cell therapy.

Disclosures:
No relevant conflicts of interest to declare.