bluuebunny/crossref_metadata_2025_split huggingface dataset:
PR1 Vaccine Elicited Immunological Response after Hematopoietic Stem Cell Transplantation Is Associated with Better Clinical Response and Event-Free Survival.
Authors: Qazilbash Muzaffar H. , Wieder Eric D. , Thall Peter F. , Wang Xuemei , Rios Rosa L. , Lu Sijie , Kant Shreya , Giralt Sergio A. , Estey Elihu H. , Cortes Jorge , Komanduri Krishna , Champlin Richard E. , Molldrem Jeffrey J. 
Published: October 2019

Abstract
Background: PR1 peptide has been established as a human myeloid leukemia-associated antigen. We studied PR1 peptide vaccine in a phase I/II clinical trial in HLA-A2 + patients with AML, MDS and CML. To address whether prior HSCT or prior use immunosuppressive drugs would prevent PR1-induce cytotoxic T lymphocyte (PR1-CTL) immunity after vaccination with PR1 peptide vaccine, we studied the outcome in 20 patients with a prior HSCT, who were treated on the PR1 vaccine trial.
Methods: Twenty patients (13 with AML or MDS, 7 with CML) were vaccinated at a median time of 9.5 months (range: 1–220) after HSCT. Sixteen patients had received a prior allogeneic HSCT (12 had allogeneic related, 3 had allogeneic unrelated, and 1 had syngeneic) and 4 patients had a prior autologous HSCT. At the time of vaccination, 5 patients were in CR, and 15 had measurable disease. Patients could not receive systemic immunosuppressive therapy for at least 4 weeks prior to vaccination, and had to be free of acute or chronic GVHD requiring systemic therapy. The vaccine was given subcutaneously every 3 weeks for a total of 3 injections at one of three dose levels: 0.25, 0.5 and 1.0 mg. GM-CSF at a dose of 75 mg was injected subcutaneously into the same site. Immune response to the vaccine (IRV) was defined as > 2-fold increase in PR1-CTL by PR1/HLA-A2 tetramer assay.
Results: After a median follow up of 56.5 months (range: 27–89), toxicity was limited to grade I/II injection site reactions in 7 (35%) patients. IRV were observed in 11/20 (55%) patients. Nine of 11 (82%) IRV+ patients versus 1 of 9 (11%) IRV- patients had clinical responses (p = .005). Median event-free survival (EFS) was 23.8 months in IRV+ patients versus 1.9 months in IRV- patients (p=0.03). Median overall survival (OS) in IRV+ patients has not yet been reached vs. 40 months in IRV- patients (p = 0.08). Only 2 patients with pre-existing, limited chronic GVHD experienced a mild exacerbation within 3 months of vaccination, which was controlled with topical steroids. PR1-CTL were enriched in central memory phenotype (TCM) that persisted up to 4 years in clinical responders. Univariate and multivariate Cox proportional hazards analyses showed a low pre-vaccine bone marrow blast count (<10%) was associated with a lower risk of progression (p=0.001 and 0.001, respectively). Type of HSCT, interval between HSCT and PR1 vaccine, PR1 dose level and disease status at HSCT did not have a significant impact on EFS or OS.
Conclusion: PR1 vaccine produced PR1-CTL in 11/20 (55%) patients after HSCT. IRV was associated with significantly better clinical response and longer EFS.
Figure Figure
Minimal Residual Disease Detected Prior to Transplantation Is Associated with Adverse Outcome in Pediatric Acute Lymphoblastic Leukemia.
Authors: Foster Jennifer H , Woolfrey Anne , Wood Brent , Thomson Blythe 
Published: October 2019

Abstract
Background: Acute lymphoblastic leukemia (ALL) is the most common form of malignancy in children. Advances in treatments have made ALL the disease highly curable; however for those patients who relapse, hematopoeitic stem cell transplantation (HSCT) offers a reasonable chance of cure. Minimal residual disease (MRD) detection by Multiparametric Flow Cytometery (MPF) is being used for risk adapted treatment decisions in many ALL trials. We present a series of 31 pediatric ALL patients who had morphologic and MPF evaluation of disease burden prior to ablative HSCT.
Methods: Thirty one patients were treated at Children’s Hospital and Regional Medical Center, Seattle, WA for relapsed or very high risk ALL, were in complete morphologic remission, and received an ablative HSCT from May 2006-May 2008. Twelve patients were in second or third complete remission (CR) and 19 were in first CR. Eleven patients received a matched related donor, 20 patients received a unrelated donor graft. All patients underwent marrow evaluation including morphology and MPF within four weeks of their transplant date. The MPF was done by 7 or 9 color flow cytometry using the following reagents for B lineage: CD10, CD19, CD20, CD34, CD38, CD58 and CD45 and for T lineage: CD2, CD3, CD4, CD5, CD7, CD8, CD34, CD56, and CD45. Transplant regimens were total body irradiation-based (1320 cGy) with either cyclophosphamide (n=24) or fludarabine (n=6). MRD+ was any detectable leukemia >0.01% of cells. All patients were in morphologic remission (< 5% blasts) at time of transplant. Events were defined as relapse or deaths.
Results: 21 patients were MRD-, 10 were MRD+. The 2 year event free survival (EFS) for the entire group was 56% (+/−22%). The EFS at 20 months for those patients in CR1 and CR2/3 were 62% (+/−32%) and 40% (+/−32%), respectively. EFS, relapse risk and non relapse mortality was analyzed with respect to MRD status:
MRD+ (n=10) MRD- (n=21) p value EFS 36% (+/−32%) 68% (+/−26%) 0.037 Relapse Risk 48% (+/−36%) 13% (+/−16%) 0.036 Non-relapse Mortality 30% (+/−36%) 23% (+/−26%) 0.45
Discussion: We present a single institution series of patients treated for high risk or relapsed ALL who underwent disease evaluation prior to HSCT with MPF. With the small number of patients evaluated, it appears that any amount of disease detected by MPF was an adverse risk factor for recurrence. Those patients who were MRD+ experienced a higher risk of death from relapse, however, experienced no difference in non-relapse mortality. Resistant disease as detected by MRD analysis at time of transplant is a marker for poor outcome.
Allogeneic Stem Cell Transplantation for Patients with Chemo-Refractory or Progressive Aggressive Non-Hodgkin’s Lymphomas.
Authors: Hamadani Mehdi , Blum Kristie A. , Elder Patrick , Lin Thomas S , Porcu Pierluigi , Hofmeister Craig C. , Blum William , Marcucci Guido , Benson Don , Devine Steven 
Published: October 2019

Abstract
Background: Patients (pts) with chemo-refractory (Cref) and/or progressive aggressive non-Hodgkin’s lymphomas (A-NHL) generally have a poor clinical outcome. Autologous stem cell transplantation (SCT) has limited efficacy in this setting. Studies reporting outcomes of allogeneic (Allo) SCT in pts with Cref A-NHL are limited.
Methods: 108 pts with A-NHL underwent Allo-SCT between 1988 and 2007 at our institution. 46 A-NHL pts with Cref (i.e pts with <50% reduction in tumor size and/or persistent bone marrow involvement following chemotherapy) or progressive disease (PD) by CT-criteria were eligible for this analysis. Positron emission tomography (PET) or PET/CT scans were not performed to assess response.
Results: The median age was 46 years (range 22–63 yrs). 39 pts received matched sibling allografts, while 7 underwent unrelated donor SCT. All except 3 pts received myeloablative conditioning. 38 pts received BU/CY-based conditioning, while BEAM (n=5) or Flu/Bu (n=3) was employed in the remaining pts. Diagnosis included diffuse large B-cell lymphoma (n=18), Burkitt’s lymphoma (n=3), transformed lymphoma (n=5), mantle cell lymphoma (n=11) and T-cell lymphomas (n=9). The median number of prior therapies was 3 (range 1–8). 32 pts had Cref disease, while 14 had PD. 41 pts had stage III/IV disease, 23 had elevated LDH, while 36 had extranodal involvement. Median follow-up of surviving pts following Allo-SCT is 5-yrs. The 5-yr overall survival (OS), progression free survival (PFS), and relapse rate for the whole cohort (n=46) was 38%, 34%, and 35% respectively. Rate of grade II-IV acute graft-versus-host disease (GVHD) was 43% (n=20). Among the 33 evaluable pts rate of chronic GVHD was 75%. Overall non-relapse mortality rate was 37%. No significant difference in the baseline characteristics of pts with Cref and PD was present. The 5-yr OS and PFS rates for pts with Cref and PD were 46% vs. 21% (p-value=0.01; log-rank test), and 46% vs. 7% (p-value=0.0002; log-rank test) respectively. On multivariate analysis only PD at the time of SCT predicted for worse OS and PFS.
Conclusion: Our study shows encouraging efficacy of Allo-SCT in a group of A-NHL pts with Cref disease by CT scan-criteria who often fail following Auto-SCT. However outcomes of pts with PD remain dismal despite Allo-SCT, and our data question the practice to perform allografting in A-NHL pts with PD. We hypothesize that PET scans may help better define patients with aggressive NHL appearing not to have responded to salvage chemotherapy by standard CT criteria that still may derive significant benefit from allografting.
Haploidentical Hematopoietic Stem Cell Transplantation in Children Leukemia and Lymphoma with G-CSF Mobilized Marrow Grafts without T Cell Depletion: A Single Center Report of 45 Cases.
Authors: Wang HengXiang , Yan Hong-Min , Duan Lian-Ning , Zhu Ling , Xue Mei , Liu Jing 
Published: October 2019

Abstract
Haploidentical hematopoietic stem cell transplantation (Haplo-SCT) has been increasingly used in the treatment of patients with hematopoietic malignancies without immediate HLA-matched donors. Here, we describe a protocol for the management of hematopoietic malignances in children and adolescents who received T cell replete G-CSF-mobilized bone marrow grafts from HLA-mismatched parents. The donors were administered G-CSF for 7 consecutive days before marrow grafts containing a medium nucleated cells of 8.1×108/kg (range: 6.1–11.5×108/kg) were collected. 45 patients were pre-conditioned with high-doses of cytarabine and cyclophosphamide plus total body irradiation or BU for chronic myeloid leukemia patients. The regimen for acute graft versus host disease (aGvHD) prophylaxis included antithymocyte globulin, monoclonal antibody against CD25 (Simulect), CsA, MTX and mycophenolate mofetil. Three of forty-five patients died of engraftment failure, multiple organ failure and TTP, others achieved complete donor chimerism with the medium days for neutrophil (>0.5′109/L) and platelet recovery (>20′109/L) were 17(12–23 days) and 19(12–27days). Of the 42 evaluable patients, 3 cases developed grade III/IV aGvHD, and 9 of 32 cases who survived longer than 3 months developed chronic GvHD. Twenty-one patients died within a medium follow-up of 36 months(24–63 months), including 2 of transplantation related death, 11 of leukemia relapse, 4 of CMV and fungal infections, and 2 of aGvHD and 2 cases died of other reasons. The disease-free survival rate was 53%. Multivariate analysis demonstrated that the overall survival was not significantly reduced in refractory leukemia and seemed not associated with the mismatch numbers of HLA loci. These results indicate that T cell replete SCT with mobilized bone marrow from HLA-2 or -3-antigen mismatched parents could be an optional strategy for children with hematopoietic malignancies who lack immediate access to a HLA-matched stem cell source.
Epigenetic Regulation of the WNT Canonical Pathway in Mantle Cell Lymphoma.
Authors: Peters Anthea C , Chung Randy , Wong Charles S , Young Leah C , Reiman Tony , Lai Raymond 
Published: October 2019

Abstract
Dysregulation of the WNT signalling pathway is an important event in the pathogenesis of several types of cancer, including colon cancer and acute leukemia. When a WNT protein binds to its receptor, glycogen synthase kinase (GSK)-3β is inactivated by phosphorylation (i.e. pGSK-3β) allowing β-catenin to accumulate in the nucleus and promote transcription of proliferative genes. Conversely, a protein complex that includes GSK-3β initiates destruction of β-catenin if no WNT protein binds its receptor or if an antagonist interferes with WNT ligand-receptor interaction. We previously demonstrated that the WNT canonical pathway is often constitutively active in mantle cell lymphoma (MCL), a subtype of B-cell non-Hodgkin lymphoma. We showed that GSK-3β is phosphorylated, thus inactive, in two-thirds of MCL cases, and that a high level of pGSK-3β correlates with both β-catenin expression and poor patient survival. In order to elucidate the mechanisms of constitutive WNT signalling in MCL, we investigated the RNA expression of six WNT pathway antagonists including WIF-1 using fresh tumour samples and three types of cultured MCL cells. In vivo WIF-1 expression was abundant only in tumours shown to lack pGSK-3β expression. We also examined the regulation of these WNT antagonists by promoter methylation by treating cultured cells with demethylating agent 5-aza-2’-deoxycytidine. The WNT pathway inhibitors were often negatively regulated in MCL-derived cell lines by epigenetic DNA methylation; inhibitors that were not expressed at baseline showed expression after demethylation treatment in at least one MCL cell line. Methylation-specific PCR confirmed that the promoter region of WIF-1 was methylated in almost half of MCL tumour samples. Our data demonstrates that in MCL several antagonists of the canonical WNT pathway are negatively regulated by promoter methylation, thereby allowing aberrant WNT pathway activation. This data confirms that WNT signalling is important in MCL pathogenesis, and identifies potential therapeutic targets for MCL.
Synergistic Pre-Clinical Activity of Combined Epigenetic Therapy with the Novel Histone Methyltransferase EZH2 Inhibitor 3-Deazaneplanocin and Histone Deacetylase Inhibitor Panobinostat against Human AML Cells.
Authors: Fiskus Warren , Wang Yongchao , Jillella Anand , Ustun Celalettin , Johnston Pace , Joshi Rajeshree , Rao Rekha , Ataja Peter , Marquez Victor , Bhalla Kapil N. 
Published: October 2019

Abstract
Lysine specific histone methylation and deacetylation and DNA hypermethylation are involved in the epigenetic silencing of tumor suppressor genes (TSG), e.g., p15 and p16. The multi-protein complex PRC (polycomb repressive complex) 2 that contains the three core proteins EZH2, SUZ12 and EED, has intrinsic histone methyltransferase (HMTase) activity. This is mediated by the SET domain of EZH2, which induces tri-methylation (3Me) of lysine (K)-27 on histone H3, regulates the expression of HOX genes and promotes cell proliferation and aggressiveness of neoplastic cells. In the present studies we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) dose-dependently (200 nM to 2.0 uM) depletes EZH2, SUZ12 and EED levels, inhibits 3Me K27 on H3 while inducing K27 H3 acetylation in the cultured human AML HL60 and OCI-AML3 cells and in primary, patient-derived AML blasts. DZNep treatment also induced the levels of p16, p21, p27 and FBXO32 while depleting cyclin E and HOXA9 levels. Treatment with DZNep induced PARP cleavage activity of the caspases and apoptosis in the cultured and primary AML cells. DZNep promoted proteasomal degradation of EZH2 and SUZ12, since co-treatment with bortezomib significantly restored EZH2 and SUZ12 levels in the AML cells. We had previously reported that treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) (LBH589, Novartis Pharmaceutical Corp) also depletes the levels of EZH2, SUZ12 and EED in cultured and primary AML cells (Mol Cancer Ther.2006; 5:3096). Within the PRC2 complex, EZH2 bound and recruited the DNA methyltransferases DNMT1, and treatment with PS also disrupted the interaction of EZH2 with DNMT1, attenuated DNMT1 levels and its binding to the EZH2-targeted gene promoters, e.g., p16 and JunB. Here, we also demonstrate that, as compared to treatment with either agent alone, co-treatment with DZNep and PS caused more depletion of EZH2, SUZ12 and EED, more induction of p16, p21 and p27, as well as synergistically induced apoptosis of AML cells (combination indices < 1.0). Additionally, DZNep induced apoptosis of HL-60/LR cells that are resistant to HDACs including PS, as well as sensitized HL-60/LR cells to PS. Taken together, these findings indicate that targeting EZH2 and the PRC2 complex is an effective epigenetic therapy of AML that also overcomes resistance to HDAC inhibitors. Additionally, combined epigenetic therapy with DZNep and PS exerts synergistic in vitro activity against human AML cells, suggesting that this combination may be a promising novel treatment for AML.
Haploinsufficiency of Ebf1 Collaborates with BCR-ABL1 to Decrease the Latency of Acute Lymphoblastic Leukemia.
Authors: Goorha Salil , Lenny Noel T. , Miller Christopher B , Perry S. Scott , Su Xiaoping , Williams Richard T , Mullighan Charles G , Downing James R. 
Published: October 2019

Abstract
In previously published genome-wide copy number analysis of leukemic samples from 242 pediatric acute lymphoblastic leukemia (ALL) patients, we reported that mutations in genes regulating B lymphoid development are the most common lesion in B-progenitor ALL, and these include PAX5, IKZF1, and EBF1. Mono-allelic deletion of EBF1 was observed in 8/200 B-progenitor leukemia samples, including a BCR-ABL1 ALL. EBF1 encodes a transcription factor that is required for the development of B cells, and with E2A regulates the expression of B-lineage specific genes. Mice null for Ebf1 arrest B cell development at the pro-B cell stage, whereas Ebf1+/− mice have a 50% reduction in the number of immature and mature B cells but a normal number of pro-B cells. Importantly, neither haploinsufficiency nor the complete loss of Ebf1 results in the development of leukemia in mice. To examine the role of genetic alterations targeting B-lymphoid differentiation in the pathogenesis in BCR-ABL1 ALL, we transduced Ebf1+/+ and Ebf1+/− bone marrow cells with MSCV-GFP-IRES-p185 BCR-ABL1 retrovirus and transplanted the resultant cells into lethally irradiated wild-type C57BL6 recipient mice. Mice transplanted with BCR-ABL1 Ebf1+/− cells developed B lineage ALLs at a shorter latency than observed with BCR-ABL1 Ebf1+/+ cells (median overall survival of 17 days in Ebf1+/− vs 42 days in Ebf1+/+, P<0.0001). All leukemias had a B220+Cd19+Bp1+ pre-B cell immunophenotype; however, the leukemias that developed from the Ebf1+/− cells aberrantly expressed high levels of the stem cell marker Sca1 (mean fluorescence level for Sca1 of 69.6 in Ebf1+/− (n=22) vs 16.8 in Ebf1+/+ (n=14), p<0.0001). To begin to understand how a decrease in the copy number of Ebf1 may contribute to leukemogenesis, we examined early B cell development in bone marrow (BM) cells from two week-old C57BL6 Ebf1+/− and Ebf1+/+ mice. Our analysis confirmed previous reports indicating a 2-fold reduction of B220+CD43− B cells in Ebf1+/− compared to Ebf1+/+ mice. Interestingly, however, we also detected an approximately 6-fold increase in a transitional population of B220loIL-7R+cKitlo Pre-pro B cells that also expressed Sca1 (2194 mean number of Ebf1+/− cells per 100,000 BM cells (n=10) vs 372 mean number of Ebf1+/+ cells per 100,000 BM cells (n=8), p<0.0001), an observation that raises the possibility that Ebf1 haploinsufficiency expands the pool of cells that are susceptible to transformation by BCR-ABL expression. It will be important to examine whether the accelerated tumorigenesis resulting from Ebf1 haploinsufficiency is a consequence of a subtle shift in differentiation, or some alternative mechanism of oncogenic cooperativity. Studies are underway to directly assess the role of B220loIL-7R+cKitlo Sca1+ cells in BCR-ABL1 driven ALL.
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin- Free Method] Post-Authorization Safety Surveillance (PASS): Safety and Efficacy Following Product Switch in Routine Clinical Practice.
Authors: Luu Huong , Spotts Gerald , Gajek Hartwig , Kriukov Alex , Berg Roger , Stephens Darby , Barker Kerry , Ewenstein Bruce M. 
Published: October 2019

Abstract
A prospective, non-interventional Post-Authorization Safety Surveillance (PASS) program was initiated in 2004 to document ADVATE safety and efficacy in routine clinical practice. More than 900 subjects newly prescribed ADVATE have been enrolled in the US, EU and Japan alone. Herein, we present final US and interim EU results comprising 506 treated subjects, 451 of which have completed the 1-year observation period and 20 ongoing. Age cohorts were as follows: 27 neonates/infants (0-<2 years), 128 children (2-<12 years), 54 adolescents (12-<16 years), and 285 adults (≥16 years); 12 with age unreported. At study entry, 61 patients were considered previously untreated (PUP) or minimally treated (MTPs) defined as ≤50 previous exposure days [EDs]); 437 subjects were considered previously treated patients (PTPs) (>50 previous EDs). Eight subjects had unknown exposure history. Twenty-nine PUPs/MTPs reported exact exposure history prior to ADVATE: 5 reported 0 ED; 7 reported 1 to 3 EDs; and 17 reported 4 to 50 EDs. Most study subjects had FVIII ≤2%; 46 of which were PUPs/MTPs and 389 were PTPs. Among PTPs with FVIII ≤2%, 331 had no known history of inhibitor; 58 reported having a history of inhibitor prior to receiving ADVATE. At enrollment, 58% of subjects were prescribed prophylaxis, while 42% were treated on-demand. A total of 4848 bleeds in 343 subjects were treated. The on-demand efficacy was rated only as excellent/good in 94% of subjects. Subjects who were prescribed ADVATE prophylaxis (N=291) received a mean of 3 infusions per week at 29 IU/kg/ infusion. The median annual bleed rate on prophylaxis was 2.4 bleeds per year. Prophylactic efficacy assessments were provided for 268 subjects; 92% received only excellent/good ratings. Similar efficacy results were seen for the various populations with or without history of inhibitor. No unusual or unexpected AEs were seen in the study. One de novo, low-titer (1.4 BU), transient inhibitor was reported in 331 PTPs with FVIII ≤2% and no prior inhibitor history, providing a de novo inhibitor incidence estimate of 0.3% (95% CI, 0.01% – 1.67%). Two recurrent, low-titer inhibitors (≤1.5 BU) were reported in PTPs with FVIII ≤2%. One de novo, high-titer and 1 de novo, low-titer inhibitor were reported in PTPs with FVIII >2%. Two high-titer inhibitors were reported among 61 PUPs/MTPs. Other SAEs included 1 headache, 2 allergic reactions, 1 ineffective drug response in a subject with inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Results from the US and EU PASS registries validate the ADVATE safety and efficacy profile in the general hemophilia A population, in real-world clinical settings. Consistent with the formal clinical study findings ADVATE continues to demonstrate low risk for inhibitor development in PTPs.