bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic HSC Transplantation for Multiple Myeloma: A Single Institution Experience.
Authors: Costa Luciano J. , Kumar Shaji , Dispenzieri Angela , Hayman Suzanne E. , Buadi Francis K. , Litzow Mark R. , Gertz Morrie A. , Lacy Martha Q. 
Published: October 2019

Background: Despite development of new therapies and advances in autologous hematopoietic stem cell transplantation (HSCT), MM remains, for the most part, an incurable condition. Allogeneic HSCT, through induction of a graft-versus-myeloma effect, can potentially overcome resistance to conventional therapy and induce prolonged disease control. Such approach is limited by the risk of acute and chronic GVHD and the high treatment-related mortality and has been restricted to young patients with aggressive or refractory disease. We reviewed our experience with allogeneic HSCT at Mayo Clinic, Rochester, MN.
Methods: Retrospective single-institution review of consecutive allogeneic transplants performed for multiple myeloma between 1991 and 2006.
Results: Thirty-three patients underwent a myeloablative (52%) or reduced-intensity conditioning (48%) HSCT 3.2 months to 15 years after their diagnosis of multiple myeloma (n=31) or plasma cell leukemia (n=2). Median age at the time of HSCT was 48 years (range 33–61) and 19 patients (57%) had received one (n=12) or two (n=7) prior autologous HSCT. Donors were HLA-matched siblings in 25 cases (76%), matched unrelated (n=8), and 5/6 (n=1) and 6/6 (n=1) match, non-sibling family members. Source of HSC was peripheral blood exclusively in 21 (64%) and bone marrow in 12 (35%) transplants. Outcomes are being reported after a median follow up of 21.8 months (25.6 for survivors). Day+100 mortality was 21.2% and the incidences of any grade and grades 3/4 acute GVHD were 54.5% and 33.3% respectively. Among the 26 patients surviving beyond day+100, 57.7% developed chronic extensive GVHD. All 6 patients transplanted after a complete response (CR) to prior therapy remained so after the transplant. Of the 27 patients with measurable disease, disease reassessment could be performed for 20 after the transplant. Ten patients (50%) achieved a CR or near-CR and 8 patients (40%) obtained a partial response. Median time to progression and overall survival (Figure) after HSCT were 21.8 and 40.6 months respectively. Twenty-one patients have died, 10 as a consequence of disease progression. Twelve patients are alive, including 6 patients in CR, 8.3 to 172.7 months after the transplant. In a multivariate model the use of a non-sibling donor and peripheral blood HSC were associated with decreases risk of relapse, but had no effect on overall survival.
Conclusion: Allogeneic HSCT is a feasible treatment for young patient with adverse disease features. Graft-versus-myeloma can induced myeloma eradication and prolonged disease control.
Figure Figure
Efficacy of Allogeneic Stem-Cell Transplantation for T/NK-Cell Lymphomas in Adults.
Authors: Le Gouill Steven , Milpied Noel-Jean , Buzyn Agnes , de la Tour Regis Peffault , Vernant Jean-Paul , Mothy Mohamad , Ifrah Norbert , Bouabdallah Krimo , Bulabois Claude-Eric , Dupuis Jehan , Rio Bernard , Attal Michel , Yakoub-Aga Ibrahim , Tournilhac Olivier , Gratecos Nicole , Blaise Didier , Volteau Christelle , Michallet Mauricette 
Published: October 2019

Abstract
Mature peripheral T/Natural killer (NK)-cell neoplasms represent 10–15% of non-Hodgkin’s lymphoma (NHL) in adults. T/NK-NHL have a worst prognosis compared with B-cell lymphomas. Allogeneic stem cell transplantation (allo-SCT) is an attractive option for these patients. On behalf of the SFGM-TC group, we conducted a retrospective analysis and included seventy-seven T/NK-cell lymphoma patients. Diagnosis were: ALCL (n=27), Peripheral T-cell Lymphoma Not-Otherwise Specified (PTCL-NOS) (n=27), Angioimmunoblastic T-cell Lymphoma (AITL) (n= 11), Hepatosplenic g/d lymphoma (HSL) (n=3), T-cell granular lymphocytic leukemia (T-GLL) (n=1), nasal NK/T-cell lymphoma (nasal-NK/L) (n=3) case or non-nasal NK/T-cell lymphoma (non nasal-NK/L) (n=2), enteropathy-Type T-cell (n=1) and HTLV-1 lymphoma (n=2). Fifty-seven patients received myeloablative conditioning regimen prior allo-SCT. Donors were HLA-matched in 70 cases and related in 60 cases. Patients status at the time of allo-SCT was CR in 31 cases, PR in 26 cases and SD/PD in other cases. Five-year toxicity-related mortality (TRM) rate was 34%. Major cause of death was infection. Five-year OS and EFS rates were 57% and 53.3%, respectively. In a multivariate analysis, chemoresistance disease (SD, refractory or progressing disease at the time of allo-SCT and aGVHD grade III/IV were the only adverse prognostic factors for OS (p= 0.027 and p=0.033, respectively). Disease status at transplantation influenced EFS (p= 0.0032) and a HLA-mismatched donor increased TRM (p= 0.0386). A plateau was reached after one and a half year after allo-SCT. Only 5 out of 59 patients in CR after allo-SCT experienced a relapse. The 5-year OS rate for chemo-resistant patients was also encouraging. These patients were not curable with conventional approaches and near of one third have taken advantage of allo-SCT. Furthermore, two patients received DLI at relapse and they both reached a second durable CR. Taken together, this suggests that there is a graft versus T-/NK-lymphoma effect which may play a role in the curative potential of allo-SCT. we conclude that randomized clinical trials comparing allo-SCT versus conventional chemotherapy upfront for PTCL, aggressive AITL or histopathological subtypes (HSL, HTLV-1 lymphomas) have to be encouraged.
Effect of HLA-Matching on Outcome of Hematopoietic Stem Cell Transplantation from Unrelated Donors: A IBMDR-GITMO Study.
Authors: Crocchiolo Roberto , Ciceri Fabio , Oneto Rosa , Bruno Barbara , Pollichieni Simona , Sacchi Nicoletta , Sormani Maria Pia , Fanin Renato , Bandini Giuseppe , Bosi Alberto , Rambaldi Alessandro , Alessandrino Paolo Emilio , Falda Michele , Bacigalupo Andrea 
Published: October 2019

Abstract
Background HLA-matching between patient and donor is critical for outcome of haematopoietic stem cell transplantation (HSCT) performed from an unrelated donor, together with other non-HLA factors. A 10/10-matched donor is the most suitable for HSCT, when possible; however, a certain degree of HLA-incompatibility has to be accepted when such a donor is not available.
Aim of the study This is a prospective multicenter GITMO study in which patients were enrolled as 6/6” matched (matched at loci A, B at low resolution level and DRB1 at high resolution) or as “5/6” matched (one low-resolution mismatch (MM) at locus A or B). High resolution typing is now available as well.
Patients. Eligible were patients with a haematological malignancy, aged > 18 years old, activating an unrelated donor search in Italy from January 1999 to June 2006. Patients with chronic myeloid leukaemia were excluded from the analysis. A total of 1069 patient-donor pairs were analyzed; median follow-up for alive pts was 23 months (range: 3–96). According to disease status at HSCT, pts were classified as “early” (de novo acute myeloid or lymphoblastic leukemia in first complete remission, n=241) and “advanced” (all others, n=828) pts. Univariate and multivariate analysis with Cox regression included main non-HLA factors known to be associated with HSCT outcome. No differences in overall survival (OS) was observed between 5/6-matched (n=101) and 6/6-matched (n=968) pts (fig.1). There was a non-statistically significant trend toward a lower relapse-related death (RRD) in 5/6-matched compared to 6/6-matched pts was observed (5y-RRD: 18% vs 24%, respectively; p=0.13). We then proceeded to test the effect of the C locus: in multivariate analysis, the presence of an antigenic MM at locus C was associated with a worse OS, regardless of matching at loci A or B (RR 1.18, 95% C.I.: 1.00–1.40, p=0.05); the presence of a MM at locus B and/or C significantly affected transplant-related mortality (TRM) (RR 1.57, 95% C.I.: 1.02–2.44, p=0.04; RR 1.31, 95% C.I.: 1.04–1.65, p=0.02, respectively), MM at locus B or C was also associated with development of grade II-IV acute graft-versus-host disease (aGVHD) on multivariate analysis, together with “non-use” of ATG (ATG use: RR 0.70, 95% C.I. 0.52–0.95, p=0.02).
Conclusions, The outcome of so called 5/6 and 6/6 HLA matched unrelated donor transplants is comparable: this may be due to the fact that the C locus is not taken in to account in the “5/6 or 6/6” definition. Indeed a mismatch at locus C is associated with worse outcome. MM at locus B or C, but not at locus A, increases the risk of developing grade II-IV aGVHD. Use of ATG reduces aGVHD rates, thus attenuating the adverse effect of MMs at loci B and C on HSCT outcome.
c-Abl Kinase Inhibitors Overcome CD40-Mediated Drug Resistance in CLL.
Authors: Hallaert Delfine Y. , Jaspers Annelieke , van Noesel Carel J. , Van Oers Marinus H.J. , Kater Arnon P. , Eldering Eric 
Published: October 2019

Abstract
In chronic lymphocytic leukemia (CLL), proliferation centers reside in lymph node (LN) and possibly also bone marrow, where the environment protects CLL cells from apoptotic and cytotoxic triggers. This protective milieu may well contribute to the lack of curative chemotherapy in CLL, and our recent analysis of the distinct profiles of apoptosis regulators in CLL LN versus peripheral blood supports this notion (Smit et al., Blood 2007, 109: 1660). The aim of the present study was to define the molecular basis for the increased drug resistance and to search for novel strategies to circumvent it. To mimic the situation in CLL LN, we applied prolonged in vitro CD40 stimulation of CLL cells, which results in strong upregulation of anti-apoptotic Bcl-xL and Mcl-1. Moreover, we now also report a gradual reduction of Bim at the protein level, further contributing to the anti-apoptotic profile. Using specific inhibitors (PD98059 and MG132), we found that the decrease in Bim is due to ERK-mediated phosporylation and subsequent proteasomal degradation. ERK inhibition during CD40 triggering abrogated the decrease in Bim levels, but did however not re-establish sensitivity to various drugs (fludarabine, Velcade, Roscovitine). In chronic myeloid leukemia (CML), changes in Bcl-xL, Mcl-1 and Bim levels similar to those observed in our CLL/CD40 system are known to depend on BCR-Abl signaling. Therefore, we next applied c-Abl inhibitors Gleevec or Dasatinib in conjunction with CD40. Both drugs caused a profound reversal of most protective CD40 effects; ERK activity, Bim, Bcl-xL and Mcl-1 levels as well as sensitivity to subsequent drug treatment were restored to pre-CD40 values. These effects also occurred in CLL samples with dysfunctional p53 (n=3). Importantly, in CLL LN samples we also found strong ERK activation together with high Bcl-xL and Mcl-1 but low Bim levels, suggesting that there might be a c-Abl dependent survival pathway in proliferation centers. These data provide a molecular basis for combination strategies that could target refractory niches in CLL, using therapeutics that function independently of p53.
The Prognostic Importance of T and NK-Cells in a Consecutive Series of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia.
Authors: Palmer Shanique , Hanson Curtis A. , Zent Clive S. , Porrata Louis F. , LaPlant Betsy , Geyer Susan M. , Markovic Svetomir N. , Call Timothy G. , Bowen Deborah A. , Jelinek Diane F. , Kay Neil E. , Shanafelt Tait D. 
Published: October 2019

Abstract
Background: Patients with CLL have a variable clinical course. Current novel prognostic indicators (ZAP-70, CD38, IgVH gene mutation status, FISH) are able to identify early-stage CLL patients at high risk of rapid disease progression. These prognostic factors focus on characteristics of the malignant B cell clone and are not currently changeable factors. Identification of modifiable characteristics of the host unrelated to the leukemic B-cell but that relate to CLL-specific survival may provide opportunities for therapeutic intervention. Since the immune system is likely to modulate disease progression in CLL patients, we evaluated critical features of that system in relation to the size of the circulating clonal B-cell population in a CLL cohort.
Methods: 186 consecutive patients with CLL who were evaluated at Mayo Clinic within 2 months of diagnosis between 2000 and 2002 were identified. The primary end-point of the study was to assess if host immunity affected time to treatment (TTT). Baseline flow cytometry analysis was available for 166 patients (88%) and was used to calculate the absolute number of T-cell and natural kill (NK)-cells present at diagnosis. The size of the T-cell/NK-cell compartment relative to the size of the malignant monoclonal B-cell (MBC) compartment was then evaluated by calculating the NK:MBC ratio and T:MBC ratio. Relationships with other prognostic parameters and with TTT were evaluated.
Results: Patients exhibited substantial variation in the absolute number of T-cells and NK cells as well as T:MBC and NK:MBC ratios at the time of diagnosis. Higher T:MBC and NK:MBC ratios were observed among patients with early Rai stage and mutated IgVH genes (all P≤0.0002). As continuous variables, both the T:MBC ratio (p value=0.03) and NK:MBC ratio (p value=0.02) were associated with TTT. Since they correlated with TTT as continuous variables, thresholds to classify MBC, T:MBC ratio, and NK:MBC were identified using the method of Contal and O’Quigly. On multivariate Cox modeling including stage, CD38, absolute MBC count, T:MB ratio, and NK:MB ratio, the independent predictors of TTT were disease stage, T:MB ratio, and NK:MB ratio (Table 1).
Conclusion: Measurable characteristics of the host immune system appear to relate to the rate of disease progression in patients with newly diagnosed CLL. These characteristics can be modified and continued evaluation of immunomodulatory drugs, vaccination strategies, and cellular therapies to delay/prevent disease progression are warranted. Additional studies exploring how interactions between the host immune system and the leukemic clone influence clinical outcomes are needed.
A Genomic Strategy To Refine Prognosis and Predict Response to Therapy in Chronic Lymphocytic Leukemia.
Authors: Friedman Daphne R. , Weinberg J. Brice , Potti Anil , Volkheimer Alicia D. , Bond Karen M. , Chen Youwei , Jiang Ning , Moore Joseph O. , Gockerman Jon P. , Diehl Louis F. , Decastro Carlos M. , Nevins Joseph R. 
Published: October 2019

Abstract
Chronic Lymphocytic Leukemia (CLL) is notable for variation in aggressiveness of disease. Many patients with low-risk disease at diagnosis can be followed expectantly, while others rapidly require therapy. While a number of factors aid in determining prognosis, they have no role in predicting response to chemotherapy. We collected clinical data from a cohort of 220 patients with CLL followed at Duke University and the Durham VA Medical Centers. We assessed factors such as stage, leukocyte doubling time, IgVH mutational status, CD38 and ZAP-70 expression, cytogenetics, and time to treatment. We isolated RNA from purified CD5+, CD19+ leukemia cell samples from low and intermediate risk CLL patients, assessed the RNA expression with Affymetrix U133 Plus 2.0 GeneChips, and analyzed differential gene expression using previously developed methods of Bayesian binary regression. In a group of seventy-nine CLL patients who either eventually required (n = 45) or did not (n = 34) require therapy, CD38 status, ZAP70 expression, and cytogenetics were not statistically different (p > 0.5) while IgVH mutational status and leukocyte doubling time were different (p < 0.003). Of the patients treated, 69% were treated with chlorambucil, 51% with fludarabine, 31% with cyclophosphamide, and 49% with rituximab. Using genomic expression data, we developed a 100 gene expression signature that correlated with the need for eventual therapy. The accuracy of this signature was 94% using the leave-one-out cross validation method. Further validation using published data is currently being conducted, and data will be presented. Genes associated with the need for treatment include cell cycle regulators (such as E2F2 and CDK6), inhibitors of apoptosis (such as BAG1), and apolipoprotein B. In addition, using techniques described previously (Potti A et al, Nature Medicine, 2006, 12(11):1294), gene expression data coupled with either in vitro drug sensitivity in the NCI-60 panel of cell lines or in vivo drug response data were used to generate genomic models predictive of sensitivity to drugs commonly used in CLL including fludarabine, cyclophosphamide, and rituximab with accuracies on leave-one-out cross validation of 93%, 96%, and 79% respectively. These predictive models are currently being applied to gene expression data from leukemia samples of CLL patients to predict response to therapy (data to be presented). Thus, a genomic approach can be used to determine which CLL patients will require treatment. Importantly, models of chemosensitivity may predict response to therapy, and thus may ultimately help target the appropriate treatment for each patient.
Mechanistic Paradigm for Combination Signal Transduction Inhibitor Therapy in Zap70+ CLL Involves Bicompartmental Functions of EZH2.
Authors: Hartman Amy D. , Wilson-Weekes Annique , Ruffin Theresa , Hincher Katie J. , Cripe Larry D. , Boswell H. Scott 
Published: October 2019

Abstract
We have characterized a tonically active B cell receptor signaling module of zap70+ve CLL cells that contributes to a high-risk disease phenotype associated with rapid tumor doubling time and cellular bcl-2 overexpression. In CLL cells, syk directs tyrosine phosphorylation of certain adaptors including cbl and crkL and this is also accompanied by tyrosine phosphorylation of the interdomain-B loop of zap70 to affect its own interaction with adaptors and vav1. Vav1 along with zap70 allows JNK activation and the formation of heightened c-jun/AP-1 involved in CLL cell bcl-2 transcription. However, CLL pathogenesis is equally dependent upon ezh2/PRC2-mediated 5′-methylation of CpG islands in several tumor suppressor genes such as PTPRO (a cell-intrinsic syk inhibitor) and DAPK1. In addition, ezh2 functions not only in the nucleus for gene repression, but in cytoplasm for stabilization/perpetuation of a zap70-vav1 signal complex upstream of JNK1 in lymphocytes (IH Su et al., Cell121:425, 2005). We investigated the possible participation of ezh2 in events relevant to the outcome of syk inhibition as a primary therapy for CLL. We used R406/R788, a potent, selective syk inhibitor now in clinical trial (Rigel Pharmaceuticals). We found that R406 treatment strongly inhibited CLL viable cell recovery from culture, and this was associated with inhibition of syk (PY525/catalytic domain) phosphorylation as well as loss of zap70 PY319 (interdomain) phosphorylation with an IC50 of 1 uM R406, associated with downregulation of phospho-c-jun (S73) and of bcl-2. Failure of R406 to inhibit lyn autophosphorylation suggests strongly that syk is the upstream kinase for zap70 in this regulatory pathway. A survey of ezh2 expression showed content of ezh2 correlated with p(319)-zap70 intensity in different CLL cells. R406 caused release of syk substrate cbl from the JNK1 signalosome of R406-treated cells, but ezh2 remained tightly bound to vav1-zap70-JNK1 as demonstrated by immunoprecipitation. To overcome the bi-compartmental functions of ezh2, we used HDAC inhibitor, SBHA (suberoyl hydroxamic acid); a class of compound reported to deplete ezh2 from leukemia cells (W Fiskus et al. Mol Canc. Ther.5: 3096, 2006). In 3 different experiments, SBHA alone, 1 uM, had little inhibitory activity for CLL cell viable cell recovery, however, when combined with R406 (also at 1uM) SBHA caused massive cell death (>80%) only attainable with R406 alone at 2.5X dose. Mechanistic aspects of the reversal of tumor suppressor gene repression and of inactivation of the JNK1 signalosome by SBHA are under scrutiny to fully explain its cooperativity with R406, focused especially on the duality of roles performed by ezh2, and the depletion of ezh2 affected by HDAC inhibition.
Recombinant Activated Factor VII (rFVIIa) in the Treatment of Non-Hemophilia Patients: Physician Underreporting of Thromboembolic Adverse Events.
Authors: Hsia Cyrus C. , Zurawska Joanna H. , Tong Michael Z.Y. , Eckert Kathleen , McAlister Vivian C. , Chin-Yee Ian H. 
Published: October 2019

Abstract
Background: Recombinant activated factor VII (rFVIIa) is a potent hemostatic agent with a short half-life of 2.6 hours and is approved for various hereditary and acquired bleeding disorders. Its “off-label” utilization has increased and is the focus of a number of ongoing clinical trials. One concern is that its beneficial hemostatic effect may be offset by the potential for thromboembolic adverse events (TAEs). Despite its short half-life, rFVIIa likely produces a sustained hemostatic effect and the potential for thromboembolic events may also be prolonged. A recent review of adverse events reported to the FDA suggested that this risk was substantial. The duration that this risk may be present is unclear. Physicians may only consider adverse events to be causally related in the immediate few hours after administration of rFVIIa leading to underreporting TAEs. We conducted a retrospective review of all off-label uses of rFVIIa comparing physician reporting of TAEs to documented TAEs on chart review.
Methods: Chart review of all non-hemophilia adult patients who had received rFVIIa at our tertiary care centre was completed. Following all off-label administration, questionnaires were routinely sent to all treating physicians to report outcomes and adverse reactions with the use of rFVIIa. We included all non-hemophilia adult patients at our tertiary care centre who have received rFVIIa. Exclusion criteria were age < 18 and patients with hemophilia or other bleeding disorders for which rFVIIa use is approved. TAEs identified during chart review were compared to physician reporting on questionnaires.
Results: A total of 71 patients, 32 females and 39 males, satisfied study criteria during the period January 1, 2003 to June 30, 2007. Mean age was 54 (range 18–84). This was a high-risk population with 34 (47.9%) deaths. Mean duration of follow-up was 30 days (within 1 day to 312 days). Total doses of rFVIIa administered ranged from 2.4–19.2mg (mean 8.2mg) given in 1 to 4 divided doses. 11 arterial and 5 venous TAEs identified on chart review were deemed possibly or probably related. These occurred on average 25 days (within 2 day to 89 days) after exposure to rFVIIa. In total, 50 physician questionnaires (70%) were completed. There were no TAEs reported to the transfusion safety officer at our institution by the treating physician(s) in these questionnaires.
Conclusions: Clinically important thromboembolic events due to recombinant activated factor VII are under-reported in this high-risk population. This review was not designed to determine if rFVIIa alters the rate of TAEs but emphasizes the need for careful follow-up, both immediate as well as longterm, of patients who have hemorrhage or are at risk of hemorrhage. Physicians treating patients with rFVIIa should be vigilant for potential TAEs beyond the immediate treatment period.