bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mobilization and Chemosensitization of AML with the CXCR4 Antagonist Plerixafor (AMD3100): A Phase I/II Study of AMD3100+MEC in Patients with Relapsed or Refractory Disease.
Authors: Uy Geoffrey L. , Rettig Michael P. , McFarland Kyle M. , Hladnik Lindsay M. , Kulkarni Shashikant , Abboud Camille N. , Cashen Amanda F. , Stockerl-Goldstein Keith , Vij Ravi , Westervelt Peter , DiPersio John F. 
Published: April 2020

Abstract
The interaction of leukemic blasts with the bone marrow microenvironment is postulated to be an important mediator of chemoresistance in AML. Although a number of receptor/ligand pairs have been implicated, the CXCR4/SDF-1 axis functions as the principal regulator of homing and retention of both normal and malignant hematopoietic cells in the marrow. Plerixafor (AMD3100) is a bicyclam molecule which reversibly blocks CXCR4 binding to SDF-1 and is being developed clinically as a mobilization agent for hematopoietic stem cell transplantation. Preclinical data from our group has demonstrated that in murine models, plerixafor can disrupt the interaction of leukemic cells with the marrow microenvironment and sensitize blasts to the effect of chemotherapy. Based on these data, we have initiated a phase I/II study in patients with relapsed or refractory AML in which plerixafor is administered prior to salvage chemotherapy. Subjects were required to have AML which is
primary refractory to at least 2 induction regimens, in 1st relapse with an initial remission duration of &lt; 12 months, in 1st relapse having failed ≥ 1 salvage regimens, or in 2nd relapse or higher. Plerixafor is administered by SQ injection followed by a 24 hour observation period to analyze its effects on leukemic cell mobilization.
Then plerixafor is given daily 4 hours prior to chemotherapy consisting of mitoxantrone 8mg/m2/d, etoposide 100 mg/m2/d and cytarabine 1000 mg/m2/d x 5 days. To date, 19 patients have been treated at 3 dose levels of plerixafor: 80, 160 and 240 mcg/kg/day. We find that plerixafor can modestly mobilize leukemic cells (~ 2-fold increase) into the peripheral circulation at a peak of 6–8 hours after administration. FISH studies performed from informative samples demonstrates that this mobilization occurs equally in both non-leukemic and leukemic populations. While CXCR4 expression is increased on the surface of mobilized blasts, no clear relationship has been observed between CXCR4 expression or plerixafor dose and mobilization. At the 80 and 160 mcg/kg dose levels, a complete response (CR+CRi) was observed in 2 of 6 patients (33%). At the plerixafor 240 mcg/kg dose level, a complete response (CR+CRi) was achieved in 6 of 8 evaluable patients (75%) in this historically chemorefractory population. Plerixafor was well tolerated with no evidence of hyperleukocytosis or significant delays in neutrophil recovery (median 30 days, range 24–40). Based on this encouraging evidence of safety and efficacy, expansion of a phase II cohort is ongoing.
A Homoharringtonine-Based Protocol Is Superior to Daunorubicin and Idarubicin-Based Protocols in Elderly Patients with Newly-Diagnosed Acute Myeloid Leukemia with Comparable Effects and Low Toxicities: Experience in a Chinese Center.
Authors: Wang Jianmin , Lü Shuqing , Yang Jianmin , Song Xianmin , Chen Li , Hou Jun , Zhang Weiping , Huan Chongmei , Ni Xiong , Qiu Huiying 
Published: April 2020

Abstract
Homoharringtonine (HHT) is a plant alkaloid which has been used in China for the treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia for over 30 years. We present here a retrospective analysis designed to compare the efficacy and toxicity of HHT with daunorubicin (DNR) and idarubicin for the treatment of AML in elderly patients. Fifty-three patients over 60 years with newly diagnosed non-M3 AML between January 1998 and December 2007 were treated with cytarabine (Ara-c, 100mg/m2/day for 7 days) in combination with HHT (2mg/m2/day for 7 days; HA group; n=19), or DNR (40mg/m2/d for 3 days; DA group; n=16), or idarubicin (8mg/m2/d for 3 days; IDA group; n=18). In the HA group, 42.1% (8/19) of patients achieved complete remission (CR), 26.3% (5/19) of patients had partial remission (PR). In the DA group, the CR and PR rates were each 18.8% (3/16). In the IDA group, 55.5% (10/18) of patients achieved CR, 5.9% (1/18) patients had PR. The CR and OR rates were not significantly different between the three groups. However, whereas in the IDA and DA groups the early death rate within one month after chemotherapy was 33.3% (6/18) and 23.5% (4/16) respectively, there was no early death in the HA group. The estimated OS (overall survival) times were 23.2±7.9 months, 7.6 ±2.1 months, 14.0±3.4 months in HA, DA, and IDA groups (HA versus DA, P = 0.048; HA versus IDA, P = 0.678). The estimated mean disease-free survival (DFS) time of those patients who achieved CR in the HA group (44.3±17.3) were also significantly higher than those in the DA group (7.8±2.7; P = 0.047), and comparable with those in the IDA group (18.0±4.2; P = 0.598). In summary, the response to HA induction therapy was at least equal to that of DA and IDA induction, with relatively mild extramedullary toxicity and lower myocardial toxicity. So HHT is a particularly suitable candidate for the treatment of elderly AML patients.
Pharmacokinetics, Clinical Efficacy and Safety of Plasma-Derived Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary and Acquired Angioedema.
Authors: Hofstra J. J. , van Twuyver E. , Kleine-Budde I. , Choi C. W. , Levi M. , Leebeek F. W.G. , de Monchy J. G.R. , Ypma P. F. , Huitema A. D. , Nienhuis A. , Strengers P. F. 
Published: April 2020

Abstract
RATIONALE: From the early 70’s, C1 inhibitor concentrate manufactured from pooled human plasma has been available to patients with hereditary and acquired angioedema (HAE and AAE) and in 1997 a highly purified C1 inhibitor (Cetor®) was introduced. Many precautions have been taken to minimize the potential risk of viral transmission (e.g. rigorously controlled whole blood collection systems, extensive screening of each individual donation for a variety of blood-borne viruses, pasteurisation). To further minimize the potential risk of viral transmission, a 15 nm filtration was implemented in the manufacturing process giving rise to C1-inhibitor-N (anofiltered).
DESIGN: A randomised, double-blind, controlled cross-over phase II study was conducted in which our primary objective was to compare the pharmacokinetics of the newly developed concentrate with conventional C1-inhibitor concentrate in HAE patients without signs of an attack of angioedema. Secondly, an open-label phase III study in patients with an HAE attack was performed to investigate whether the introduction of the virus reducing 15nm filtration step in the manufacturing process of the concentrate did not affect the efficacy and safety of the product.
RESULTS: Thirteen patients were enrolled in the phase II study. No differences between conventional C1-inhibitor concentrate and nanofiltered C1-inhibitor concentrate were detected with regard to the primary pharmacokinetic parameters clearance, volume of distribution, and the fraction of C1-inhibitor-N detected by the antigen assay relative to the functional assay. Therefore incremental recovery, mean residence time, half-life and the area under curve were equivalent for both products. In the phase III study, 8 HAE patients were enrolled. In these 8 patients, 14 attacks qualified as acute angioedema attack. The mean time-to-relief for attacks treated with new C1-inhibitor concentrate was 3.0 (SD 2.5) hours. Historical data showed that treatment with conventional C1-inhibitor concentrate resulted in time-to-relief of 3.9 (SD 6.2) hours, whereas for untreated attacks this was 24.7 (SD 19.9) hours. The attacks treated with new C1-esterase inhibitor concentrate had a mean time-to-resolve of 18.6 hours (SD 13.1) whereas medical history showed an time-to-resolve of 17.8 hours (SD 17.2) for conventional C1-inhibitor. Untreated attacks showed a mean time-to-resolve of 63.6 hours (SD 31.0).
CONCLUSION: The newly developed nanofiltered C1-esterase inhibitor has equal pharmacokinetic properties compared to the conventional concentrate. The viral reduction step (15 nm filtration) in the production process of Cetor did not induce changes in the efficacy and safety in the treatment of acute angioedema attacks and in the pharmacokinetic parameters.
Safety in Patients Receiving Maintenance Rituximab for Follicular Lymphoma: Results from Phase IIIb MAXIMA Trial.
Authors: Witzens-Harig Mathias , Hipp Joachim , Ho Anthony D. , Nikolov Nikolai , Thurley Daniel , Hensel Manfred , Oertel Stefan , Wenger Michael 
Published: April 2020

Abstract
Background: The clinical benefit of improved PFS and OS for rituximab maintenance in follicular lymphoma (FL) has been reported in five randomized trials. The primary objective of the current study is to extend the safety database for rituximab maintenance following a wide range of induction therapies. The study also examines the safety profile associated with rapid-infusion of rituximab.
Methods: The sample size of this single-arm trial has been calculated to detect at least one rare event with a true incidence of 0.32% with 80% power. Patients with first line or relapsed/refractory FL achieving a response after rituximab containing induction therapy were eligible to receive rituximab at the standard dose for follicular lymphoma of 375 mg/m2 every eight weeks for a maximum of 2 years. Primary study endpoint is safety. Secondary endpoints being PFS, EFS, TTNL, and OS.
Results: 526 patients with FL have been enrolled at clinical cut-off for whom demographic data is available: Median age of the patient population is 57 years [range: 29 to 86], with 43% being male. Seventy-four percent of patients had their first lymphoma treatment prior to enrollment, while the remaining 24% of patients had up to 4 previous treatments; 71% entered the study in CR/CRu. Data on a total of 2004 infusions was available. Except for one patient who received rituximab at standard infusion speed and suffered from a TIA no SAEs were recorded within 24h of the maintenance infusion, including those patients who received rituximab via a rapid infusion protocol. A total of 31 SAEs were recorded in the 484 patients that received at least one infusion, all but one were considered unrelated. One patient with previously known cardiac arrythmias died 13 days after the 4th infusion of unknown causes. Three patients died of progressive lymphoma, another patient died due to refractory ITP. Hematologic toxicity occured in 13 patients, with one grade 5 event (ITP) and 12 grade 3/4 events, one resulting in febrile neutropenia. Data on efficicacy will be presented.
Conclusions: Rituximab maintenance q 8 weeks in FL after rituximab containing induction therapy can be safely administered, regardless if a rapid-infusion protocol is used or not.
Extended Follow-up of the International Randomized Phase 3 First-Line Indolent Trial (FIT) Shows Durable Benefit of 90 Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission in Advanced Stage Follicular Non-Hodgkin’s Lymphoma.
Authors: Morschhauser Franck , Bischof-Delaloye Angelika , Rohatiner Ama Z S , Salles Gilles Andre , Kuhlmann Jens , Van Putten Willem JL , Radford John , Soubeyran Pierre , Van Hoof Achiel , Hagenbeek Anton 
Published: April 2020

Abstract
Initial findings from the Phase 3 trial of Zevalin consolidation of first remission in patients with advanced follicular lymphoma showed a significant improvement in PFS following Zevalin consolidation as compared to no further treatment, ie, 37.5 vs. 13 months (Hagenbeek et al, ASH 2007). Patients had been randomised to either no further therapy or Zevalin consolidation (250 mg/m2 rituximab on day -7 and on day 0, followed on day 0 by Zevalin 0.4 mCi/kg; maximal dose 32 mCi). Herein we report on an additional 1-year follow-up of the FIT study, at a median of 42 months (range: 2 – 77), which includes 409 patients who achieved a complete or partial response (CR or PR), after induction therapy. Patient demographics remain similar in the Zevalin (n=202) and control groups (n= 207): males 48%/50%; median age 55/53 yrs; at diagnosis, stage III 35.2%/31%, stage IV 64%/66%. Response status prior to randomization was also similar between study arms: 107 patients in CR/CRu and 100 pts in PR in the Zevalin arm and 108 pts in CR and 88 pts in PR in the control arm. The 48-month PFS is 52% in the Zevalin arm compared with 31% in the control arm. As shown in the figure 1A, patients with a CR after induction therapy achieved a median PFS of &gt;67 months for the Zevalin arm compared with 30.8 months for patients who received no further treatment (HR 0.61 [95% CI .41–.91]; P= 0.015). In figure 1B, among patients with a PR after induction, the median PFS was 29.6 months for those on the Zevalin arm vs 6.7 months for those on the control arm (HR 0.36 [95% CI .25–.51]; P&lt;0.001). Subsequent therapy with various modalities including chemotherapy, radiotherapy, immunotherapy, Zevalin and stem cell transplantation (ASCT) was given to 63 patients in the Zevalin arm and 108 patients in the control arm, who achieved an overall response rate of 81% and 73%, respectively. A total of 11 deaths have occurred in the Zevalin arm and 8 in the control arm, with no difference in overall survival between the treatment arms (P=0.593). No additional toxicities, no congenital malformations, and no increase in the incidence of secondary malignancies have emerged during follow-up. Details on subsequent therapies and a breakdown of outcomes based on induction subgroups and FLIPI scores are anticipated for presentation.
Conclusion: Extended follow-up of the FIT trial shows that Zevalin consolidation does not preclude the use of various effective second-line treatment options. Moreover, these data confirm that the significant improvement in PFS achieved with Zevalin consolidation is durable for both patients with a PR and patients with a CR/CRu after induction.
Figure Figure
Age-Related Differences in the Glycosylation of Anticoagulant Protein C.
Authors: Berry Leslie R. , Chan Anthony K. C. 
Published: April 2020

Abstract
Thromboembolic events can result from procoagulant stimuli and the inability of native anticoagulant mechanisms to pacify thrombin generation. In the pediatric population, although thrombosis occurs in the presence of major coagulant insults, children are relatively resistant to onset of thrombotic complications. A key aspect contributing to developmental differences in the young is that coagulation factors and inhibitors have been shown to exist in different plasma concentrations and developmental forms compared to adults. Increasing evidence indicates that protein C (PC) is a major factor that, upon activation, controls coagulation by shutting down thrombin generation. In adults, PC exists as either 4 N-linked glycan (alpha-PC) or 3 N-linked glycan (beta- PC) proteins that differ in the rate at which their corresponding activated forms react with coagulation factor Va. Our previous work has shown that although plasma PC concentrations are vastly reduced in newborn plasma, inactivation of factor Va is similar to adults, suggesting a potential difference in PC molecules during development. To assess the potential for age-related PC molecule variation, we performed carbohydrate analyses to determine the relative glycoform composition of PC in newborns compared to adults. Venous plasma from either adults or umbilical cords of healthy full-term babies was collected following the ethical guidelines of our institution. Samples of plasma were run on non-reducing SDS polyacrylamide gel (7.5%) electrophoresis, followed by transfer onto PVDF blotting membranes. Blots were probed with polyclonal sheep anti-human PC, followed by anti-sheep IgG-alkaline phosphatase conjugate and then alkaline phosphatase substrate to visualize the protein bands. Relative intensity of alpha-PC and beta-PC bands was determined by laser densitometry. Analyses revealed that significant age differences existed in PC glycoform composition between adults and newborns. While the mass ratio of alpha-PC to the lower molecular weight band of beta PC was 2.3 to 1 for the adult plasma protein, newborns were observed to have an alpha-PC to beta-PC ratio of 8.8 to 1. Thus, an almost 4-fold increase in the circulating alpha-PC to beta-PC ratio was observed in newborns compared to adults. As a confirmation that the difference in migration between the alpha-PC and beta-PC bands was due to glycosylation, removal of N-glycans by treatment of newborn and adult plasma with N-glycosidase F prior to electrophoresis resulted in single bands that now migrated at the same rate for both age groups. We have demonstrated that relative expression of the 2 major PC glycoforms varies widely during development. Given that alpha-PC in its activated form has a much faster rate for factor Va inactivation compared to beta-PC, its increased appearance in newborn plasma may play a role in protecting neonates from thrombosis, despite reduced plasma inhibitor concentrations.
T Cells from Patients with Chronic Lymphocytic Leukaemia Prevent Apoptosis of Autologous CLL Cells in a Dose- and Cell:Cell-Contact Dependent Fashion; Rationale for New Therapeutic Possibilities.
Authors: Rossmann Eva , Kokhaei Parviz , Mozaffari Fariba , Palma Marzia , Osterborg Anders , Mellstedt Hakan , Choudhury A. Raja 
Published: April 2020

Abstract
Background: Multiple T cell abnormalities in Chronic Lymphocytic Leukemia (CLL) patients are well established. Compared to healthy individuals, total T lymphocyte count, CD8+ cells and CD4+ cells in CLL patients are increased and follow disease activity, i.e. increase at CLL progression. Major alterations in T cell functions and TCR repertoire have also been reported as well as T cells specifically recognizing the leukemic CLL cells. It may be hypothesized that aberrantly functioning T cells contribute to a microenvironment which may allow CLL cells to avoid apoptosis and/or support the proliferative capacity. However, the underlying mechanisms are largely unknown.
Materials and Methods: T cells and CLL cells were highly purified from PBMC of 20 patients with indolent CLL as well as normal blood B- and T-cells from healthy control donors (n=7). Autologous T cells and B cells were co-cultured at different T:B ratios for 72 h in ordinary and transwell plates. Apoptosis of B cells were assayed using Annexin-V and supernatants were analysed by Luminex for the following cytokines: RANTES, IL-10, IL-8, TNF-α, IFN-γ, IL-4, MCP-1, CD40L and GM-CSF.
Results: Apoptosis of CLL cells was significantly (p&lt;0.01) prevented by autologous T cells in a cell-dose-dependent fashion; the highest rate of apoptosis was observed when CLL cells were cultured alone in the absence of T cells. When the experiments were repeated in transwell plates the apoptosis-inhibiting effect of the T cells was completely ameliorated. No corresponding effects were observed when T cells were co-cultured with normal B cells of healthy donors. Luminex analysis revealed that the levels of IL-4, RANTES, MCP-1, TNF-α and IFN-γ were significantly higher in CLL co-culture experiments (especially at high T:B ratios) as compared to CLL cells alone.
Conclusions: Our data provide proof-of-principle that autologous T cells prevent apoptosis of CLL cells in a dose-dependent fashion and the effect was critically dependent on cell:cell contact. A number of cytokine candidates were identified for further studies. The results provide a basis for exploring therapeutic approaches aiming at selective inhibition/depletion of T cells in patients with CLL.
Platinum-Based Compounds Induce Expression of p73 and Restores Drug- Sensitivity in p53 Dysfunctional Chronic Lymphocytic Leukemia (CLL) Cells.
Authors: Tonino Sanne H. , Mulkens Chantal , Nonomura Yoshinori , Suo Guangli , Kipps Thomas J. , van Oers Marinus H.J. , Eldering Eric , Kater Arnon P. 
Published: April 2020

Abstract
Chronic lymphocytic leukemia (CLL) cells can lose function of P53 and acquire resistance to standard chemotherapy. We found that expression P73, a member of the P53 family, could be induced in CLL cells following CD40-ligation via a c-abl dependent pathway. Induced expression of P73 was associated with re-acquired sensitivity to drugs commonly used treat this disease, such as Fludarabine monophosphate. Similar effects also were noted for CLL cells transduced with an adenovirus vector encoding P731. Prior studies found that P73 also can be induced in breast and colon cancer cell lines following treatment with platinum-based compounds, potentially accounting for the activity of this class of drugs. We hypothesized that treatment of CLL cells with such compound also could induce P73 and that such induced expression also might be associated with re-acquired sensitivity of P53-deficient CLL cells to standard anti-cancer drugs. We studied the mechanisms and effects of platinum-based compounds on CLL cells lacking functional p53. Studies were done with both the p3 dysfunctional pro-lymphocytic celline MEC-1 and with primary CLL cells that lacked functional P53. Treatment of MEC-1 cells with cisplatinum or oxaliplatin induced nuclear translocation of c-Abl in several hours, which was subsequently followed by expression of P73, and then its putative target genes, encoding Bid, p21 and Fas (CD95). Platinum-induced expression of these P73-target genes could be inhibited by co-treatment of the cells with the c-Abl inhibitor imatinib. Cisplatinum treatment of MEC-1 cells resulted in cell cycle arrest. Furthermore, cis-platinum treatment of MEC-1 cells or P53-deficient CLL cells synergized with Fas-mediated apoptosis, and importantly resulted in acquired sensitivity to the drug fludarabine monophosphate in vitro, apparently via a c-Abl dependent pathway. Purified p53 dysfunctional CLL cells obtained before and after 24 and 48 hrs of in vivo cisplatinum treatment revealed de novo expression of both P73 and Bid, illustrating induction of P73 at therapeutic dosages of cisplatin. This study indicates that platinum treatment of CLL cells induces c-Abl dependent expression of P73, which can enhance the sensitivity of P53-deficient CLL cells to drugs such as fludarabine monophosphate. These results provide additional incentive to investigate the activity of platinum-based chemotherapy regimens in patients with refractory disease who have CLL cells lacking functional P53, which currently are ongoing in Europe and the United States.