bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemoimmuno-Therapy with Fludarabine, Cyclophosphamide and Alemtuzumab in Patients with Relapsed/Refractory CLL: Interim Analysis of the CLL2L Trial of the German CLL Study Group
Authors: Elter Thomas , James Rojin , Stilgenbauer Stephan , Ritgen Matthias , Hallek Michael , Engert Andreas 
Published: April 2020

Abstract
Introduction: Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. As alemtuzumab has proven to be the most effective antibody in CLL treatment, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly schedule
Methods: Fludarabine 25mg/m2 iv, cyclophosphamide 200mg/m2 iv and alemtuzumab 30 mg sc were given on days 1 – 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals.
Results: A total of 55 patients of a planned sample size of 61 patients were included in this phase-II study so far, of which 24 patients are evaluable for response and safety analysis. Median age is 63 (range 47–78) years with a medium number of 1 prior regimen; 19/24 patients completed at least four cycles with a median number of 5 cycles. Pretreatment consisted of fludarabine (8/24), fludarabine and cyclophosphamide (13/24) or rituximab combinations (3/24). Thrombocytopenia and neutropenia were the most serious side effects and detailed data will be presented. 3 CMV-reactivations, 1 Herpes-zoster-reactivation and 12 fever of unknown origin have been reported. The overall response rate was 83% with 9 CR(6 CRu) (38%), 9 PR (46%), 3 SD and 1 PD, response was independent of FISH status. A correlation of response with prior treatment was observed, with 100% ORR for fludarabine pre-treatment versus only 77% for those patients pretreated with fludarabine and cyclophosphamide. Updated data of 30 patients and MRD data will be presented.
Conclusions: The concomitant application of fludarabine, cyclophosphamide and alemtuzumab appears as a safe and effective approach for patients with relapsed CLL.
Differential Effects of the BCR-ABL-Inhibitors Imatinib, Nilotinib and Dasatinib on NK Cell Reactivity against Chronic Myeloid Leukemia (CML)
Authors: Krusch Matthias , Salih Julia , Kanz Lothar , Salih Helmut R 
Published: April 2020

Abstract
CML is characterized by the BCR-ABL fusion protein, which mediates the oncogenic signaling. This led to the development of BCR-ABL inhibitors revolutionizing therapy of CML. However, as recently reported for Dasatinib (Schade et al., Blood 111:1366 (2008); Blake et al., Blood 111:4415 (2008)), these agents may impair the activity of immune effector cells like NK cells and T cells. After initiating oncogenic events, development and progression of clinically apparent malignancy is dependent on the evasion of the tumor cells from immunosurveillance. In light of the important role of NK cell reactivity against leukemia we compared the influence of Imatinib, Nilotinib and Dasatinib on the reactivity of both resting and IL-2 activated NK cells against CML cells to identify the compound with the least immuno-compromising side effects. First, the effects of the compounds on NK cell reactivity in concentrations corresponding to plasma peak levels were studied. Dasatinib (200nM) completely abolished NK cell granule mobilization, cytotoxicity and IFN-γ production, while no substantial inhibition was observed with Imatinib (5μM) and Nilotinib (3.6μM) mediated a minor but significant inhibition (p&lt;0.05, Student’s T-test). Presence of the compounds in concentrations corresponding to IC50 levels (Imatinib 600nM, Nilotinib 30nM, Dasatinib 10nM) revealed no influence of Imatinib and Nilotinib, while Dasatinib still significantly reduced NK cell cytotoxicity and IFN-γ production up to 60%. Since Dasatinib, in addition to BCR-ABL, potently inhibits SRC kinases, which are involved in the activation of MAPK pathways and thus crucial for NK cell cytotoxicity, we determined the influence of the compounds on ERK phosphorylation. While no inhibitory effect was observed using Imatinib and Nilotinib, Dasatinib markedly reduced ERK phosphorylation in NK cells. Our data demonstrate that NK cell anti-tumor reactivity is not inhibited by clinically relevant concentrations of Imatinib. While Nilotinib may mediate a minor effect, Dasatinib substantially impairs NK cell reactivity by inhibition of signaling pathways crucial for NK cell effector functions. For a given patient, the choice and dosing of the most suitable BCR-ABL inhibitor may thus require careful consideration of its influence on the immune system, especially in view of the important role of NK cells in the immunesurveillance of residual leukemia.
Dose-Intensified Combined Modality Treatment with 2 Cycles of BEACOPP Escalated Followed by 2 Cycles of ABVD and Involved Field Radiotherapy (IF-RT) Is Superior to 4 Cycles of ABVD and IFRT in Patients with Early Unfavourable Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Study Group (GHSG) HD14 Trial
Authors: Borchmann Peter , Engert Andreas , Pluetschow Annette , Fuchs Michael , Markova Jana , Lohri Andreas , Kral Zdenek , Greil Richard , Topp Max , Villalobos Matthias , Zijlstra Jose , Soekler Martin , Stein Harald , Eich Hans Theodor , Mueller Rolf Peter , Diehl Volker 
Published: April 2020

Abstract
Purpose: Combined modality treatment consisting of 4 cycles of chemotherapy and IF-RT is the standard treatment for early unfavourable HL. Overall survival (OS) and freedom from treatment failure (FFTF) in this group of patients was 91% and 83%, respectively, at 5 years in our prior HD8 study. Thus, the rationale for HD14 was to improve on these results by increasing dose intensity using BEACOPP escalated.
Methods: Between January 2003 and January 2007, 1.216 patients aged 16–60 with untreated early unfavourable stage HL (CS I, IIA with one of the following risk factors: large mediastinal mass (a), extranodal disease (b), elevated ESR (c), or ≥ 3 nodal areas (d); IIB with risk factors c and d) were randomized to either 4 cycles of ABVD (arm A) or 2x BEACOPP escalated followed by 2x ABVD (arm B). All patients received 30Gy IF-RT after chemotherapy. Primary objective was the improvement of the FFTF. Here we present the results of the predefined 3rd interim analysis within the prespecified group sequential test design.
Results: Of the 1.216 patients included, 1.010 were evaluable for this analysis. Patient characteristics were well balanced between both arms. At 3 years, the FFTF for arm A is 90% (95% CI: 87%–93%), and for arm B 96% (95% CI: 94%–98%). Since the observed inverse normal test statistic exceeds the critical level, the null hypothesis of equal FFTF in each arm can already be rejected. The improved FFTF is mainly due to differences in progression and early relapses (arm A 5.9% versus arm B 1.8%). Protocol adherence for chemotherapy was high and not different in both arms (arm A 98.8%, am B 97.3%). Though the chemotherapy-intensity was higher in the experimental arm, safety was comparable to the standard treatment. Secondary neoplasias occurred in 8 patients in each arm so far.
Conclusion: Based on the significantly superior FFTF of the intensified therapy (2x BEACOPP escalated + 2x ABVD + IF-RT) compared to the prior standard (4x ABVD + IF-RT), this more aggressive treatment strategy will become the new standard for early unfavourable HL patients within the GHSG. Whether the improved FFTF translates into an improved overall survival must be awaited. Future strategies should aim at identification of those patient subgroups that profit most from this approach.
Pharmacological Inhibition of NF-KB Underpins the Strong Synergy Between LC-1 and Fludarabine in Chronic Lymphocytic Leukaemia Cells
Authors: Hewamana Saman , Lin Thet Thet , Fegan Chris , Knapper Steven , Burnett Alan , Brennan Paul , Rowntree Clare , Pepper Chris 
Published: April 2020

Abstract
Chronic lymphocytic leukaemia (CLL) is incurable with conventional chemotherapy and all currently available agents eventually fail because of drug resistance or unacceptable toxicities. We have recently shown that the novel NF-κB inhibitor LC-1 is effective in primary CLL cells and is capable of overcoming drug resistance. In this study, we elucidated the mechanism of action of LC-1, evaluated its relative cytotoxicity in prognostic subsets (n=96) and investigated its potential synergistic interaction with fludarabine (n=26). LC-1 induced cell death was associated with caspase-3 activation that was mediated via the upstream activation of both caspase-8 and caspsase-9. Apoptosis was preceded by a reduction in nuclear Rel A DNA binding and down regulation of the anti-apoptotic NF-κB target genes CFLAR, BIRC5 and BCL2. Importantly, LC-1 was able to overcome the cytoprotective effects by IL-4 and CD40 ligand indicating that it would retain its potency in vivo even in the solid tissue micro-environment. LC-1 was equally effective in CLL cells derived from good and bad prognostic subsets and exhibited strong synergy with fludarabine (mean combination index 0.26). The combination produced a highly significant mean dose reduction index of &gt;1000 that would facilitate a theoretical 3 log reduction in the standard clinical dose of fludarabine. Taken together our data confirm the therapeutic potential of LC-1 both as a single agent and in combination with fludarabine and provide a compelling rationale for early clinical trials of this agent in CLL patients.
Inhibited Maturation of Ter119+CD71+ Erythroid Precursors in Mice with Chronic Sterile Abscess.
Authors: Prince Olivier D. , Prince Ian C. , Walston Jeremy , Andrews Nancy C. , Civin Curt I. , Roy Cindy N. 
Published: April 2020

Abstract
Anemia associated with inflammation or chronic disease (AICD) is a mild, normocytic, normochromic anemia that is additionally characterized by a blunted response of erythroid precursors to erythropoietin, decreased erythrocyte survival, adequate or increased iron in macrophages, and low serum iron. AICD is classically associated with chronic disease states that generate systemic inflammatory mediators, including rheumatoid arthritis, infections, severe trauma, congestive heart failure, chronic renal failure, and cancer. Many laboratory animal models of AICD have been developed based on relatively short periods of inflammation (less than 24 hours) and resulting hypoferremia. To investigate the anemia associated with chronic inflammation, we induced experimental chronic sterile abscess in C57BL/6 mice. Three weeks of abscess resulted in a mild anemia similar to that of mice with chronic over-expression of the hepcidin (hepc) transgene, but additionally characterized by moderately elevated interleukin-6 production. We previously found hepc transgenic mice have significantly reduced serum iron and non-heme liver iron concentrations, but we found no significant reduction in serum iron concentration or liver non-heme iron stores in mice with abscess at this time point. To better understand changes in erythroid precursor development in the sterile abscess model, we analyzed markers of erythroid maturation in mouse bone marrow. Flow cytometric analysis of bone marrow erythroid progenitor-precursors revealed elevated mean CD71 expression in Ter119+CD71+ precursors from mice with sterile abscess as compared to controls. This result suggests a greater proportion of Ter119+CD71+ precursors are less mature in mice with abscess. These data support the hypothesis that chronic inflammation may continue to inhibit maturation of erythroid precursors even after iron sequestration is relieved. Mice with sterile abscess are a valuable in vivo model for assessment of the various regulatory systems contributing to AICD.
Phosphatidic Acid Enhances Procoagulant Activity and Thrombosis through Phosphatidylserine Exposure in Human Erythrocytes.
Authors: Noh Ji-Yoon , Lim Kyung-Min , Chung Jin-Ho 
Published: April 2020

Abstract
The increased phospholipase D (PLD) activity and phosphatidic acid (PA) level are frequently observed in various disease states including cancers, diabetes, inflammation, sepsis, and thrombosis. While PA has been previously regarded as a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG), increasing evidence suggests the biological activities of PA, itself. Here we demonstrated that the PA can enhance procoagulant activities in human erythrocytes and thrombus formation mediated through phosphatidylserine (PS) exposure. Conspicuously, the PS exposure by PA was substantially greater than that of LPA and we examined its mechanism of action in an effort to elucidate the biological significance of PA. In human erythrocytes, PA treatment resulted in PS exposure without microvesicle generation or hemolysis as determined by flow cytometry. These effects were not attenuated by inhibitors of phospholipase A2 and phosphatidate phosphatase, that convert PA to LPA and DAG, respectively, suggesting that PA directly induced PS exposure. PA exposed erythrocytes showed significantly high intracellular calcium level and resultant protein kinase C (PKC) a activation. Consistent with these findings, the activity of scramblase was enhanced by PA treatment, while that of flippase was inhibited. Furthermore, PA-exposed erythrocytes were aggregated, accelerated thrombin generation, and increased adherence to endothelial cells, implying PA treatment enhanced the thrombogenic activities of erythrocytes indeed. Of note, these procoagulant activations by PA were confirmed in rat in vivo venous thrombosis model. These results suggest that PA can contribute to enhanced thrombosis, mediated through PS exposure on erythrocytes. With this study, we believe a novel insight was given into the role of PA in cardiovascular diseases.
Varialibility of Neurological Complications in the Treatment of Acute Lymphoblastic Leukemia:Experience of a Single Pediatric Institution
Authors: Parasole Rosanna , Petruzziello Fara , Marra Nicoletta , Marchese Luciano , Mangione Argia , Cianciulli Ernesto , Menna Giuseppe , Misuraca Aldo , Poggi Vincenzo 
Published: April 2020

Abstract
Intensive chemotherapy significantly improves the outcome of pediatric acute lymphoblastic leukemia (ALL) but unfortunately increases the incidence and severity of acute adverse events. The current study analyses the incidence of central nervous system (CNS) complications during ALL treatment in a single pediatric institution. CNS leukemic infiltration at diagnosis, therapy-related peripheral neuropathy and leukoencephalopathy and neurocognitive defects after treatment were excluded by the study. From September 2000 to July 2008, two hundred and forty ALL patients (pts) were treated in our Institution according to BFM-AIEOP ALL 2000 protocol. Twenty-four out of 240 patients (10 %) (15 females and 9 males, median age at the event 7.7 years, range 2–16 years) developed CNS complications during treatment. Thirteen presented tonic-clonic seizures, four showed dyskinesia and dyslalia, one presented visual impairment and enuresis, and six had loss of consciousness. In 18 pts a rapid resolution of the event was obtained by administration of benzodiazepines or barbiturates; 6 pts required admission in intensive care unit, instead. Only two out of twenty-four patients presented neurological sequelae (one pts with recurrent seizures and one pts with right limb disability). Co-morbidity at the time of neurological accident included: blood pressure increase (6 pts), electrolytes imbalance (4 pts), LDH increase (4 pts), coagulation disorders (6 pts), hepatic enzyme increase (2 pts), severe anemia (1 pts), severe thrombocytopenia (4 pts), renal failure (1 pts), and Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (1 pts). Radiological scanning (either CT or MRI) and electroencephalography (EEG) performed within 48 hr from the onset of the clinical symptoms revealed different etiologies: 8 posterior reversible leukoencephalopathies (PRES), 3 cerebral bleedings, 2 ischemic cerebral diseases, 2 methotrexate toxicity, 1 SIADH, 2 temporal lobe epilepsy and 6 unidentified problems. In conclusion this retrospective study on CNS complications during ALL treatment shows that the most frequent neurological accident (33%) is the PRES.
Analysis of T Cell Cloanlity of Ph+ Acute Lymphoblastic Leukemia with Chronic Gvhd in Continuous Remission after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Wu Xiuli , Liu Qifa , Li Yangqiu , Chen Shaohua , Du Xuan , Zha Xianfeng , Zhou Shuyun 
Published: April 2020

Abstract
Chronic graft-versus-host disease (cGVHD) is one of the major complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, recent study suggested that the presence of cGVHD might reduce the risk of relapse in Ph+ acute lymphoblastic leukemia (ALL) after allo-HSCT. GVHD is mediated by proliferation of special T-cell clones, we analyzed the T cell receptor (TCR) Vβ repertoire and cloanlity in Ph+ ALL patients undergone cGVHD after allo-HSCT in order to find the special T-cell clones associated with continuous remission.
Allogeneic transplantations were performed in the first complete remission (CR) (6 ALLP190+ patients). The numbers of BCR-ABL copies in peripheral blood samples were assessed with the real-time quantitative RT-PCR (RQ-PCR) test at diagnosis, and every month after HSCT. The quantity of BCR-ABL transcript was normalized for normal ABL expression and the result was expressed as the ratio of BCR-ABL copies to ABL copies. With monitoring BCR-ABL copies of 6 BCR-ABLP190+ ALL patients after HSCT (the mean ratio of BCR-ABLP190/ABL at diagnose was 0.41 ± 0.39%), we found that 4 patients with extensive cutancous cGVHD had no evidence of leukemia recurrence, and the BCRABL transcripts of patients with cGVHD were remaining 0 copy, while 2 patients without cGVHD relapsed (the mean ratio of BCR-ABLP190/ABL was 7.56 ± 2.49%) and even dead within six months of HSCT.
The expression and cloanlity analysis of TCR Vβ repertoire was detected in peripheral blood samples from patients with cGVHD by RT-PCR and genescan technique. TCR Vβ repertoires with polyclonal pattern were identified in normal controls and donor groups. However, the skew expression pattern of TCR Vβ repertoire could be detected in patients with cGVHD even more than 1 year after allo-HSCT. Among the 24 Vβ subfamilies, there were only 11~17 Vβ subfamilies expressed in cGVHD patients. Oligoclonal or monoclonal expanded T cells were identified in TCR Vβ 1, 2, 3, 7, 8, 12, 14, 16~20, 22 and 23 subfamilies in 4 ALL patients (BCR-ABLP190 remission) with cGVHD. As a contrast, oligoclonal or monoclonal expanded T cells were identified in TCR Vβ 2, 7, 8, 14, 17, 20, and 22 subfamilies in 2 chronic myeloid leukemia patients (BCR-ABLP210 remission) with cGVHD.
In conclusion, the predominant usage and clonal expansion of TCR Vβ subfamily T cells could be found in Ph+ ALL patients with cGVHD and these groups of specific T-cell clones (Vβ 1, 3, 12, 16, 18, 19 and 23) were potentially associated with cGVHD in ALL and might be responsible for maintaining CR in Ph+ ALL patients after allo-HSCT. Research Funding.
Results of the Hyper-CVAD Regimen in Elderly Acute Lymphocytic Leukemia (ALL)
Authors: O’Brien Susan , Thomas Deborah , Ravandi-Kashani Farhad , Faderl Stefan , Pierce Sherry , Kantarjian Hagop 
Published: April 2020

Abstract
Background. Understanding the causes of failure in older patients with ALL may help improve treatment strategies for this age group.
Study Aims. To define the causes of death in older (age ≥60 years) patients with ALL during induction and consolidation-maintenance with the dose intensive Hyper-CVAD regimen, and compare their outcome to those of older patients treated previously with less intensive regimens, and to those of younger patients treated with Hyper-CVAD.
Study Groups. 122 older patients treated with Hyper-CVAD were compared with 34 older patients treated with less intensive regimens, and 409 younger patients treated with Hyper-CVAD.
Results. The outcome in older patients on Hyper-CVAD, older patients on other regimens, and younger patients on Hyper-CVAD are shown in the Table.
Conclusion. Intensifying the chemotherapy in older patients with ALL reduced the incidence of leukemia resistance but increased the incidence of death in CR from myelosuppression-associated infections. The overall benefit: risk was favorable. Identifying novel low-intensity agents/regimens for older patients with ALL may improve the results.
Parameter Older; Hyper CVAD Older; Other Younger; Hyper CVAD P value Most deaths during induction and in CR were related to infections Number 122 34 409 % CR 84 59 92 &lt;0.001 % Induction mortality 10 12 2 NS for older % Resistance 5 27 2 &lt;0.001 % Death in CR 34 15 7 &lt;0.001 % Relapse 40 80 48 0.004 % 5-year survival 20 9 48 &lt;0.001
Single-Institution Experience with HyperC-VAD Protocol for Adult Acute Lymphoblastic Leukemia
Authors: Costa Maria Joao , Santos-Sousa Pedro Miguel A , Guerra Maria Lurdes , Gomez Maria Belén , Lopes Conceição , Esteves Graça , Fajardo José , Raposo João , d’Oliveira José João Gomes 
Published: April 2020

Abstract
Acute lymphoblastic leukemia (ALL) is much rarer in adult age than in childhood, accounting for less than a quarter of acute leukemias, and with an overall survival rate at 5 years below 38%. The authors report the group experience in the treatment of adult ALL with HyperC-VAD protocol. From 2004 to 2007, 21 patients with adult ALL (15 male/6 female), with a median age at diagnosis of 29 years [18;58], were treated: four with ALL-L3/Burkitt lymphoma, six with T cell ALL/lymphoblastic lymphoma, eight with B cell ALL/lymphoblastic lymphoma, and three with ALL with t(9;22). The protocol consists of 4 courses of HyperC-VAD (cyclophosphamide 300mg/m2 IV q12h, on days 1–3; vincristine 2mg IV qd, on days 4 and 11; doxorubicin 50mg/m2 IV, on day 4; dexamethasone 40mg IV/PO qd, on days 1–4 and 11–14) that alternate with 4 courses of HD MTX-ARAC (methotrexate 1g/m2 IV, on day 1; cytarabine 3g/m2 IV q12h, on days 2–3). Those patients with ALL with t(9;22) received imatinib 400mg IV qd, on days 1–14 of each course; and CD20-positive cases received rituximab 375mg/m2 IV qd, on days 1 and 11 (odd courses) or on days 1 and 8 (even courses) of the first 4 courses. All patients received central nervous system prophylaxis in each course with methotrexate 12mg intrathecal on day 2 and cytarabine 100mg intrathecal on day 8. All patients (21/21) achieved complete remission after the first course of chemotherapy. Two patients abandoned the protocol due to neurologic and hematologic toxicity. The relapse rate was 47.6% (10/21), and the overall survival was 61.9% (13/21) – all deaths were due to disease progression. Overall, 131 courses were completed (69 odd courses/62 even courses). The most frequent complication was febrile neutropenia (32.8% - 18 in odd courses; 25 in even courses). The most severe complications were gram-negative septic shock (2 in even courses) and severe axonal polyneuropathy (1 in an odd course; 1 in an even course). Although these results are consistent with the literature, a longer follow up is needed to draw definitive conclusions.