bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III Trial of 2-Weekly CHOP with Rituximab for Aggressive B-Cell Non-Hodgkin’s Lymphoma in Elderly Patients.
Authors: Sonneveld Pieter , van Putten Wim , Biesma Douwe , Holte Harald , van Marwijk Kooij Marinus , Kramer Mark Henri H. , Wijermans P.W. , Steijaert Monique , van Imhoff Gustaaf W. , Lugtenburg P.J. , Huijgens P.C. , Eriksson Mikael 
Published: October 2019

Abstract
Treatment results in elderly patients (> 65 yrs) with aggressive Non-Hodgkin lymphoma (NHL) are associated with a lower complete response (CR) rate and a worse survival (OS). Efforts have been made to improve the outcome by adding Rituximab to standard CHOP chemotherapy or by intensifying CHOP from 21 days to 14 days intervals (2-weekly CHOP, CHOP14). The Dutch HOVON and the Scandinavian Nordic groups have performed a prospective, multi-center, randomized phase III trial to compare 8 cycles of CHOP14 chemotherapy with or without 6 administrations of Rituximab (R-CHOP14), supported by G-CSF in previously untreated, older patients with intermediate or high-risk B-cell NHL. Inclusion criteria were mantle cell lymphoma, follicular lymphoma grade III or diffuse large B-cell lymphoma; intermediate or high age adjusted IPI score; CD20-positive NHL; age greater than 65 yrs. The target number was 400 patients to be accrued in 5 years based on an expected increase in failure free survival with hazard ratio HR=0.70. Based on a planned interim analysis the Data and Safety Monitoring Board stopped the trial because of a significant difference for primary endpoints. At final analysis 243 of 261 patients were eligible and evaluable. The median follow up was 20 months (range 3–46). The median age was 72 years (range 65–85 years), 80 % had DLBCL, 60 % had intermediate-high/high age-adjusted IPI score, 65 % had increased serum LDH. 64% of patients completed the planned treatment, while 22% went off treatment because of toxicity, of which 2 % was cardiovascular. 14% of patients experienced CTC grade 3–4 infections.
The number of patients who went off treatment because of toxicity was 15 % in those aged < 70 and increased with age up to 38 % in those over 75 yrs. After 3–4 cycles 16 % of the patients in the R-CHOP arm achieved a CR(u) as compared to 12 % with CHOP14; after 8 cycles the difference was 66 % vs 46 %. Overall response (PR+CRu) was 92 % and 83 %, respectively. Overall survival (OS) by Cox regression analysis adjusted for aaIPI and diagnosis was better with R-CHOP14 than with CHOP14 (relative hazard ratio HR=0.69, 95 % CI 0.46-1.05, p=0.09). The primary endpoint Failure free survival (FFS) was better in the R-CHOP14 arm (38 failures: 9 non-responders, 29 relapses, FFS2yr =55%)) than in the CHOP14 arm (65 failures: 20 non-responders, 45 relapses, FFS2yr =33%) with hazard ratio HR=0.60 (P=0.007). In the subgroup of DLBCL, FFS2yr was 62 %, while log-rank OS (p=0.05) and FFS (p=0.004) were both superior with R-CHOP14. These data indicate that in an elderly population (median age 72 yrs) with highly aggressive NHL, the CHOP14 regimen is tolerable and achievable in > 60 % of patients, and that the addition of Rituximab improves CR rate, OS and FFS.
Methylprednisolone Influences Zap-70 in B-CLL In Vitro.
Authors: Boelens Jerina , Lust Sofie , Janssens Ann , Philippé Jan , Poelman Martine , Offner Fritz 
Published: October 2019

Abstract
Zap-70 is accepted as a surrogate marker for mutational status of immunoglobulin heavy-chain variable region genes in B-CLL. Whether Zap-70 is a functional target for treatment of the more aggressive CLL cells that express unmutated IgVH is still under investigation.
The use of methylprednisolone (Mp) is widespread in the treatment of B-CLL related concomitant auto-immune disorders. We have recently demonstrated that Zap-70+ B-CLL cells are more resistant to chemotherapy but more susceptible to apoptotic cell death by steroids than Zap-70 negative cells in vitro. We investigated the possible influence of Mp on the expression of Zap-70 in B-CLL cells.
Mononuclear cells of 15 patients with B-CLL were isolated by Ficoll centrifugation and incubated with different concentrations of Mp (range 0.1–500 μM). After 24h and 48h, Zap-70 expression, phospho-ZAP-70 (Tyr 319 and Tyr 493) and apoptosis were evaluated by flow cytometry (indirect staining ZAP-70 and phospho-ZAP-70 and Annexin V-FITC/propidium iodide double staining for apoptosis) and Western blotting when appropriate. Student’s t-test was used for statistical analysis. Mp induces time and dose dependent apoptosis in B-CLL cells (LD50 48h=16.8 μM). After 24h and 48h of incubation at doses of 50 μM, Zap-70 expression decreased significantly (50 μM: p<0.001) and more prominently in B-CLL than in T cells. We also observed a time but not concentration dependent decrease of phospho-ZAP-70 expression, on flow cytometry and western blotting. The observed down-regulation of phospho-ZAP-70 after Mp treatment is probably more important than the down-regulation of ZAP-70, since the phosphorylated form of ZAP-70 is responsible for signal transduction. The effect on P-ZAP-70 can theoretically be explained by an increase in phosphatase activity, a reduction in kinases or an increased susceptibility of the unphosphorylated form to proteasomal degradation. The effect of Mp on P-Zap-70 was inhibitable with the pan-tyrosine-phosphatase inhibitor sodium orthovanadate, but not with the proteasome inhibitor MG0132. Inhibition of the glucocorticoid receptor with mifepristone inhibited induction of apoptosis but not ZAP-70-decrease. Fludarabine treatment of the cells caused comparable levels of apoptosis but negligible decrease of ZAP-70 expression suggesting the decrease in Zap-70 phosphorylation is not due to the apoptosis by itself. On the other hand since mifepristone can inhibit the apoptotic effect of Mp but not the decrease of Zap-70 expression, the potential inhibiting Zap-70 phosphorylation as a therapeutic target should be questioned, and apoptosis induced by methylprednisolone may not depend on it.
Chromosomal Abnormalities in Philadelphia Chromosome (Ph)-Negative Metaphases Appearing during Novel Tyrosine Kinase Inhibitors (NTKI) Therapy in Patients (pts) with Chronic Myeloid Leukemia (CML) after Imatinib-Failure.
Authors: Jabbour Elias , Kantarjian Hagop , Abruzzo Lynne , Giles Francis , Rios Mary Beth , Cortes Jorge 
Published: October 2019

Abstract
The development of chromosomal abnormalities in the Ph-negative metaphases during IM therapy of CML has been recognized in pts with CML. This is different from clonal evolution where the abnormalities are observed in the Ph-positive metaphases. This phenomenon has not been yet systematically assessed to date in patients treated with NTKIs such as dasatinib and nilotinib. By definition, this phenomenon is evaluable only among pts who achieve at least a minor cytogenetic response. We assessed the frequency and the significance of this event among 107 pts with CML after imatinib failure receiving dasatinib (=70) or nilotinib (n=37) therapy between June 2003 and March 2006. After a median follow-up of 13 months (range, 3–32 months), 12 pts (11%) (chronic phase n=6, accelerated phase n=6) receiving dasatinib (n=6) or nilotinib (n=6), developed 21 chromosomal abnormalities in Ph-negative metaphases. Ten (48%) of these abnormalities have been seen in 2 or more metaphases. The median time from the start of the NTKI to appearance of abnormalities was 7 months (range, 0–15 months). The most common cytogenetic abnormalities were: trisomy 8 (n=3, 14%) and del 20q (n=3, 14%). Excluding loss of chromosome Y abnormalities and abnormalities observed in only one metaphase, the incidence was 5%. At the time, abnormalities were detected, 8 pts were in major cytogenetic response (complete in 6) and 4 in minor cytogenetic response. In all but 4 pts these events have been transient and disappeared after a median of 4 months (range, 3–9 months). In 4 pts (+8 n=2, −Y n=1, and add1q, del10q, and del20q n=1), they persisted for a median of 5+ months (range, 3+ – 9+ months). One pt on dastinib developed refractory anemia with ringed sideroblasts (associated with trisomy 8); he had CML for 16 years, failed prior therapy with interferon, imatinib, and nilotinib, and achieved a complete cytogenetic response on dasatinib; none of the other pts has any feature of myelodysplasia. At the last follow-up, all pts are alive: 2 pts lost their response; one of them underwent allogeneic stem cell transplantation and achieved a major molecular remission. The other 10 pts remained in major cytogenetic response (complete in 8). We conclude that cytogenetic abnormalities occur in Ph-negative cells in a small fraction of patients (11%; 5% if loss of Y and abnormalities in one metaphase excluded) treated with the NTKIs. These are frequently transient and usually have no clinical significance, but in rare instances they could signal the emergence of a new malignant clone.
BCR/ABL Promotes Neutrophil Differentiation through Downregulation of c-jun Expression.
Authors: Kobayashi Shinichi , Kimura Fumihiko , Ikeda Takashi , Osawa Yukiko , Torikai Hiroki , Sato Ken , Motoyoshi Kazuo 
Published: October 2019

Abstract
The BCR/ABL fusion protein transforms hematopoietic stem cells and causes chronic myeloid leukemia (CML). An increasing number of mature neutrophils is a characteristic feature in the chronic phase of CML. However, the mechanism by which stem cells transformed by Bcr/Abl differentiate mainly to mature neutrophils remains obscure. To investigate this mechanism, we compared the gene expression profile of CML neutrophils with that of normal neutrophils by microarray analysis. The genes encoding neutrophil granule proteins were upregulated in CML neutrophils, and C/EBPα and C/EBPε, critical transcription factors that regulate granulocytic differentiation, were also upregulated in these neutrophils. On the contrary, the expression of c-jun, a transcriptional factor that contributes to monopoiesis, was downregulated in CML neutrophils. Differences in the expressions of these genes were confirmed by quantitative RT-PCR. A BCR/ABL tyrosine kinase inhibitor, imatinib, released the downregulation of c-jun expression in primary CML neutrophils, showing that Bcr/Abl inhibited the expression of c-jun.
Next, to explore the roles of these transcriptional factors in the chronic phase of CML, we established sublines of KCL22, a cell line derived from CML blastic crisis, in which C/EBPα or C/EBPε expression was inducible (KCL22/α or KCL22/ε respectively). Overexpression of either C/EBP protein resulted in morphological changes, such as a reduction of the nuclear to cytoplasmic ratio, more condensed nuclear chromatin, and segmented nuclei, as well as the expression of differentiation specific markers including G-CSF receptor. These data indicate that C/EBPα/ε expression is sufficient to induce myeloid differentiation in BCR/ABL-positive CML cells. Imatinib treatment released the down regulation of c-jun in KCL22, KCL22/α, and KCL22/ε cells in a manner similar to that in primary cells. Interestingly, imatinib induces monocytic differentiation of KCL22/α cells instead of granulocytic differentiation. This effect of imatinib is independent from C/EBPα induction in KCL22/α cells. The monocytic differentiation and the inhibition of granulocytic differentiation in KCL22/α cells were accompanied by c-jun upregulation. To investigate whether these effects on differentiation of KCL22/α cells depend on releasing the downregulation of c-jun expression with imatinib, we knocked down c-jun expression with siRNA in KCL22/α cells after induction of C/EBPα protein and with imatinib treatment. In the fraction of KCL22/α cells with segmented nuclei, the G-CSF receptor increased when c-jun expression was inhibited with siRNA, indicating that the level of c-jun expression controlled the differentiation fate of CML cells. These findings suggest that Bcr/Abl promotes neutrophil differentiation through downregulation of c-jun accompanied by elevated expressions of C/EBPα/ε.
Imatinib Treatment of Philadelphia Positive (Ph+) Chronic Myeloid Leukemia (CML). For Late Chronic Phase Patients Who Achieve a Complete Cytogenetic Response 5-Year Survival Is as High as for Early Chronic Phase Patients.
Authors: Iacobucci Ilaria , Martinelli Giovanni , Amabile M. , Poerio A. , Soverini S. , Castagnetti F. , Colarossi S. , Gnani A. , Testoni N. , Breccia M. , Abruzzese E. , Martino B. , Cilloni D. , Saglio G. , Pane F. , Rosti G. , Baccarani M. 
Published: October 2019

Abstract
Background: Imatinib (IM) is the drug of choice for the treatment of Ph+ CML, where a complete cytogenetic response (CCgR) is achieved in more than 80% of early chronic phase (ECP) patients, with a 5-year survival of 90% (Simonsson B, Blood 2005). In the patients who initiated the treatment in late chronic phase (LCP) the response rate is lower and the long-term effect on survival is not yet determined.
Aim: We monitored the hematologic, cytogenetic and molecular response to IM in a cohort of 291 patients who were treated with IM in LCP, with focus on progression-free survival and overall survival of complete cytogenetic responders.
Methods: Two hundred and ninety-one patients with Ph+ CML in LCP were enrolled in a national prospective study of the GIMEMA CML Working Party in 2001, and were monitored for cytogenetic response and for molecular response every 6 months. Cytogenetics was performed on bone marrow cells with conventional methods. Molecular response was assessed on bone marrow or peripheral blood samples by quantitative PCR (RQ-PCR) using TaqMan methodology and expressing the results as a ratio of BCR-ABL to ABL x100. Patient age ranged from 19 to 82 years (median 52 years). The duration of chronic phase prior to IM treatment ranged from 1 to 202 months (median 38 months). Treatment was IM 400 mg daily through all the study period, with a few exceptions of dose increase to 600 or 800 mg. The median follow-up time after the first IM dose is 62 months.
Results: One hundred and sixty patients (55%) achieved a CCgR in 3 to 62 months (median 6 months) after the first IM dose and 126 of them (79%) are still in continuous CCgR after 5 years. For the 160 patients the 5-year survival free from progression to accelerated or blastic phase is 95% and overall survival is 91%. These data are very similar to those reported for the ECP patients in the IRIS study (Simonsson B, Blood 2005). At 5 years, 107 patients were evaluated for molecular response; 62% of them were in major molecular response with a BCR-ABL/ABL ratio lower than 0.10. The BCR-ABL transcript was undetectable in 7 cases by RQ-PCR and in 2 cases by nested PCR. No patient developed heart failure.
Conclusions: We confirm that in LCP the CCgR rate to IM is lower than in ECP, but we show that for the complete cytogenetic responders progression-free and overall survival are likely to be as good as for ECP patients, suggesting that the quality of the CCgR is prognostically more important than the duration of leukemia prior to IM treatment.
Figure Figure
Comparison of Combination Therapy of Imatinib with Trisenox Versus Imatinib Monotherapy for Chronic Myeloid Leukemia Patients in Chronic Phase.
Authors: Yang Dongguang , Zhang Ri , Shen Yunfeng , Zhang Xuhui , Wu De Pei 
Published: October 2019

Abstract
Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients.
Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),--defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),--defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively.
Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.
Dasatinib (SPRYCEL®) in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Chronic Phase (CML-CP).
Authors: Cortes Jorge , O’Brien S. , Jones D. , Borthakur G. , Giles F. , Nicaise C. , Kantarjian H.M. 
Published: October 2019

Abstract
Dasatinib (SPRYCEL®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity, leading to FDA approval in pts with CML-CP who are resistant to or intolerant of imatinib (im), the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤0.05% by qPCR) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Blood counts were done weekly for the first 4 weeks (wks), every 4–6 wks for the first year, and then every 3–4 mo; bone marrow aspirates with cytogenetics were obtained at baseline and every 3–4 mo during the first year, and then every 6–12 mo; molecular monitoring of BCR-ABL transcript levels by qPCR was done at baseline, every 3-4 mo for the first year, and then every 6–12 mo. Of the first 24 pts enrolled between November 2005 and June 2006, pooled across dosing schedule, 54% were female; median age was 44 years (range 18–76). Nine (38%) of the pts were Sokal intermediate-risk and 1 (4%) was high-risk. Median baseline WBC count was 17.4 x109/L (range 3.7–300.0). At 3 mo, complete hematologic response (CHR) and major cytogenetic response (MCyR) was seen in 17 (89%) of 19 pts who had received at least 3 mo of therapy, and complete cytogenetic response (CCyR) was seen in 15 pts (79%). This compares favorably with a CCyR at 3 mo of 37% with im 400 mg/day and 61% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. qPCR at 3 months was <1% (ie, approximately 2-log reduction) in 5 (26%), and was <10% in 9 (47%) of these 19 pts. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in 3 pts and was gr 1–2 in all. Hematologic toxicity included anemia in 8 pts (4 gr 3), pancytopenia in 4 pts (3 gr 3, 1 gr 4), and thrombocytopenia in 4 pts (2 gr 3, 2 gr 4). With a median duration of therapy of 5 mo, there were 10 pts who required interruption of treatment, 6 due to non-hematologic toxicities, 2 due to hematologic toxicities, and 2 due to both. Dose reductions occurred in 6 pts, 3 due to non-hematologic toxicity, 1 due to hematologic toxicity, and 2 due to both. Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML-CP. Accrual to this trial continues, and updated efficacy and safety data will be presented at the meeting.
Combination of the Histone Deacetylase Inhibitor Vorinostat and Dasatinib Increases Apoptosis in Bcr-abl+ Cells and Reverses Changes Associated with CML Progression.
Authors: Kretzner Leo , Scuto Anna , Juhasz Agnes , Jove Richard , Yen Yun , Forman Stephen J. , Kirschbaum Mark 
Published: October 2019

Abstract
Chronic myelogenous leukemia (CML) is associated with the bcr-abl fusion gene product, a constitutively active non-receptor tyrosine kinase driving cell division. The potent bcr-abl kinase inhibitor, dasatinib, is now FDA approved for imatinib-refractory patients, being active in most cases other than those with the T315I mutation. However, accelerated phase CML is typified by further genetic changes, including the suppression of various DNA damage response and apoptosis related proteins (Radich, et al PNAS 2006). Thus a novel approach which may reverse these changes, might provide better treatment of accelerated phase CML.
A new class of agents targeting epigenetic processes, the histone deacetylase inhibitors (HDACi), is believed to act upon chromatin allowing re-expression of tumor suppressor genes believed to be closed off to transcription by the tumor in its effort to grow in an uncontrolled manner. We reasoned that adding an HDACi to dasatinib treatment of CML cells could promote re-expression of genes responding to genetic instability in these cells. To test this hypothesis we tested dasatinib (D) and the HDACi Vorinistat (V, suberoylanilide hydroxamic acid, SAHA) alone and in combination, using K562 cells. Apoptosis was measured by Annexin V staining after 48 hours.
Apoptosis results: 1uM Vorinostat: 10%; 2 uM V: 16%. Dasatinib 0.5 nM: 28%, 1 nM D: 44% In combination, 1uM V + 0.5 nM D: 41%, 1 uM V + 1nM D: 64%, 2 uM V + 0.5 nM D: 65%, 2 uM V + 1 nM D: 67%, suggesting significant increase in apoptosis for the combination over either single agent treatment alone.
We therefore began surveying panels of DNA damage- and apoptosis-related genes by means of RT-PCR. Studying the combination of 2 uM V + 1 nM D, we found increased expression of several proteins, including GADD45G and FANCG, both DNA damage response proteins suppressed in the progression to accelerated phase CML. Other proapoptotic proteins were increased such as MAP2K6, SEMA4A, BIK, and TNF superfamily members 7 and 25. This data suggests that the changes associated with progression from chronic phase to accelerated and blast crisis CML may be epigenetic in nature, and that these changes may be reversed by the combination of vorinostat and dasatinib. A clinical trial of dasatanib and vorinostat in advanced phase CML would be of value.