bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Pilot Study of Imatinib Mesylate Combined with Induction Chemotherapy in Blast-Phase CML and Ph+ ALL.
Authors: Lickliter Jason , Arthur Chris , D’Rozario James , Hui Chi-hung , Szer Jeffrey , Taylor Kerry , Watson Anne-Marie , McCarron Jennifer , Lynch Kevin , Bradstock Ken 
Published: April 2020

Abstract
CML in blast crisis (BC) and Philadelphia chromosome-positive (Ph+) ALL are incurable with conventional chemotherapy and in most cases respond only transiently to the Bcr-Abl kinase inhibitor imatinib mesylate. We hypothesized that pretreatment with imatinib would overcome inherent drug resistance to induction chemotherapy mediated by Bcr-Abl, and evaluated the combination in 17 patients with Ph+ acute leukemias (5 CML in BC, 6 de-novo Ph+ ALL, 6 relapsed Ph+ ALL). All patients received a 1-week prephase of imatinib alone at 600 mg daily. In CML in BC and relapsed Ph+ ALL, imatinib was continued concomitantly with induction chemotherapy (standard-dose idarubicin/ara-C with vincristine/prednisone added for lymphoid leukemias) for an additional week. Imatinib was then ceased, but recommenced as a single agent after blood-count recovery. Patients with de-novo Ph+ ALL received the imatinib prephase and then commenced the French LALA94 protocol without concomitant imatinib. Neutrophils recovered to ≥ 1.0 x 109/L at a median of day 28 (range 21–56) of induction chemotherapy. During induction, 1 patient died from sepsis and multi-organ failure, and 1 patient died on day 7 from CNS leukemia.
Subsequently, 1 patient died on day 37 from massive hemoptysis and 1 patient developed pulmonary fibrosis and died on day 144. Among 14 evaluable patients, combined imatinib and chemotherapy induction resulted in 9 (64%) complete hematological responses and there were 5 complete and 3 major cytogenetic responses. Notably, 2 out of 3 patients with CML in myeloid BC achieved major cytogenetic responses. The in-vivo effects of imatinib on Bcr-Abl activity were monitored in leukemic blasts during the imatinib-only prephase. Western blots revealed a decrease in CrkL phosphorylation to &lt; 25% of the pretreatment level in peripheral-blood samples from 5 out of 6 evaluable cases and in marrow samples from 1 of 2 evaluable cases. Bcl-xL expression levels revealed no consistent in-vivo responses to imatinib. However, all 7 cases evaluable for Bcl-2 protein showed strong expression levels, which were unaffected by imatinib in 5 cases and decreased in 2 cases. Imatinib potently inhibited Bcr-Abl activity in vivo in Ph+ acute leukemic blasts and its combination with induction chemotherapy was tolerable and shows promising activity.
Monitoring of BCR-ABL Transcirpt Levels after Discontinuation of Imatinib Therapy in Chronic Myelogenous Leukemia Patients Achieving Complete Cytogenetic Response.
Authors: Kim Yoo-Jin , Kim Dong-Wook , Lee Seok , Eom Ki-Seong , Min Chang-Ki , Kim Hee-Je , Lee Jong-Wook , Min Woo-Sung , Kim Chun-choo 
Published: April 2020

Abstract
Background Imatinib induces a high complete cytogenetic response (CCR) rate in chronic myelogenous leukemia (CML). None of the studies addressed the important question of how long imatinib treatment should be continued. To answer this question, we tried to assess the minimal residual disease after cessation of imatinib in patients achieving CCR.
Methods A total of 23 patients were enrolled and their disease status at the start of imatinib was chronic phase in 7, accelerated phase in 3, blast crisis in 1, and post-transplant relapse in 12 patients. All the patients were in CCR when imatinib was discontinued and BCR-ABL transcript was undetectable in 9 of them. Minimal residual disease was monitored using nested RT-PCR, real-time quantitative RT-PCR, and conventional cytogenetics.
Findings Duration of imatinb treatment and CCR before cessation of imatnib was a median of 13 months (range, 6–25 months) and 10 months (range, 1–22 months), respectively. After cessation of imatinib treatment, cytogenetic relapse was observed in 12 (53%) of 23 patients and hematological relapse was followed in 8 (67%) of them. Extramedullary relapse was documented in 1 patient. Prior allogenetic transplantation, molecular remission at the time of cessation, and time to CCR were potential variables affecting probability of cytogenetic relapse. Normalized BCR-ABL transcript level progressively increased after cessation of imatinib in all but 3 patients who had been treated with allogeneic transplantation. Restart of imatinib induced down-regulation of normalized BCR-ABL transcript level in 5 patients with available data.
Interpretation Imatnib should be maintained in the most of patients who achieve a short duration of CCR as in the cases with interferon treatment. However, this study suggests that it seems possible to stop imatinib treatment in the minority of CML patients who was treated with allogeneic transplantation.
Quality of Life and Economic Impact of Red Blood Cell (RBC) Transfusions on Patients with Myelodysplastic Syndromes (MDS).
Authors: Brechignac S. , Hellstrom-Lindberg E. , Bowen D. T. , DeWitte T. M. , Cazzola M. , Fenaux P. 
Published: April 2020

Abstract
Background: Supportive care with blood product transfusions is the primary management strategy for the majority of patients with MDS. Approximately 80% of MDS patients are anemic at the time of presentation and more than 40% require regular RBC transfusions at some stage of disease, while platelet transfusions are less often required.
Methods: In an effort to systematically study quality of life and economic cost associated with transfusion dependency (especially RBC transfusions), The MDS Foundation has disseminated a practices and treatment survey to its Centers of Excellence and is also accumulating transfusion data. Retrospective and prospective data collected include hematologic parameters defining transfusion need; percentage (%) of MDS patients requiring transfusion; % of transfusion-dependent MDS patients by subtype and International Prognostic Scoring System (IPSS) risk group; per patient frequency of transfusions; % of patients requiring iron chelation therapy.
Results: A total of 30 Centers have replied to the survey to date, and responses reveal that a substantial proportion of MDS patients receive multiple RBC transfusions with most of these patients needing chelation therapy with desferoxamine (generally subcutaneous administration, 4-times weekly): Table 1.
In addition, detailed data are available from 4 European Centers that have provided transfusion records from randomly selected multiply-transfused MDS patients: 38 patients (median age: 73) received a median of 42 transfusions over the last 24 months (range: 11–207). The average per transfusion costs calculated from estimates provided by the 4 European centers is 436 euros or $ 526 ($1 US dollar = 0.83 euros), where the per transfusion cost includes 2 filtered red blood cell units, blood collection, administrative costs, and staff time, resulting in a median per patient cost over the last 24 months of 11,118 euros (range: 5668–21,800 euros). This does not include the cost of chelation therapy (300 euros/month for desferioxamine SC) and indirect costs (e.g., time spent at transfusion facility, travel time for patient to facility, travel and wait time for private caretaker or family member).
Conclusion: Preliminary data analysis from the ongoing retrospective study suggests that the transfusion burden to MDS patients and to society, in terms of quality of life and cost, is much greater than generally appreciated. Updated data of this study will be presented.
Table 1: RBC Transfusion-dependent MDS patients
Mean % IPSS low risk 39 IPSS intermediate-1 risk 50 IPSS intermediate-2 risk 63 IPSS high risk 79 Iron chelation therapy 28
Treatment of Del(5q) Myelodysplastic Syndrome with All-Trans-Retinoic Acid and Tocopherol-α.
Authors: Giagounidis Aristoteles A.N. , Haase Sabine , Germing Ulrich , Schoch Claudia , Schlegelberger Brigitte , Wilkens Ludwig , Büsche Guntram , Kreipe Hans H. , Aivado Manuel , Lübbert Michael , Ganser Arnold , Aul Carlo 
Published: April 2020

Abstract
All-trans-retinoic acid (ATRA) alone or in combination with cytokines and vitamins has shown erythroid remitting capacities in low-grade myelodysplastic syndromes (MDS). We performed a phase II study on 29 patients with MDS and isolated del(5q) including bands 5q31–5q33 to determine the efficacy and safety of ATRA in combination with tocopherol-α. All patients had low/intermediate-1 risk MDS according to the international prognostic scoring system. Inclusion criteria were isolated del(5q), medullary blast count of &lt;10%, hemoglobin &lt;10g/dl or transfusion dependent anemia, and ECOG performance score &lt;3. Included were 18 women and 11 men. Median age of patients was 64 years. FAB subtypes were 25 refractory anemias, 1 refractory anemia with ring sideroblasts, 3 refractory anemias with excess of blasts. Median MDS duration before ATRA treatmnet was 31.7 months. Median hemoglobin level was 8.4 g/dl at study entry. Patients received 45 mg/m² ATRA day 1 to 90, and 90 mg/m² day 91 to 180. Tocopherol dosage was 600 IU three times daily. 24 patients completed dose level I, 12 patients dose level II. 86% of patients experienced side effects. 13 interrupted study drug treatment due to adverse events: Skin reactions (NCI grade 3), conjunctivitis (grade 3), headache and joint pain (grade 3) were the worst recorded. Other adverse events included hair loss, CNS symptoms, cheilitis, stomatitis, creatinine elevation, hypertriglyceridemia, hypercholesterinemia, nausea and vomiting, and elevation of liver function tests. 3 patients were admitted to hospital for side effects and these were therefore qualified as serious. Response criteria were qualified as recommended by the international working group for MDS. One patient (3%) achieved a major erythroid response resulting in transfusion independence throughout the study. He became transfusion dependent again within one month after study termination. 4 patients (14%) achieved a minor erythroid response with reduction of &gt;50% of transfusion needs. No patient had a cytogenetic response. Responders did not show a reduction in del(5q) as determined in interphase fluorescence in-situ hybridization. There was no significant improvement in quality of life in responding patients as measured by the EORTC quality of life questionnaire. We conclude that the combination of ATRA and tocopherol-α is not recommended for the treatment of del(5q) MDS.
The Expression of Platelet Membrane Glycoproteins in Patients with Myelodysplastic Syndrome (MDS).
Authors: Girtovitis Fotios I.F. , Papagiannis Vasilis , Klonizakis Ioannis , Papadopoulos Athanasios , Bougiouklis Dimitris , Boutou Afroditi A.K. , Makris Pantelis P.E.M. 
Published: April 2020

Abstract
The receptors of platelet membrane have a significant function. Most of them are glycoproteins and play a major role in the adhesion and aggregation of platelets, in a way that any change of their quantity or quality will lead to functional defects of the second.
Aim of this study is to determine the qualitative expression of platelet membrane glycoproteins among patients (pts) with MDS, as a reflection of the various defects that characterize those syndromes.
Materials and methods: 24 pts were studied, 15 male and 9 female with mean age 73.2 ± 13,4 years old, who suffered from all of the types of MDS (FAB classification).
Specifically, 9 patients (pts) presented RA, 2 pts RARS, 7 pts RAEB, 2 pts RAEB-t and 4 CMML. All of the pts, as well as 16 normal subjects (8 male and 8 female with 68,4±9.7 old age) who were used as controls, were investigated using flow cytometry and certain monoclonal antibodies(CD42a and CD42b for glycoproteins GPIb-V-IX, CD41 and CD61 for glycoproteins GPIIb-IIIa and CD62P for P-selectin). The statistical method used was the comparison of mean values by t-test.
Conclusions: As shown in the table above, GPIb IX-V (CD42b), P selectin and GpIIb are reduced in all of the categories of pts. As long as GpIIIa is concerned, it is reduced only among pts with RARS and RAEB. On the contrary, CD42a (GpIb) does not seem to have been affected by these hemopoietic disturbances. It is possible that the reduction of those receptors a) reflects changes in the normal production of platelets and b) explains functional disorders of platelets.
n CD42a % CD42b % CD41 % CD61 % CD62 % RA 9 97.6±3,29 49.5±25,2 60±32,4 91.8±17,2 8.2±7,4 RARS 2 80.5±17,5 52.8±42,8 36±35,8 72±26 6.7±3,3 RAEB 7 89.4±14,1 58.9±29,9 58.8±29 77.6±28,2 6.3±4,5 CMML 4 97.3±2,08 37,8±20,7 70.3±25,7 95.8±2,7 2±0,5 RAEB-t 2 95.3±2,15 32.8±4,95 44.1±9,15 93.9±1,85 7.2±6,7 Total 24 92±20,1 46.3 ±27,9 53.8±29,8 86.2±21,8 6±6 Controls 16 95.9±3,4 78.23±17,5 85.5±8,5 95.36±3,01 14.1±10,6
Prolonged Administration of Arsenic Trioxide (Trisenox®) for Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) at MD Anderson Cancer Center: A Phase II Study.
Authors: Beran Miloslav , Verstovsek Srdan , Kornblau Steven M. , Estey Elihu H. , Giles Francis , Garcia-Manero Guillermo , Kantarjian Hagop M. 
Published: April 2020

Abstract
The value of prolonged administration of arsenic trioxide (ATO) was examined in patients (pts) with MDS and CMML. ATO (0.25 mg/kg) was given intravenously over 1 hour daily for five days followed by 0.25 mg/kg twice weekly for 11 weeks. Pts were assessed at 4 weeks, at the end of the first course, and then monthly. Pts with stable disease were eligible for further courses. The study included 14 RBC transfusion-dependent MDS pts (6 RA/RARS, 8 RAEB; 12 IPSS risk Low/Int1, 2 Int2/High), and 3 CMML pts. Median age was 67 years (range 46–84). Six pts had a history of previous treatment other than supportive care. 16 pts were evaluable for toxicity and response. One pt received 3 courses, 3 received 2 courses, and 13 received 1 course. Hematologic responses (IWG criteria) were observed in 4 pts (25%) and 9 (6 MDS,3 CMML) had stable disease:
FAB Type of response Time to response Duration RA Minor erythroid 2 months 3 mo, RBC independence RAEB Major neutrophil and platelet 2 mo 3 mo RAEB BM blast decrease 18% to &lt;5% 1 mo 14 mo, stable pancytopenia RAEB Hematologic/cytogenetic CR 1 mo 6 mo
Hematologic/cytogenetic CR was achieved in one pt: a 76 year old male, RAEB-2, Int 2, complex chromosomal abnormalities, who had previously failed thalidomide for 6 months and thalidomide + cyclosporin A for 3 months. Of the 3 CMML pts, one had transient reduction of absolute monocyte counts during each of 2 courses; all 3 had stable disease. In 24 courses there were 6 febrile episodes in 4 patients, requiring admission, all in pts with pre-existing neutropenia; 1 Grade 3 and 1 Grade 4 thrombocytopenia, 1 Grade 3 neutropenia, all requiring dose modification; 1 episode of accelerated functional cardiac rhythm; and 1 anemia-precipitated congestive heart failure, which was unlikely related to the drug. There were 22 episodes of Grade 1 or 2 drug-related toxicities. Four responses of 3–7+ mo. duration were observed, including 1 CR, suggesting activity in an as yet undefined subgroup of MDS pts. No benefit of prolonged treatment was documented. ATO was safe in this outpatient setting for elderly patients. Observed low toxicity and documented activity support future trials of ATO in combination with other agents in treatment of MDS.
2 Chlorodeoxyadenosine (2-CdA) and Cytarabine (ara-C) Combination Is Effective and Safe in Idiopathic Hypereosinophilic Syndrome (HES).
Authors: Jabbour Elias , Verstovsek Srdan , Gandhi Varsha , Cortes Jorge , Giles Francis , Koller Charles , O’Brien Susan , Plunkett William , Garcia-Manero Guillermo , Jackson Ellen , Kantarjian Hagop , Andreeff Michael 
Published: April 2020

Abstract
Hypereosinophilic syndrome (HES) is rare, disabling, and incurable disease. In a pilot study, the combination of 2-CdA and ara-C chemotherapy has been evaluated in 9 patients. The median time from diagnosis to therapy was 25 months. All patients had signs and symptoms of end-organ involvement. Seven patients received prior therapies. The median eosinophil count at presentation was 14 x109/L (0.3–110 x109/L) and the median percent eosinophilic bone marrow infiltration was 23% (6%–43%). Ara-C (1g/m2) was given intravenously over 2 hours at hours 0, 48, 72, 96, and 120; 2-CdA (12 mg/m2/day) was given as continuous infusion intravenously over 5 days starting at 24 hours. A second course at the same level was administered for patients who achieved complete remission (CR) and for patients who had &gt;50% reduction in eosinophilic infiltration. Two patients studied for pharmacokinetics of ara-CTP (active metabolite of ara-C) in the circulating blood cells accumulated either similar or higher levels of ara-CTP after infusion of 2-CdA. Five patients (55%) achieved CR, one requiring 2 cycles. Elimination of eosinophilia was accompanied by the resolution of symptoms. The median disease free survival was 26 months; 1 patient remains disease free (after allogeneic transplantation) at 42 months. The median overall survival from diagnosis for CR patients was 44 mo. Treatment was well tolerated. Febrile neutropenia occurred in 28% of the 14 cycles given. The median time to recovery from neutropenia and thrombocytopenia was 17 and 39 days, respectively. There was one death related to disease progression. We conclude that 2-CdA + ara-C combination regimen is safe alternative therapy for HES. The addition of consolidation therapy or imatinib may improve the results.
Detailed Analysis of Apoptotic Responses to Cytokine Stimulation in B-Cell Chronic Lymphocytic Leukaemia.
Authors: Jewell Andrew P. , Smith Wendy , van Schie Rob , Porakishvili Nina , Lydyard Peter M. 
Published: April 2020

Abstract
Introduction B cell Chronic lymphocytic leukemia (BCLL) is characterized by the accumulation of monoclonal malignant CD5+ B cells that show resistance to apoptosis in vivo, but are susceptible to apoptosis when incubated in vitro. A number of cytokines have been reported to protect against apoptosis in vitro, but it is not clear whether the effects of these cytokines are mediated in similar ways. We have therefore studied the regulation of apoptosis in B-CLL cells in vitro, in response to various cytokines.
Methods B-CLL cells were purified and incubated with the following agents; Interferon-gamma, IL-4, IL-10, IL-13, TNF-alpha and GM-CSF, each at 3 different concentrations. Apoptosis was measured after 70 hours by Annexin/PI staining and analysed for early apoptosis (Annexin V positive), late apoptotic (Annexin V and PI positive), and necrotic (PI positive).
Results The percentage of live cells in unstimulated B-CLL cells was 42.4±2.3%. Co-incubation of B-CLL cells with IL-4 at 100ng/ml increased the percentage of live cells to 63.2±8.4%, while in the presence of interferon-gamma the percentage of live cells was 48.7±5.9%. In contrast, co-incubation with TNF-alpha reduced the percentage of live cells to 30.8±6.8%. IL-10, IL-13 and GM-CSF had no effect on B-CLL cells survival at any of the concentrations used.. No significant differences in the pattern of early/late apoptosis or necrosis were seen between the different cytokines used.
Figure Figure
Molecular Events Underlying the Induced Differentiation of CLL Cells Are Recapitulated in Cess B Cells.
Authors: Battle Traci E. , Frank David A. 
Published: April 2020

Abstract
Although much progress has been made in recent years in understanding the molecular pathogenesis of CLL, new therapeutic approaches are critical to improving patient outcome. One attractive approach is differentiation therapy, in which the malignant B cells are induced to mature into non-replicative cells with a shorter lifespan. We have shown previously that the natural product Bryostatin 1 induces differentiation of CLL cells through activation of the transcription factor STAT1. To identify genes activated by STAT1 that mediate Bryostatin 1-induced differentiation of CLL cells we used gene expression microarrays. Using this approach, we identified seven genes that were potential STAT1 target genes, including GADD45β, IFI16, caspase 3, topoisomerase I, and the known STAT1 target IRF-1. Given the limitations of genetically manipulating primary CLL cells, we evaluated whether B lymphocytic cell lines recapitulated the molecular and cellular differentiation responses to Bryostatin 1 that we observed in CLL cells. We found that Bryostatin 1 is a potent inducer of differentiation of CESS B lymphoblastoid cells, as measured by growth arrest, downregulation of MHC II, and IgG secretion. Bryostatin 1 also induced signaling events in CESS cells similar to those observed in CLL cells, including activation of STAT1 and induction of STAT1 target genes. These findings suggest that STAT1 and its targets may be important mediators of malignant B cell differentiation and that the CESS cell line can be used to further study the potential clinical application of differentiation therapy in CLL.
Correlative Study of ZAP-70 Gene Expression by Quantitative PCR and CD-38 Surface Marker in Patients with Chronic Lymphocytic Leukemia (CLL).
Authors: Larson Melissa L. , Shammo Jamile M. , Enschede Sari H. , Venugopal Parameswaran , Russell Daniel , Coon John S. , Gregory Stephanie A. 
Published: April 2020

Abstract
Patients with chronic lymphocytic leukemia have heterogeneous clinical courses. Many possible prognostic factors have been evaluated as a way to predict each patient’s future course. Two such prognostic factors are IgVH gene mutational status and CD38 expression. Recently, ZAP-70 expression has been found to correlate with IgVH gene mutation, but little is known about the correlation between ZAP-70 and CD 38 expression. We sought to evaluate the concordance between the two. METHODS: A procedure was developed at our institution to evaluate ZAP-70 transcripts by PCR. The results were then confirmed by flow cytometry. The blood or bone marrow samples of 14 patients diagnosed with CLL were analyzed by PCR for ZAP-70 transcripts and flow cytometry for ZAP-70 protein expression and CD38 expression. The results of the ZAP-70 transcripts and CD38 expression were then correlated to the clinical courses of the patients. RESULTS: Of the 14 patients analyzed, the majority had Rai Stage I disease at diagnosis (4 Stage 0, 8 Stage I, and 2 Stage II). There was a median follow-up of 28 months. The median number of treatments for these patients was one (range 0–6). Overall, the results for ZAP-70 and CD38 expression were concordant in eight with CD38 data unavailable for 2 patients. In the four patients with discordant results, 3 of them had high CD38 expression and low ZAP-70. However, patients with high ZAP-70 were more likely to require multiple treatments once treatment was indicated. Patients with high CD38 were also more likely to be treated. Cytogenetic data was available for 9 patients with the following results: 5 with normal cytogenetics, 1 with deletion of 11q, 1 with deletion of 13q, and 2 with deletion of 17p. Five of the nine patients had high ZAP-70 expression. CONCLUSIONS: In our institution, the results of ZAP-70 and CD38 expression were concordant 67% of the time. Longer follow-up is necessary and may further delineate the roles of cytogenetics, ZAP-70 expression, and CD38 expression on prognosis in CLL.