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  • 1
    Language: English
    In: Cancer, 15 December 2006, Vol.107(12), pp.2807-16
    Description: Anemia occurs as a comorbidity in from 80% to 85% of patients with myelodysplastic syndromes (MDS): It causes fatigue, increases transfusion needs, and reduces quality of life. Darbepoetin alpha (DA) is an erythropoiesis-stimulating protein (ESP) that is more highly glycosylated and has a longer half-life relative to recombinant human erythropoietin (rHuEPO), thus, allowing less frequent administration, increased convenience, and better compliance. This retrospective analysis included 81 patients with MDS who were enrolled at 9 Spanish centers and who received once-weekly, subcutaneous DA (75-300 microg) for 16 weeks. Fifty-five percent of all patients (38 of 69 evaluable patients) achieved responses; 30.4% of were major responses, and 24.6% were minor responses; 64.7% of rHuEPO-naive patients and 45.7% rHuEPO-treated patients responded; and 43.2% had received previous rHuEPO. Most responses (65.8%) occurred at or before Week 8. The median age at diagnosis was 70 years (range, 38-87 years), the median age at the initiation of DA treatment was 75 years (range, 39-91 years), and 56.8% of patients were women. The median time from last ESP dose to DA initiation was 16.8 weeks (range, 0.0-159.0 weeks; 〈1 week in 53.1% of patients). According to the French-American-British classification system (n = 81 patients), 39.5% had refractory anemia (RA), 46.9% had RA with ringed sideroblasts, 9.9% had RA with excess blasts (RAEB), 1.2% had RAEB in transformation, and 2.5% had chronic myelomonocytic leukemia. According to the International Prognostic Scoring System (n = 47 patients), 55.3% of patients were in the low-risk group, and 36.2% of patients were in the intermediate-1-risk group. The median baseline hemoglobin level was 8.9 g/dL (range, 8.4-9.1 g/dL). The Starting DA dose was 75 microg per week in 3.7% of patients, 150 microg per week in 65.4% of patients, and 300 microg per week in 29.6% of patients (the dose was increased in 18.5% of patients and reduced in 9.9% of patients; median time to dose adjustment, 8 weeks). Five patients received granulocyte colony-stimulating factors. No DA-related adverse reactions occurred. In the current study, 55% of evaluable patients with MDS safely achieved an erythroid response.
    Keywords: Anemia -- Drug Therapy ; Erythropoietin -- Analogs & Derivatives ; Hematinics -- Therapeutic Use ; Myelodysplastic Syndromes -- Complications
    ISSN: 0008-543X
    E-ISSN: 10970142
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  • 2
    Language: English
    In: Cancer, 15 October 2001, Vol.92(8), pp.2016-2022
    Description: BACKGROUND: Autoimmune cytopenias are a frequent complication in patients with chronic lymphocytic leukemia (CLL). Anecdotal reports suggest that cyclosporin A (CsA) may be beneficial for patients with CLL-associated pure red cell aplasia. In the current study, the authors investigated the use of CsA in the management of anemia or thrombocytopenia of presumed autoimmune etiology associated with CLL.METHODS: Thirty-one patients with CLL and anemia or thrombocytopenia of presumed autoimmune etiology were treated with CsA at a dose of 300 mg/day. Sixteen patients (52%) had anemia (hemoglobin 〈or= 11 g/dL) and 29 patients (94%) had thrombocytopenia (platelet count 〈or= 100 x 10(9)/L). Seventeen patients (55%) had cytopenia that developed during the course of treatment with fludarabine-based regimens. Nineteen patients (61%) had received prior therapy for this complication using steroids, intravenous immunoglobulin, and/or splenectomy.RESULTS: Eighteen patients (62%) with thrombocytopenia and 10 patients (63%) with anemia had a major response defined as an increase in the platelet count 〉or= 50 x 10(9)/L or an increase in hemoglobin 〉or= 3 g/dL. The median time to initial response was 3 weeks (range, 1-13 weeks) and the median time to best response was 10.5 weeks (range, 1-48 weeks). The median duration of response was 10 months (range, 1+-39+ months). Three patients with fludarabine-associated cytopenias were able to receive further therapy with fludarabine with a lesser decrease in the platelet count. A modest decrease in the tumor burden was observed in six patients. The most common toxicity was 〈or= Grade 2 (according to the National Cancer Institute's Common Toxicity Criteria) elevation of creatinine, which was observed in 6 patients (19%). Three patients developed opportunistic infections.CONCLUSIONS: CsA is an effective alternative for the treatment of anemia or thrombocytopenia of suspected autoimmune etiology, including those cases occurring in the course of treatment with fludarabine. A modest antileukemic effect was observed in some patients.
    Keywords: Cyclosporine A ; Chronic Lymphocytic Leukemia ; Anemia ; Thrombocytopenia
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 3
    Language: English
    In: Cancer Immunology, Immunotherapy, 2015, Vol.64(6), p.665(12)
    Description: Byline: Carlos Cuesta-Mateos (1,2), Javier Loscertales (3), Anna Kreutzman (1), Beatriz Colom-Fernandez (1), Itxaso Portero-Sainz (1), Juan Jose Perez-Villar (1), Fernando Terron (2), Cecilia Munoz-Calleja (1) Keywords: CCR7; mAb; p53; Fludarabine; CLL Abstract: Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti-CCR7 mAb is an effective and promising future treatment in high-risk CLL. Author Affiliation: (1) Servicio de Inmunologia, Departamento de Inmunologia, Instituto de Investigacion Sanitaria Hospital Universitario de La Princesa, C/Diego de Leon 62, 28006, Madrid, Spain (2) IMMED S.L., Immunological and Medicinal Products, Madrid, Spain (3) Departamento de Hematologia, Instituto de Investigacion Sanitaria Hospital Universitario de La Princesa, Madrid, Spain Article History: Registration Date: 16/02/2015 Received Date: 16/09/2014 Accepted Date: 14/02/2015 Online Date: 28/02/2015 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00262-015-1670-z) contains supplementary material, which is available to authorized users.
    Keywords: Tumor Proteins – Risk Factors ; Tumor Proteins – Care and Treatment ; Chronic Lymphocytic Leukemia – Risk Factors ; Chronic Lymphocytic Leukemia – Care and Treatment
    ISSN: 0340-7004
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  • 4
    Language: English
    In: ClinicoEconomics and Outcomes Research, Annual, 2016, Vol.8, p.475(10)
    Description: Objective: To evaluate the cost-effectiveness of obinutuzumab in combination with chlorambucil (GClb) versus rituximab plus chlorambucil (RClb) in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy, from the perspective of the Spanish National Health System. Methods: A Markov model was developed with three mutually exclusive health states: progression-free survival (with or without treatment), progression, and death. Survival time for the two treatments was modeled based on the results of CLL11 clinical trial and external sources. Each health state was associated with a utility value and direct medical costs. The utilities were obtained from a utility elicitation study conducted in the UK. Costs and general background mortality data were obtained from published Spanish sources. Deterministic and probabilistic analyses were conducted, with a time frame of 20 years. The health outcomes were measured as life years (LYs) gained and quality-adjusted life years (QALYs) gained. Efficiency was measured as the cost per LY or per QALY gained of the most effective regimen. Results: In the deterministic base case analysis, each patient treated with GClb resulted in 0.717 LYs gained and 0.673 QALYs gained versus RClb. The cost per LY and per QALY gained with GClb versus RClb was €23,314 and €24,838, respectively. The results proved stable in most of the univariate and probabilistic sensitivity analyses, with a probabilistic cost per QALY gained of €24,734 (95% confidence interval: €21,860–28,367). Conclusion: Using GClb to treat patients with previously untreated CLL for whom full-dose fludarabine-based therapy is unsuitable allows significant gains in terms of LYs and QALYs versus treatment with RClb. Treatment with GClb versus RClb can be regarded as efficient when considered the willingness to pay thresholds commonly used in Spain.
    Keywords: Chronic Lymphocytic Leukemia -- Development And Progression ; Chronic Lymphocytic Leukemia -- Economic Aspects ; Chronic Lymphocytic Leukemia -- Analysis ; Markov Processes -- Economic Aspects ; Markov Processes -- Analysis ; Antineoplastic Agents -- Economic Aspects ; Antineoplastic Agents -- Analysis ; Comorbidity -- Development And Progression ; Comorbidity -- Economic Aspects ; Comorbidity -- Analysis
    ISSN: 1178-6981
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  • 5
    Language: English
    In: ClinicoEconomics and outcomes research : CEOR, 2016, Vol.8, pp.475-484
    Description: To evaluate the cost-effectiveness of obinutuzumab in combination with chlorambucil (GClb) versus rituximab plus chlorambucil (RClb) in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy, from the perspective of the Spanish National Health System. A Markov model was developed with three mutually exclusive health states: progression-free survival (with or without treatment), progression, and death. Survival time for the two treatments was modeled based on the results of CLL11 clinical trial and external sources. Each health state was associated with a utility value and direct medical costs. The utilities were obtained from a utility elicitation study conducted in the UK. Costs and general background mortality data were obtained from published Spanish sources. Deterministic and probabilistic analyses were conducted, with a time frame of 20 years. The health outcomes were measured as life years (LYs) gained and quality-adjusted life years (QALYs) gained. Efficiency was measured as the cost per LY or per QALY gained of the most effective regimen. In the deterministic base case analysis, each patient treated with GClb resulted in 0.717 LYs gained and 0.673 QALYs gained versus RClb. The cost per LY and per QALY gained with GClb versus RClb was €23,314 and €24,838, respectively. The results proved stable in most of the univariate and probabilistic sensitivity analyses, with a probabilistic cost per QALY gained of €24,734 (95% confidence interval: €21,860-28,367). Using GClb to treat patients with previously untreated CLL for whom full-dose fludarabine-based therapy is unsuitable allows significant gains in terms of LYs and QALYs versus treatment with RClb. Treatment with GClb versus RClb can be regarded as efficient when considered the willingness to pay thresholds commonly used in Spain.
    Keywords: Chlorambucil ; Chronic Lymphocytic Leukemia ; Cost-Effectiveness ; Obinutuzumab ; Rituximab
    ISSN: 1178-6981
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 6
    Language: English
    In: Cancer Immunology, Immunotherapy, 2015, Vol.64(6), pp.665-676
    Description: Chronic lymphocytic leukemia (CLL) with deletions of the p 53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti-CCR7 mAb is an effective and promising future treatment in high-risk CLL.
    Keywords: CCR7 ; mAb ; p53 ; Fludarabine ; CLL
    ISSN: 0340-7004
    E-ISSN: 1432-0851
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  • 7
    Language: English
    In: Leukemia & Lymphoma, 01 June 2010, Vol.51(6), pp.1142-1143
    Keywords: Medicine
    ISSN: 1042-8194
    E-ISSN: 1029-2403
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  • 8
    Language: English
    In: Cancer, 15 December 2006, Vol.107(12), pp.2807-2816
    Keywords: Anemia ; Darbepoetin Α ; Erythroid Response ; Myelodysplastic Syndrome
    ISSN: 0008-543X
    E-ISSN: 1097-0142
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  • 9
  • 10
    Language: English
    In: Experimental Hematology, 2010, Vol.38(9), pp.756-764.e4
    Description: The CCR7 chemokine receptor has been reported to promote homing of B-cell chronic lymphocytic leukemia (CLL) cells into lymph nodes and support their survival, but the mechanisms mediating these effects are largely unknown. We investigated the role of different signaling pathways triggered by CCR7 engagement by its ligands, the chemokines CCL19 and CCL21, in the control of CLL migration and survival. Chemotaxis and apoptosis assays were performed in the presence of pharmacologic inhibitors and genetic mutants of the phosphatidylinositol-3-OH kinase (PI3K), Rho guanosine triphosphatase, and mitogen-activated protein kinase (MAPK) signaling cascades to assess the role of these pathways on primary CLL migration and survival in response to CCR7 activation. Kinase activation was determined by immunoblotting and pull-down experiments. CLL chemotactic activity induced by CCL19 or CCL21 was markedly reduced by inhibitors of PI3K and the Rho effector molecule Rho-associated coiled-coil forming protein kinases (ROCK), and also by the expression of dominant negative forms of PI3K and RhoA, whereas constitutively activated PI3K and RhoA mutants strongly promoted CLL migration. In contrast, MAPKs were not significantly involved in CLL migration to CCL19/CCL21. Conversely, extracellular signal-regulated kinase and c-Jun-N-terminal kinase, along with PI3K, had a role in CCR7-mediated CLL cell survival. Biochemical experiments confirmed that CCL19/21 induced PI3K-dependent phosphorylation of Akt/protein kinase B, activation of the Rho/Rho-associated coiled-coil forming protein kinases/myosin light chain pathway and MAPKs phosphorylation. The role of PI3K, Rho guanosine triphosphatases, and MAPKs in CCR7-mediated CLL cells migration and survival suggests that these signal transduction pathways could represent promising targets for CLL therapy.
    Keywords: Medicine
    ISSN: 0301-472X
    E-ISSN: 1873-2399
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