Publications (11)46.45 Total impact
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Article: Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia.
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ABSTRACT: In patients with chronic myeloid leukemia (CML), use of the BCR-ABL1-specific tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib has greatly improved patient survival and prolonged disease remission. More than 10 years of data from imatinib clinical studies and many years of data for nilotinib and dasatinib have demonstrated that these TKIs are well tolerated in most patients with CML. However, these inhibitors are not entirely BCR-ABL1-specific, and this lack of specificity could account for the off-target effects of these drugs. Adverse events (AEs) are off-target effects that are detrimental to the patient. The underlying mechanisms that contribute to these effects are poorly understood and the long-term consequences of chronic TKI therapy remain largely unknown, particularly with the newer agents. Here, we review the preclinical and clinical data for several of the more frequent AEs associated with TKIs and discuss the therapeutic relevance of these AEs for patients with CML.Leukemia & lymphoma 05/2012; · 2.40 Impact Factor -
Article: Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet.
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ABSTRACT: The treatment policy of chronic myeloid leukemia (CML), particularly with tyrosine kinase inhibitors, has been influenced by several recent studies that were well designed and rapidly performed, but their interpretation is of some concern because different end points and methodologies were used. To understand and compare the results of the previous and future studies and to translate their conclusion into clinical practice, there is a need for common definitions and methods for analyses of CML studies. A panel of experts was appointed by the European LeukemiaNet with the aim of developing a set of definitions and recommendations to be used in design, analyses, and reporting of phase 3 clinical trials in this disease. This paper summarizes the consensus of the panel on events and major end points of interest in CML. It also focuses on specific issues concerning the intention-to-treat principle and longitudinal data analyses in the context of long-term follow-up. The panel proposes that future clinical trials follow these recommendations.Blood 04/2012; 119(25):5963-71. · 9.90 Impact Factor -
Article: Pneumocystis jirovecii pneumonia as first manifestation of late relapse angioimmunoblastic T-cell lymphoma.
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ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma (PTCL) with peculiar and frequent clinical features of immune deregulation. Another hallmark of this disease is the secondary immunodeficiency. In this paper, we report a case of Pneumocistis jirovecii infection as the first manifestation of AITL relapse, after 8 years in continuous complete remission.Leukemia research 05/2011; 35(9):e143-4. · 2.36 Impact Factor -
Article: Nilotinib is superior to imatinib as first-line therapy of chronic myeloid leukemia: the ENESTnd study.
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ABSTRACT: Nilotinib (Tasigna(®)) is a more potent BCR-ABL inhibitor than imatinib and was designed to overcome imatinib's deficiencies. Nilotinib has significant efficacy in patients with chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blastic phase, following imatinib failure. Based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, the US FDA has granted accelerated approval of nilotinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Imatinib has changed our perceptions of the therapeutic power of targeted inhibition of a pathologically active kinase. Nilotinib, a designer agent built on the imatinib scaffold, has proven superior to its template agent by every significant surrogate marker we use in monitoring CML. Nilotinib's clinical superiority over imatinib, as demonstrated by the ENESTnd study, has established it as an agent that we believe is a significant further step towards the cure of CML.Expert Review of Hematology 12/2010; 3(6):665-73. · 1.16 Impact Factor -
Article: Phase II study of three dose levels of continuous erythropoietin receptor activator (C.E.R.A.) in anaemic patients with aggressive non-Hodgkin's lymphoma receiving combination chemotherapy.
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ABSTRACT: Anaemia is a common complication in the treatment of patients with aggressive non-Hodgkin lymphoma (NHL), but there are no published data on the effect of erythropoiesis-stimulating agents in such patients. This is the first open-label, phase II, dose-finding study to evaluate the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.). Ninety-three anaemic patients with aggressive NHL who were receiving chemotherapy (including many advanced NHL, heavily pretreated patients) were randomised to receive 2.1, 4.2 or 6.3 microg/kg C.E.R.A. subcutaneously once every 3 weeks for 12 weeks. Haematopoietic response was achieved in 45%, 57% and 65% of patients at the respective dose level. During weeks 5-13, the mean haemoglobin changes from baseline in the intent-to-treat population were increases of 0.2, 2.4, and 5.7 g/l in the 2.1, 4.2, and 6.3 microg/kg treatment groups, respectively, and 4.4, 5.7 and 6.8 g/l in the per-protocol population at the respective dose levels. C.E.R.A. was generally well tolerated in all three groups. C.E.R.A. appeared to have dose-dependent clinical activity in most anaemic patients with aggressive NHL who were receiving chemotherapy.British Journal of Haematology 04/2007; 136(5):736-44. · 4.94 Impact Factor -
Article: [Relapsing polychondritis associated with a lymphoplasmocytic lymphoma and erythema nodosum].
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ABSTRACT: Relapsing polychondritis is a disease of unknown etiology characterized by episodic inflammation of cartilaginous tissues. More rarely, it has been described as a paraneoplastic phenomenon mainly associated with myelodysplastic syndromes or other haematologic diseases. We present a case of relapsing polychondritis associated to low degree lymphoplasmocytic lymphoma whose picture was punctuated by cutaneous erythema nodosum and anterior uveitis. The clinical evolution was satisfactory with glucocorticoids and rituximab treatment.Reumatología Clínica 01/2007; 3(1):45-7. -
Article: The impact of the combination of baseline risk group and cytogenetic response on the survival of patients with chronic myeloid leukemia treated with interferon alpha.
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ABSTRACT: This study was aimed at examining major cytogenetic response (MCR) as a valid predictor of the course of chronic myeloid leukemia (CML) and at assessing the survival of CML patients treated with interferon alpha (IFN) in dependence on the combination of MCR (yes or no) with the baseline risk group of the New CML score. MCR was defined as a reduction of Philadelphia chromosome-positive bone marrow cells to <or= 35%. The New CML score discriminated three risk groups with significantly different survival probabilities. Data from individual patients with a confirmed diagnosis of Philadelphia chromosome-positive CML treated with IFN were collected from 10 prospective studies in Europe and Japan. Stratified for baseline risk group, patients with a major cytogenetic response by 21 months after the start of therapy (n=171) were compared with patients achieving a minor response or less (n=487). Survival probabilities after the landmark at 21 months were compared by using the two-sided log-rank test. MCR was a major predictor for low- and intermediate-risk patients (log-rank test, p <or= 0.0001), but not for high-risk patients. Ten-year survival probabilities for the low- and intermediate-risk patients who had a MCR were 75% (95 CI: 65-86%) and 56% (95 CI: 37-75%), respectively. The corresponding probabilities for patients who did not achieve a MCR were 21% (95 CI: 6-35%) and 16% (95 CI: 6-25%). Cytogenetic response per se is not a valid surrogate marker, as it is dependent on the baseline prognostic profile. The combination of risk group and cytogenetic response does, however, provide useful clinical information. The survival data presented here can serve as a benchmark for the assessment of the long-term effectiveness of imatinib.Haematologica 04/2005; 90(3):335-40. · 6.42 Impact Factor -
Article: Imatinib mesylate therapy of chronic phase chronic myeloid leukemia resistant or intolerant to interferon: results and prognostic factors for response and progression-free survival in 150 patients.
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ABSTRACT: Imatinib mesylate has recently been shown to be highly effective in chronic-phase chronic myeloid leukemia (CML). The results of imatinib treatment in chronic-phase CML patients resistant or intolerant to interferon (IFN) and the factors predicting therapeutic response and progression-free survival were analyzed. One hundred and fifty patients with chronic-phase CML resistant (n=111) or intolerant (n=39) to IFN were treated with imatinib. Prognostic factors for response and disease progression were assessed by multivariate analysis. The median time from diagnosis was 43 months (0.5-188), median IFN therapy 21.5 months (0.5-140) and median follow-up from starting imatinib 13.6 months (range: 3-23). Complete hematologic response was achieved in 96 of 97 patients. Complete, partial and minor cytogenetic responses were present in 44%, 22%, and 8% of patients at 12 months. Grade III-IV neutropenia, thrombocytopenia, and anemia developed in 33%, 16%, and 6% of patients, respectively. Sixty-five patients discontinued treatment for a median of 4 weeks (1-36) due to toxicity. The rate of progression-free survival (lack of accelerated/blastic phase with persistent response) was 89.2% (95% CI: 84-94.4) at 12 months and 80.2% (95% CI: 72.2-88.2) at 18 months. Platelets > 450x10(9)/L and treatment discontinuation > 4 weeks were associated with a lower rate of major (complete plus partial) cytogenetic response. Patients in Sokal's high-risk group and those who did not achieve a major cytogenetic response had significantly shorter progression-free survival. Imatinib is highly effective in chronic-phase CML patients resistant or intolerant to IFN, especially in those with normal platelet counts and in those not requiring prolonged treatment discontinuation due to neutropenia.Haematologica 10/2003; 88(10):1117-22. · 6.42 Impact Factor -
Article: Chronic myeloid leukemia patients resistant to or intolerant of interferon alpha and subsequently treated with imatinib show reduced immunoglobulin levels and hypogammaglobulinemia.
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ABSTRACT: Imatinib mesylate inhibits ABL tyrosine kinase. This protein serves a complex role in cell cycling and is important in lymphopoiesis. We describe the immunologic findings in patients with chronic myeloid leukemia resistant to or intolerant of interferon (IFN) a who were treated with imatinib. This aspect could be of interest since patients with these characteristics may be exposed to this treatment for long periods. Immunologic and hematologic evaluation (including immunoglobulin levels and parameters of autoimmunity), immunophenotyping analysis of peripheral blood and bone marrow, and cytogenetic bone marrow analysis were performed at sequential time points of the treatment (0, 3, 6, and 9 and 12 months). The relationships among immunologic variables, and between the immunologic findings and response, were investigated. Hypogammaglobulinemia IgG, IgA and IgM developed in 28%, 14% and 22% of the patients, respectively. Lymphocyte counts decreased significantly along the treatment. No correlation was found between Ig levels and lymphocyte counts or CD4, CD8 or CD19 subpopulations in peripheral blood, nor between Ig levels and bone marrow B-lineage precursors. No autoimmune phenomena were detected. Hypogammaglobulinemia had no clinical repercussions in patients who developed it. The percentage reductions of IgG, IgA and IgM levels were higher in patients with major genetic response to imatinib. Hypogammaglobulinemia can develop in as many as 20-25% of patients with chronic myeloid leukemia previously exposed to IFN a and who are then treated with imatinib. The reduction of Ig is greater in patients with a better cytogenetic response, perhaps reflecting that the efficacy of imatinib in blocking BCR-ABL kinase activity runs in parallel with ABL inhibition, leading to a dysregulation of B-lymphocyte function. Close immunologic evaluation is recommended in these patients.Haematologica 08/2003; 88(7):762-8. · 6.42 Impact Factor -
Article: Allogeneic Hematopoietic Stem Cell
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ABSTRACT: y different between the elderly and young groups: 51% vs. 55% for all patients; 87% vs. 69% in chronic myeloid leukemia; 79% vs. 62% in standard risk patients and 13% vs. 31% in high risk ones. In multivariate analyses no significant difference in overall survival was found between age groups. Interpretation and Conclusions. According to our experience, age alone (between 50-59), should not be considered a contraindication to a conventional HLA identical sibling transplant. 2002, Ferrata Storti Foundation Key words: allogeneic stem cell transplantation; age; elderly; HLA identical sibling; myeloablative conditioning regimen. T he median age of the patients who receive a stem cell transplantation (SCT) is between 25 and 30 years. 1,2 Nonetheless the majority of patients with hematologic malignancies have a median age well over 50 at diagnosis. Thus, for chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), lymphoma and myeloma10/2002; -
Article: Allogeneic hematopoietic stem cell transplantation in patients 50 years of age and older.
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ABSTRACT: The population of elderly patients with hematologic malignancies is increasing and so will the activity of stem cell transplantation (SCT) in this population. The aim of this study was to analyze the toxicity and survival of allogeneic SCT in patients 50 years and older (elderly group), and compare the results with a standard adult population (young group). Thirty-two elderly patients (median age 52.5, range 50-59 years) and 97 young patients (median 32, range 20-40) received a myeloablative, allogeneic SCT from HLA-identical siblings at a single institution, and formed the basis of this retrospective study. The majority of transplants in both groups were performed with non-T-cell-depleted bone marrow, conditioned with busulfan + cyclophosphamide and received cyclosporine + methotrexate as graft-versus-host disease (GVHD) prophylaxis. The percentage of high-risk patients was nearly double in the elderly group (41% vs. 23%, p = 0.06). We observed a low incidence of toxicities in the elderly group, including veno-occlusive disease, acute and chronic GVHD, transplant-related mortality, time to engraftment, and relapse incidence, without significant differences compared within the young group. The 3-year survival rates were not statistically different between the elderly and young groups: 51% vs. 55% for all patients; 87% vs. 69% in chronic myeloid leukemia; 79% vs. 62% in standard risk patients and 13% vs. 31% in high risk ones. In multivariate analyses no significant difference in overall survival was found between age groups. According to our experience, age alone (between 50-59), should not be considered a contraindication to a conventional HLA identical sibling transplant.Haematologica 10/2002; 87(9):965-72. · 6.42 Impact Factor
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Institutions
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2003–2012
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Hospital Universitario de La Princesa
Madrid, Madrid, Spain
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