9 results on '"PATIENTS RECEIVING IMATINIB"'
Search Results
2. Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia
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Hanna Rajala, Leif Stenke, Bjørn Tore Gjertsen, Jeroen Janssen, Johan Richter, Henrik Hjorth-Hansen, Perttu Koskenvesa, Anna Kreutzman, Mohamed El Missiry, Berit Markevärn, Satu Mustjoki, Kourosh Lotfi, Anniina Ruusila, Tim H. Brümmendorf, Ulla Olsson-Strömberg, Jesper Stentoft, Clinicum, Hematologian yksikkö, Department of Oncology, University of Helsinki, Department of Medicine, Medicum, Department of Clinical Chemistry and Hematology, HUS Comprehensive Cancer Center, HUSLAB, and HUS Internal Medicine and Rehabilitation
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Male ,0301 basic medicine ,Cancer Research ,NILOTINIB ,Tyrosine kinase inhibitor ,PHILADELPHIA-CHROMOSOME ,Tyrosine-kinase inhibitor ,Hypogammaglobulinemia ,0302 clinical medicine ,hemic and lymphatic diseases ,CML ,B-Lymphocytes ,B cell ,DASATINIB ,Aniline Compounds ,biology ,PATIENTS RECEIVING IMATINIB ,Myeloid leukemia ,General Medicine ,Middle Aged ,Protein-Tyrosine Kinases ,3. Good health ,Dasatinib ,Treatment Outcome ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Imatinib Mesylate ,Quinolines ,Female ,Antibody ,medicine.drug ,Adult ,medicine.drug_class ,BONE-MARROW ,3122 Cancers ,ANTIGEN ,Bone Marrow Cells ,Philadelphia chromosome ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Nitriles ,medicine ,Immunoglobulin ,Humans ,COMBINATION ,Protein Kinase Inhibitors ,business.industry ,CHRONIC-PHASE ,HYPOGAMMAGLOBULINEMIA ,medicine.disease ,Immunity, Humoral ,Immunoglobulin A ,Pyrimidines ,030104 developmental biology ,Immunoglobulin M ,Nilotinib ,Immunoglobulin G ,Immunology ,biology.protein ,business ,FOLLOW-UP - Abstract
Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity.Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry.Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia.Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.
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- 2017
3. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia
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Steegmann, J. L., Baccarani, M., Breccia, M., Casado, L. F., Garcia-Gutierrez, V., Hochhaus, A., Kim, D-W, Kim, T. D., Khoury, H. J., Le Coutre, P., Mayer, J., Milojkovic, D., Porkka, Kimmo, Rea, D., Rosti, G., Saussele, S., Hehlmann, R., Clark, R. E., Clinicum, Department of Medicine, Hematologian yksikkö, and Department of Oncology
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DIAGNOSED CHRONIC-PHASE ,DASATINIB 100 MG ,PULMONARY ARTERIAL-HYPERTENSION ,PATIENTS RECEIVING IMATINIB ,CHRONIC MYELOGENOUS LEUKEMIA ,CHROMOSOME-POSITIVE LEUKEMIAS ,3122 Cancers ,IMATINIB MESYLATE THERAPY ,TYROSINE-KINASE INHIBITOR ,ACUTE-RENAL-FAILURE ,ACUTE LYMPHOBLASTIC-LEUKEMIA - Abstract
Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.
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- 2016
4. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia
- Abstract
Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better q
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- 2016
5. Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party
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Gugliotta, G, Castagnetti, F, Palandri, F, Breccia, M, Intermesoli, T, Capucci, A, Martino, B, Pregno, P, Rupoli, S, Ferrero, D, Gherlinzoni, F, Montefusco, E, Bocchia, M, Tiribelli, M, Pierri, Ivana, Grifoni, F, Marzocchi, G, Amabile, M, Testoni, N, Martinelli, G, Alimena, G, Pane, F, Saglio, G, Baccarani, M, Rosti, G, Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, Gugliotta, G, Castagnetti, F, Palandri, F, Breccia, M, Intermesoli, T, Capucci, A, Martino, B, Pregno, P, Rupoli, S, Ferrero, D, Gherlinzoni, F, Montefusco, E, Bocchia, M, Tiribelli, M, Pierri, I, Grifoni, F, Marzocchi, G, Amabile, M, Testoni, N, Martinelli, G, Alimena, G, Pane, Fabrizio, Saglio, G, Baccarani, M, Rosti, G, Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working, Party, Gugliotta G., Castagnetti F., Palandri F., Breccia M., Intermesoli T., Capucci A., Martino B., Pregno P., Rupoli S., Ferrero D., Gherlinzoni F., Montefusco E., Bocchia M., Tiribelli M., Pierri I., Grifoni F., Marzocchi G., Amabile M., Testoni N., Martinelli G., Alimena G., Pane F., Saglio G., Baccarani M., and Rosti G.
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Myeloid ,Male ,chronic myeloid leukemia ,imatinib ,elderly ,Biochemistry ,Piperazines ,hemic and lymphatic diseases ,80 and over ,Young adult ,Aged, 80 and over ,Leukemia ,Mortality rate ,Myeloid leukemia ,Hematology ,Middle Aged ,Phase III as Topic ,Survival Rate ,Treatment Outcome ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Female ,Complete Hematologic Response ,Adult ,medicine.medical_specialty ,Adolescent ,Immunology ,Alpha interferon ,Antineoplastic Agents ,Young Adult ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Humans ,Clinical Trials ,bone-marrow-transplantation ,chronic myelogenous leukemia ,complete cytogenetic response ,early chronic phase ,elderly-patients ,european-leukemianet ,interferon-alpha ,line treatment ,mesylate therapy ,patients receiving imatinib ,Survival rate ,Aged ,business.industry ,Clinical Trials, Phase III as Topic ,Health Surveys ,Pyrimidines ,Phase II as Topic ,Cell Biology ,medicine.disease ,Surgery ,Imatinib mesylate ,Chronic-Phase ,business ,CHRONIC MYELOID LEUKEMIA (CML) ,Chronic myelogenous leukemia - Abstract
The median age of chronic myeloid leukemia (CML) patients is ∼ 60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (≥ 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failure-free survival (78% vs 92%), progression-free survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www.clinicaltrials.gov as #NCT00514488 and #NCT00510926.
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- 2011
6. Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia
- Author
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Saglio, G, Kim, Dw, Issaragrisil, S, le Coutre, P, Etienne, G, Lobo, C, Pasquini, R, Clark, Re, Hochhaus, A, Hughes, Tp, Gallagher, N, Hoenekopp, A, Dong, M, Haque, A, Alimena, Giuliana, Larson, Ra, Kantarjian, Hm, and Enestnd, Investigators
- Subjects
Myeloid ,Male ,bcr-abl ,Fusion Proteins, bcr-abl ,Kaplan-Meier Estimate ,Pharmacology ,PHASE CML-CP ,Gastroenterology ,Piperazines ,chemistry.chemical_compound ,hemic and lymphatic diseases ,80 and over ,Medicine ,Aged, 80 and over ,Leukemia ,PATIENTS RECEIVING IMATINIB ,Medicine (all) ,HARMONIZING CURRENT METHODOLOGY ,CHRONIC MYELOGENOUS LEUKEMIA ,Ponatinib ,General Medicine ,Middle Aged ,BCR-ABL TRANSCRIPTS ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Antagonists & inhibitors ,Adolescent ,PHASE CML-CP, HARMONIZING CURRENT METHODOLOGY, CHRONIC MYELOGENOUS LEUKEMIA, PATIENTS RECEIVING IMATINIB, UP SUSTAINED SURVIVAL, BCR-ABL TRANSCRIPTS, FOLLOW-UP, PATIENTS PTS, 800 MG, MOLECULAR RESPONSES ,Antineoplastic Agents ,Chronic phase chronic myelogenous leukemia ,Young Adult ,PATIENTS PTS ,Internal medicine ,Omacetaxine mepesuccinate ,Humans ,Protein Kinase Inhibitors ,MOLECULAR RESPONSES ,Aged ,business.industry ,Blast Crisis ,Pyrimidines ,Fusion Proteins ,Imatinib ,800 MG ,medicine.disease ,Imatinib mesylate ,UP SUSTAINED SURVIVAL ,chemistry ,Nilotinib ,Chronic-Phase ,FOLLOW-UP ,business ,Chronic myelogenous leukemia - Abstract
Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P
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- 2010
7. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib
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Castagnetti, F, Gugliotta, G., Breccia, M., Stagno, F., Iurlo, A., Albano, F., Abruzzese, E., Martino, B., Levato, L., Intermesoli, T., Pregno, P., Rossi, G., Gherlinzoni, F., Leoni, P., Cavazzini, F., Venturi, C., Soverini, S., Testoni, N., Alimena, G., Cavo, M., Martinelli, G., Pane, F., Saglio, G., Rosti, G., Baccarani, M., on behalf of the GIMEMA CML Working Party (Lucarelli, G., Polimeno, G., Ladetto, M., Pini, M., Rupoli, S., Scortechini, A. R., Galieni, P., Bigazzi, C., Cantore, N., Palmieri, F., Specchia, G., Russo, Rossi., Rambaldi, A., Ferrari, M. L., Palandri, F., Luatti, S., Iacobucci, I., Bochicchio, M. T., Apolinari, M., Fogli, M., Cervello, I., Capucci, A., Giuliani, G., Malpignano, A., Girasoli, M., Angelucci, E., Usala, E., De Biasi, E., Tagariello, G., Sartori, R., Di Raimondo, F., Vigneri, P., Molica, S., Lentini, M., Lanza, F., Viganò, C., Grasso, M., Rapezzi, D., Cuneo, A., Ciccone, M., Bosi, A., Gozzini, A., Gobbi, M., Pierri, I., Chianese, R., De Blasio, A., Ciccone, F., Capochiani, E., Pelosini, M., Musolino, C., Russo, S., Cortelezzi, A., Luppi, M., Marasca, R., Pogliani, E. M., Gambacorti-Passerini, C., Luciano, L., Izzo, B., Ferrara, F., Annunziata, M., Mettivier, V., Sessa, U., Latte, G., Noli, D., Rege-Cambrin, G., Fava, C., Semenzato, G., Binotto, G., Fabbiano, F., Turri, D., Siragusa, S., Caracciolo, C., Musso, M., Porretto, F., Cazzola, M., Orlandi, E., Falini, B., Falzetti, F., Visani, G., Isidor, I., Di Bartolomeo, P., Di Lorenzo, R., Vallisa, D., Trabacch, I., Pizzuti, M., Zuffa, E., Salvucci, M., Ronco, F., Lelo, D., Merli, F., Avanzini, P., Tosi, P., Merli, A., Sica, S., Sorà, F., Latagliata, R., De Fabritiis, P., Trawiska, M., Amadori, S., Cantonetti, M., Majolino, I., Pacilli, L., Ronci, B., Cedrone, M., Mengarelli, A., Romano, A., Tafuri, A., Montefusc, O., Iuliano, F., Infusino, S., Dore, F., Fozza, C., Bocchia, M., Defina, M., Liberati, Am., Luzi, D., Boccadoro, M., Ferrero, D., Vitolo, U., Nicolosi, M., Gottardi, M., Calistri, E., Fanin, R., Tiribelli, M., Pizzolo, G., Bonifacio, M., Rodeghiero, F., Di Bona, E. )., Castagnetti, F, Gugliotta, G., Breccia, M., Stagno, F., Iurlo, A., Albano, F., Abruzzese, E., Martino, B., Levato, L., Intermesoli, T., Pregno, P., Rossi, G., Gherlinzoni, F., Leoni, P., Cavazzini, F., Venturi, C., Soverini, S., Testoni, N., Alimena, G., Cavo, M., Martinelli, G., Pane, F., Saglio, G., Rosti, G., Baccarani, M., and on behalf of the GIMEMA CML Working Party [, Palandri F.], Pane, Fabrizio, Gugliotta, G, Breccia, M, Stagno, F, Iurlo, A, Albano, F, Abruzzese, E, Martino, B, Levato, L, Intermesoli, T, Pregno, P, Rossi, G, Gherlinzoni, F, Leoni, P, Cavazzini, F, Venturi, C, Soverini, S, Testoni, N, Alimena, G, Cavo, M, Martinelli, G, Pane, F, Saglio, G, Rosti, G, Baccarani, M, and GAMBACORTI PASSERINI, C
- Subjects
DIAGNOSED CHRONIC-PHASE ,Oncology ,Male ,Cancer Research ,Time Factors ,bcr-abl ,Fusion Proteins, bcr-abl ,Antineoplastic Agent ,Hematology ,Anesthesiology and Pain Medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Cumulative incidence ,Young adult ,Chronic ,Aged, 80 and over ,Leukemia ,PATIENTS RECEIVING IMATINIB ,CHRONIC MYELOGENOUS LEUKEMIA ,TYROSINE KINASE INHIBITORS ,BCR-ABL1 TRANSCRIPT LEVELS ,EARLY MOLECULAR RESPONSE ,CML WORKING PARTY ,3-YEAR FOLLOW-UP ,EUROPEAN LEUKEMIANET ,400 MG ,Myeloid leukemia ,Middle Aged ,Prognosis ,Treatment Outcome ,Retreatment ,Imatinib Mesylate ,Female ,Tyrosine kinase ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Time Factor ,Adolescent ,Prognosi ,Protein Kinase Inhibitor ,Socio-culturale ,Antineoplastic Agents ,Treatment results ,Follow-Up Studie ,Young Adult ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Fusion Proteins ,Imatinib ,Follow-Up Studies ,Surgery ,Imatinib mesylate ,BCR-ABL Positive ,business ,Myelogenous - Abstract
For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.
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- 2015
8. Deletions of the derivative chromosome 9 do not influence the response and the outcome of chronic myeloid leukemia in early chronic phase treated with imatinib mesylate: GIMEMA CML Working Party analysis
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Castagnetti, Fausto, Testoni, Nicoletta, Luatti, Simona, Marzocchi, Giulia, Mancini, Marco, Kerim, Simonetta, Giugliano, Emilia, Albano, Francesco, Cuneo, Antonio, Abruzzese, Elisabetta, Martino, Bruno, Palandri, Francesca, Amabile, Marilina, Iacobucci, Ilaria, Alimena, Giuliana, Pane, Fabrizio, Martinelli, Giovanni, Saglio, Giuseppe, Baccarani, Michele, Rosti, Gianantonio, GIMEMA CML working party, Bocchia, Monica, Castagnetti, F., Testoni, N., Luatti, S., Marzocchi, G., Mancini, M., Kerim, S., Giugliano, E., Albano, F., Cuneo, A., Abruzzese, E., Martino, B., Palandri, F., Amabile, M., Iacobucci, I., Alimena, G., Pane, Fabrizio, Martinelli, G., Saglio, G., Baccarani, M., Rosti, G., Castagnetti F, Testoni N, Luatti S, Marzocchi G, Mancini M, Kerim S, Giugliano E, Albano F, Cuneo A, Abruzzese E, Martino B, Palandri F, Amabile M, Iacobucci I, Alimena G, Pane F, Martinelli G, Saglio G, Baccarani M, Rosti G, Castagnetti, F, Testoni, N, Luatti, S, Marzocchi, G, Mancini, M, Kerim, S, Giugliano, E, Albano, F, Cuneo, A, Abruzzese, E, Martino, B, Palandri, F, Amabile, M, Iacobucci, I, Alimena, G, Martinelli, G, Saglio, G, and Baccarani, M
- Subjects
Oncology ,poor-prognosis ,Myeloid ,Male ,Cancer Research ,Kaplan-Meier Estimate ,Severity of Illness Index ,Piperazines ,European LeukemiaNet ,fusion gene transcripts ,Reference Values ,hemic and lymphatic diseases ,80 and over ,Prospective Studies ,stem-cell transplantation ,In Situ Hybridization ,In Situ Hybridization, Fluorescence ,Aged, 80 and over ,Adolescent ,Adult ,Age Factors ,Aged ,Benzamides ,Chromosomes, Human, Pair 9 ,Cytogenetic Analysis ,Disease-Free Survival ,Dose-Response Relationship, Drug ,Drug Administration Schedule ,Female ,Humans ,Imatinib Mesylate ,Italy ,Leukemia, Myeloid, Chronic-Phase ,Logistic Models ,Maximum Tolerated Dose ,Middle Aged ,Multivariate Analysis ,Probability ,Prognosis ,Pyrimidines ,Reverse Transcriptase Polymerase Chain Reaction ,Risk Assessment ,Statistics, Nonparametric ,Survival Analysis ,Treatment Outcome ,Young Adult ,Gene Deletion ,Medicine (all) ,Leukemia ,philadelphia-chromosome ,Statistics ,Myeloid leukemia ,chronic myelogenous leukemia ,medicine.anatomical_structure ,abl tyrosine kinase ,bcr expression ,cytogenetic responses ,minimal-residual-disease ,patients receiving imatinib ,Drug ,medicine.drug ,Human ,Pair 9 ,medicine.medical_specialty ,Derivative chromosome ,Chromosomes ,Fluorescence ,Dose-Response Relationship ,chronic myeloid leukemia ,Internal medicine ,medicine ,Nonparametric ,business.industry ,Imatinib ,medicine.disease ,Imatinib mesylate ,Immunology ,Chronic-Phase ,Bone marrow ,business - Abstract
Purpose Deletions of the derivative chromosome 9 [der(9)] have been associated with a poor prognosis in chronic myeloid leukemia (CML) across different treatment modalities. In the imatinib era, the prognostic impact of der(9) deletions has been evaluated mainly in patients with late chronic-phase (CP) CML, giving partially conflicting results. Few data are available in the early CP setting. For this reason, in 2006, the European LeukemiaNet recommendations still considered der(9) deletions as a candidate adverse prognostic factor and required a careful monitoring of the patient. Patients and Methods To investigate the prognostic value of der(9) deletions in early CP CML, we performed an analysis of three prospective imatinib trials of the Italian Group for Hematological Malignancies of the Adult (GIMEMA) CML Working Party. Results A fluorescent in situ hybridization (FISH) analysis of bone marrow cells was performed at diagnosis; der(9) deletions were detected in 60 (12%) of 521 evaluable patients. At 60 months, the cumulative incidence of complete cytogenetic response and major molecular response—and the probability of event-free survival, failure-free survival, progression-free survival, and overall survival—in patients with and without deletions were not statistically different. Conclusion Our data strongly support the notion that, when investigated by FISH, der(9) deletions are not a poor prognostic factor in patients with early CP CML treated with imatinib.
- Published
- 2010
9. BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia
- Author
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Hantschel, Oliver, Warsch, Wolfgang, Eckelhart, Eva, Kaupe, Ines, Grebien, Florian, Wagner, Kay-Uwe, Superti-Furga, Giulio, and Sexl, Veronika
- Subjects
Dna-Binding Activity ,hemic and lymphatic diseases ,Tyrosine Phosphorylation ,Polycythemia-Vera ,Follow-Up ,Philadelphia-Chromosome ,food and beverages ,Myeloproliferative Neoplasms ,Jak2 Inhibitor ,neoplasms ,Patients Receiving Imatinib ,Chronic Myelogenous Leukemia ,Kinase Inhibitor - Abstract
Constitutive activation of STAT5 is critical for the maintenance of chronic myeloid leukemia (CML) characterized by the BCR-ABL oncoprotein. Tyrosine kinase inhibitors (TKIs) for the STAT5-activating kinase JAK2 have been discussed as a treatment option for CML patients. Using murine leukemia models combined with inducible ablation of JAK2, we show JAK2 dependence for initial lymphoid transformation, which is lost once leukemia is established. In contrast, initial myeloid transformation and leukemia maintenance were independent of JAK2. Nevertheless, several JAK2 TKIs induced apoptosis in BCR-ABL(+) cells irrespective of the presence of JAK2. This is caused by the previously unknown direct 'off-target' inhibition of BCR-ABL. Cellular and enzymatic analyses suggest that BCR-ABL phosphorylates STAT5 directly. Our findings suggest uncoupling of the canonical JAK2-STAT5 module upon BCR-ABL expression, thereby making JAK2 targeting dispensable. Thus, attempts to pharmacologically target STAT5 in BCR-ABL+ diseases need to focus on STAT5 itself.
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