101 results on '"Martinelli, Giovanni"'
Search Results
2. Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients
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Castagnetti, Fausto, Breccia, Massimo, Gugliotta, Gabriele, Martino, Bruno, D’Adda, Mariella, Stagno, Fabio, Carella, Angelo Michele, Avanzini, Paolo, Tiribelli, Mario, Trabacchi, Elena, Visani, Giuseppe, Gobbi, Marco, Salvucci, Marzia, Levato, Luciano, Binotto, Gianni, Capalbo, Silvana Franca, Bochicchio, Maria Teresa, Soverini, Simona, Cavo, Michele, Martinelli, Giovanni, Alimena, Giuliana, Pane, Fabrizio, Saglio, Giuseppe, Rosti, Gianantonio, Baccarani, Michele, GIMEMA CML Working Party, Bocchia, Monica, Castagnetti, Fausto, Breccia, Massimo, Gugliotta, Gabriele, Martino, Bruno, D'Adda, Mariella, Stagno, Fabio, Carella, Angelo Michele, Avanzini, Paolo, Tiribelli, Mario, Trabacchi, Elena, Visani, Giuseppe, Gobbi, Marco, Salvucci, Marzia, Levato, Luciano, Binotto, Gianni, Capalbo, Silvana Franca, Bochicchio, Maria Teresa, Soverini, Simona, Cavo, Michele, Martinelli, Giovanni, Alimena, Giuliana, Pane, Fabrizio, Saglio, Giuseppe, Rosti, Gianantonio, Baccarani, Michele, Breccia, M, Martino, B, D'Adda, M, Stagno, F, Carella, Am, Avanzini, P, Tiribelli, M, Trabacchi, E, Visani, G, Gobbi, M, Salvucci, M, Levato, L, Binotto, G, Capalbo, Sf, Bochicchio, MARIA TERESA, Alimena, G, Pane, F, and Saglio, G
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Blood Glucose ,Myeloid ,Male ,030204 cardiovascular system & hematology ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,High-density lipoprotein ,80 and over ,Chronic Myelogenous Leukemia ,Aged, 80 and over ,Leukemia ,Hematology ,Incidence (epidemiology) ,Remission Induction ,Myeloid leukemia ,Articles ,Middle Aged ,Cholesterol ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Molecular response ,Young Adult ,03 medical and health sciences ,Aged ,Humans ,Protein Kinase Inhibitors ,Pyrimidines ,Thrombosis ,Triglycerides ,chronic myeloid leukemia ,Internal medicine ,medicine ,Adverse effect ,Tyrosine kinase inhibitors ,business.industry ,Nilotinib ,Discontinuation ,Surgery ,chemistry ,Arterial Thrombosi ,Chronic-Phase ,Glycated hemoglobin ,business - Abstract
The introduction and the extended clinical use of nilotinib in the first-line treatment of chronic myeloid leukemia have been based on company-sponsored trials. Independent confirmations are extremely important. We report an investigator-sponsored study of nilotinib 300 mg twice daily in 130 chronic myeloid leukemia patients in early chronic phase. A deep molecular response was achieved in 46% (MR4.0) and 17% (MR4.5) of patients at 2 years; 58% of the enrolled patients achieved a MR4.0 at least once, with a sustained MR4.0 in 52% of them. With a median observation of 29 months (range 24–37 months), 77% of patients were still on treatment with nilotinib. The reasons for permanent discontinuation were: 3% progression, 5% failure or suboptimal response, 8% adverse events, 1% treatment-free remission, and 5% other reasons. Thirteen thrombotic arterial events were reported in 12 patients. A prospective evaluation of metabolic effects showed an increase of fasting glucose without significant variations of glycated hemoglobin, an increase of total cholesterol (both low density lipoprotein and high density lipoprotein fractions) and a decrease of triglycerides. This study confirms a high and rapid efficacy of nilotinib 300 mg twice daily and provides detailed information on the type and incidence of non-hematologic and metabolic adverse events (clinicaltrials.gov identifier: 01535391).
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- 2016
3. Front-line treatment of Philadelphia positive chronic myeloid leukemia with imatinib and interferon- : 5-year outcome
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Palandri, Francesca, Iacobucci, Ilaria, Castagnetti, Fausto, Testoni, Nicoletta, Poerio, Angela, Amabile, Marilina, Breccia, Massimo, Intermesoli, Tamara, Iuliano, Francesco, Rege Cambrin, Giovanna, Tiribelli, Mario, Miglino, Maurizio, Pane, Fabrizio, Saglio, Giuseppe, Martinelli, Giovanni, Rosti, Gianantonio, Baccarani, Michele, GIMEMA CML Working Party, Bocchia, Monica, Palandri F, Iacobucci I, Castagnetti F, Testoni N, Poerio A, Amabile M, Breccia M, Intermesoli T, Iuliano F, Rege-Cambrin G, Tiribelli M, Miglino M, Pane F, Saglio G, Martinelli G, Rosti G, Baccarani M, GIMEMA Working Party on CML., Francesca, Palandri, Ilaria, Iacobucci, Fausto, Castagnetti, Nicoletta, Testoni, Angela, Poerio, Marilina, Amabile, Massimo, Breccia, Tamara, Intermesoli, Francesco, Iuliano, Giovanna Rege, Cambrin, Mario, Tiribelli, Maurizio, Miglino, Pane, Fabrizio, Giuseppe, Saglio, Giovanni, Martinelli, Gianantonio, Rosti, Michele, Baccarani, and G. I., M.
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Oncology ,medicine.medical_specialty ,Time Factors ,Phases of clinical research ,Alpha interferon ,IMATINIB ,Disease-Free Survival ,Piperazines ,Cohort Studies ,Chronic myeloid leukemia ,Imatinib ,Interferon-alpha ,Long-term results ,Antineoplastic Combined Chemotherapy Protocols ,Benzamides ,Cytogenetics ,Follow-Up Studies ,Humans ,Imatinib Mesylate ,Immunologic Factors ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Patient Compliance ,Pyrimidines ,Treatment Outcome ,Hematology ,Pegylated interferon ,Internal medicine ,medicine ,Chronic ,Interferon alfa ,CHRONIC MYELOID LEUKEMIA ,Leukemia ,business.industry ,Myeloid leukemia ,medicine.disease ,Imatinib mesylate ,Immunology ,BCR-ABL Positive ,business ,Myelogenous ,medicine.drug ,Chronic myelogenous leukemia - Abstract
In 2004, we reported the short-term results of a multicentric, phase 2 study of imatinib 400 mg daily and pegylated interferon-alpha in the treatment of 76 early chronic phase Philadelphia-positive chronic myeloid leukemia patients. In this report, we update the results with an observation time of five years. After two years of treatment, all but 10 patients (13%) had discontinued pegylated interferon-alpha. The complete cytogenetic response rate at five years was 87%, and 94% of complete cytogenetic responders maintained the complete cytogenetic response after five years. All but one complete cytogenetic response also achieved a major molecular response. These data confirm the excellent response to imatinib front-line and the stability of the complete cytogenetic response. Any possible additional benefit of the combination with interferon-alpha remains uncertain, due to low patient compliance.
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- 2008
4. Abstract 1766: Distinct pattern of alterations in tp53 mutated and wild type acute myeloid leukemia (AML) patients
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Valentina Robustelli, Giovanni Marconi, Viviana Guadagnuolo, Eugenio Fonzi, Nicoletta Testoni, Giorgia Simonetti, Carmen Baldazzi, Emanuela Ottaviani, Anna Maria Ferrari, Margherita Perricone, Marco Manfrini, Martinelli Giovanni, Claudia Venturi, Andrea Ghelli Luserna di Rorà, Maria Chiara Fontana, Cristina Papayannidis, Antonella Padella, Stefania Paolini, Maria Chiara Abbenante, Enrica Imbrogno, Elisa Zuffa, and Eugenia Franchini
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Cancer Research ,Oncology ,Cancer research ,Wild type ,Myeloid leukemia ,Biology - Abstract
Background: Mutations in TP53 gene predict a poor prognosis in patients with AML. The reported TP53 mutation rate in AML is low (2.1%) by contrast AML with a complex karyotype (CK) is higher (69-78%) and have a poor outcome. Quite common is to found paired TP53 mutation together and a segmental 17p deletion. Aims: To investigate the frequency, the types of mutations, the associated cytogenetic, the correlation with known molecular alterations and the prognostic role TP53 mutations in adult AML pts. Moreover we would identify genes/pathways that are mainly affected in the mutated TP53 group compared to the wt one. Patients and Methods: 258 adult AML pts with miscellaneous cytogenetic abnormalities and normal karyotype were examined in our Institution for TP53 mutations using several methods, including Sanger sequencing, NGS and HiSeq2000 platform and were correlated with cytogenetic analysis. 124/258 samples were genotyped with SNP arrays (Affymetrix, 3 250K, 43 SNP 6.0, 78 CytoScan HD). Copy Number Alterations (CNAs) analyses were performed using Chromosome Analysis Suite (Affymetrix) and Nexus Copy Number (BioDiscovery) software. Results: Mutation analysis detected TP53 mutations on 39 patients with 48 different types of mutations (32 deleterious point mutations; 4 deletions); nine pts have 2 mutations. We found 34/48 (70%) missense mutations, 5 mutations in the splice sites, 4 deletions ,2 intronic and and 3 others mutations. The mutation rate is of 15.1%. Mostly (28/39) of the TP53 mutated pts (71.8%) had CK while only 11/39 (28.2%) mutated pts have “no CK” (P>0.0001). Alterations of TP53 were significantly associated with poor outcome (OS and EFS p Conclusions: Our data demonstrated that TP53 mutations occur in 15.1% of AML with a higher frequency in the subgroup of CK-AML (p Citation Format: Anna Ferrari, Eugenio Fonzi, Maria Chiara Fontana, Andrea Ghelli Luserna Di Rorà, Marco Manfrini, Antonella Padella, Carmen Baldazzi, Cristina Papayannidis, Giovanni Marconi, Stefania Paolini, Viviana Guadagnuolo, Margherita Perricone, Valentina Robustelli, Enrica Imbrogno, Eugenia Franchini, Claudia Venturi, Elisa Zuffa, Maria Chiara Abbenante, Giorgia Simonetti, Nicoletta Testoni, Emanuela Ottaviani, Martinelli Giovanni. Distinct pattern of alterations in tp53 mutated and wild type acute myeloid leukemia (AML) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1766. doi:10.1158/1538-7445.AM2017-1766
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- 2017
5. Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA WP on CML analysis
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Marzocchi, Giulia, Castagnetti, Fausto, Luatti, Simona, Baldazzi, Carmen, Stacchini, Monica, Gugliotta, Gabriele, Amabile, Marilina, Specchia, Giorgina, Sessarego, Mario, Giussani, Ursula, Valori, Laura, Discepoli, Giancarlo, Montaldi, Anna, Santoro, Alessandra, Bonaldi, Laura, Giudici, Giovanni, Cianciulli, Anna Maria, Giacobbi, Francesca, Palandri, Francesca, Pane, Fabrizio, Saglio, Giuseppe, Martinelli, Giovanni, Baccarani, Michele, Rosti, Gianantonio, Testoni, Nicoletta, GIMEMA CML Working Party, Bocchia, Monica, Marzocchi, G, Castagnetti, F, Luatti, S, Baldazzi, C, Stacchini, M, Gugliotta, G, Amabile, M, Specchia, G, Sessarego, M, Giussani, U, Valori, L, Discepoli, G, Montaldi, A, Santoro, A, Bonaldi, L, Giudici, G, Cianciulli, Am, Giacobbi, F, Palandri, F, Pane, Fabrizio, Saglio, G, Martinelli, G, Baccarani, M, Rosti, G, Testoni, N, Gruppo Italiano Malattie EMatologiche dell'Adulto Working Party on Chronic Myeloid, Leukemia, Marzocchi G., Castagnetti F., Luatti S., Baldazzi C., Stacchini M., Gugliotta G., Amabile M., Specchia G., Sessarego M., Giussani U., Valori L., Discepoli G., Montaldi A., Santoro A., Bonaldi L., Giudici G., Cianciulli A.M., Giacobbi F., Palandri F., Pane F., Saglio G., Martinelli G., Baccarani M., Rosti G., and Testoni N.
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Immunology ,Chromosomal translocation ,Imatinib therapy ,Biology ,Biochemistry ,Piperazines ,Young Adult ,European LeukemiaNet ,diagnosis/drug therapy/genetics ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,80 and over ,medicine ,Humans ,Philadelphia Chromosome ,Chronic ,Aged ,Aged, 80 and over ,Leukemia ,medicine.diagnostic_test ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,Survival Analysis ,Pyrimidines ,Imatinib mesylate ,Adolescent, Adult, Aged, Aged ,80 and over, Cytogenetic Analysis, Female, Humans, Leukemia ,Myelogenous ,BCR-ABL Positive ,diagnosis/drug therapy/genetics, Male, Middle Aged, Philadelphia Chromosome, Piperazines ,therapeutic use, Prognosis, Pyrimidines ,therapeutic use, Survival Analysis, Young Adult ,therapeutic use ,Benzamides ,Cytogenetic Analysis ,Female ,Imatinib Mesylate ,CHRONIC MYELOID LEUKEMIA (CML) ,Tyrosine kinase ,Fluorescence in situ hybridization ,medicine.drug - Abstract
Variant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.
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- 2011
6. 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
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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.
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- 2010
7. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
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Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA, [in the IRIS Investigators, MARTINELLI, GIOVANNI, Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM, Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA, [in the IRIS Investigator, Martinelli G, and ]
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Cancer Research ,medicine.medical_specialty ,IMATINIB ,Piperazines ,law.invention ,chemistry.chemical_compound ,Randomized controlled trial ,law ,Internal medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Omacetaxine mepesuccinate ,medicine ,Humans ,neoplasms ,Survival analysis ,Heart Failure ,CHRONIC MYELOID LEUKEMIA ,business.industry ,Remission Induction ,Myeloid leukemia ,Imatinib ,Neoplasms, Second Primary ,Hematology ,medicine.disease ,Survival Analysis ,Surgery ,Imatinib mesylate ,Pyrimidines ,Treatment Outcome ,Oncology ,chemistry ,Benzamides ,Cytarabine ,Disease Progression ,Imatinib Mesylate ,business ,Chronic myelogenous leukemia ,medicine.drug ,Follow-Up Studies - Abstract
Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
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- 2009
8. Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party
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Castagnetti, Fausto, Palandri, Francesca, Amabile, Marilina, Testoni, Nicoletta, Luatti, Simona, Soverini, Simona, Iacobucci, Ilaria, Breccia, Massimo, Cambrin, Giovanna Rege, Stagno, Fabio, Specchia, Giorgina, Galieni, Piero, Iuliano, Franco, Pane, Fabrizio, Saglio, Giuseppe, Alimena, Giuliana, Martinelli, Giovanni, Baccarani, Michele, Rosti, Gianantonio, GIMEMA CML Working Party, Bocchia, Monica, Castagnetti, F, Palandri, F, Amabile, M, Testoni, N, Luatti, S, Soverini, S, Iacobucci, I, Breccia, M, Rege Cambrin, G, Stagno, F, Specchia, G, Galieni, P, Iuliano, F, Pane, Fabrizio, Saglio, G, Alimena, G, Martinelli, G, Baccarani, M, and Rosti, G.
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Oncology ,Male ,Biochemistry ,Piperazines ,Adult ,Aged ,Antineoplastic Agents ,Benzamides ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Imatinib Mesylate ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Middle Aged ,Patient Compliance ,Prospective Studies ,Pyrimidines ,Risk Factors ,Treatment Outcome ,Hematology ,Cell Biology ,Immunology ,law.invention ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Chronic ,Leukemia ,Myeloid leukemia ,Tolerability ,Sokal Score ,medicine.drug ,medicine.medical_specialty ,Adult, Aged, Antineoplastic Agents ,administration /&/ dosage/adverse effects, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia ,Myelogenous ,BCR-ABL Positive ,drug therapy/epidemiology, Male, Middle Aged, Patient Compliance, Piperazines ,administration /&/ dosage/adverse effects, Prospective Studies, Pyrimidines ,administration /&/ dosage/adverse effects, Risk Factors, Treatment Outcome ,administration /&/ dosage/adverse effects ,Internal medicine ,medicine ,business.industry ,Imatinib ,medicine.disease ,drug therapy/epidemiology ,Surgery ,Clinical trial ,Imatinib mesylate ,business ,Chronic myelogenous leukemia - Abstract
Imatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.
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- 2009
9. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia
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Rosti, Gianantonio, Palandri, Francesca, Castagnetti, Fausto, Breccia, Massimo, Levato, Luciano, Gugliotta, Gabriele, Capucci, Adele, Cedrone, Michele, Fava, Carmen, Intermesoli, Tamara, Cambrin, Giovanna Rege, Stagno, Fabio, Tiribelli, Mario, Amabile, Marilina, Luatti, Simona, Poerio, Angela, Soverini, Simona, Testoni, Nicoletta, Martinelli, Giovanni, Alimena, Giuliana, Pane, Fabrizio, Saglio, Giuseppe, Baccarani, Michele, GIMEMA CML Working Party, Bocchia, Monica, Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M, GIMEMA CML Working Party., Rosti, G, Palandri, F, Castagnetti, F, Breccia, M, Levato, L, Gugliotta, G, Capucci, A, Cedrone, M, Fava, C, Intermesoli, T, Rege Cambrin, G, Stagno, F, Tiribelli, M, Amabile, M, Luatti, S, Poerio, A, Soverini, S, Testoni, N, Martinelli, G, Alimena, G, Pane, Fabrizio, Saglio, G, and Baccarani, M.
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Aged ,Aged, 80 and over ,Antineoplastic Agents ,Female ,Fusion Proteins, bcr-abl ,Humans ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Middle Aged ,Pyrimidines ,Treatment Outcome ,Young Adult ,Hematology ,Biochemistry ,Cell Biology ,Immunology ,medicine.drug_class ,bcr-abl ,NILOTINIB ,Phases of clinical research ,Gastroenterology ,Tyrosine-kinase inhibitor ,Internal medicine ,hemic and lymphatic diseases ,medicine ,80 and over ,Chronic ,CHRONIC MYELOID LEUKEMIA ,Leukemia ,business.industry ,Myeloid leukemia ,Fusion Proteins ,Imatinib ,medicine.disease ,Surgery ,Nilotinib ,BCR-ABL Positive ,business ,Chronic myelogenous leukemia ,medicine.drug ,Myelogenous - Abstract
Nilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph+ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.
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- 2009
10. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: The GIMEMA CML Working Party experience after a 7-year follow-up
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Palandri, Francesca, Castagnetti, Fausto, Alimena, Giuliana, Testoni, Nicoletta, Breccia, Massimo, Luatti, Simona, Rege Cambrin, Giovanna, Stagno, Fabio, Specchia, Giorgina, Martino, Bruno, Levato, Luciano, Merante, Serena, Liberati, Anna Maria, Pane, Fabrizio, Saglio, Giuseppe, Alberti, Daniele, Martinelli, Giovanni, Baccarani, Michele, Rosti, Gianantonio, GIMEMA CML Working Party, Bocchia, Monica, Francesca, Palandri, Fausto, Castagnetti, Giuliana, Alimena, Nicoletta, Testoni, Massimo, Breccia, Simona, Luatti, Giovanna Rege, Cambrin, Fabio, Stagno, Giorgina, Specchia, Bruno, Martino, Luciano, Levato, Serena, Merante, Anna Maria, Liberati, Pane, Fabrizio, Giuseppe, Saglio, Daniele, Alberti, Giovanni, Martinelli, Michele, Baccarani, Gianantonio, Rosti, Palandri, F, Castagnetti, F, Alimena, G, Testoni, N, Breccia, M, Luatti, S, Rege Cambrin, G, Stagno, F, Specchia, G, Martino, B, Levato, L, Merante, S, Liberati, Am, Saglio, G, Alberti, D, Martinelli, G, Baccarani, M, Rosti, G., Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S, Rege-Cambrin G, Stagno F, Specchia G, Martino B, Levato L, Merante S, Liberati AM, Pane F, Saglio G, Alberti D, Martinelli G, Baccarani M, and Rosti G.
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Oncology ,Myeloid ,Male ,imatinib KeyWords Plus:CHRONIC MYELOGENOUS LEUKEMIA ,ABL TYROSINE KINASE ,PHILADELPHIA-CHROMOSOME ,long-term results ,Tyrosine-kinase inhibitor ,Piperazines ,accelerated phase ,hemic and lymphatic diseases ,80 and over ,Leukemia ,INHIBITOR ,Myeloid leukemia ,Hematology ,Middle Aged ,chronic myeloid leukemia ,imatinib ,Survival Rate ,Treatment Outcome ,Benzamides ,Cytogenetic Analysis ,Imatinib Mesylate ,Female ,Complete Hematologic Response ,medicine.drug ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Author Keywords:chronic myeloid leukemia ,CHRONIC GRANULOCYTIC LEUKEMIA ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,STEM-CELL TRANSPLANTATION ,INTERFERON-ALPHA ,BLAST CRISIS ,MESYLATE ,Internal medicine ,Multicenter trial ,medicine ,Humans ,Survival rate ,Aged ,business.industry ,Accelerated phase ,Chronic myeloid leukemia ,Imatinib ,Long-term results ,Aged, 80 and over ,Follow-Up Studies ,Leukemia, Myeloid, Accelerated Phase ,Pyrimidines ,Original Articles ,medicine.disease ,Surgery ,Imatinib mesylate ,business ,Chronic myelogenous leukemia - Abstract
BACKGROUND: Imatinib mesylate is the first line treatment for chronic myeloid leukemia. The advent of imatinib increased survival significantly in patients in an advanced phase of the disease. However, few long-term data on the outcome of these patients based on large, prospective and controlled trials are available. DESIGN AND METHODS: A phase 2 multicenter trial of the use of imatinib 600 mg/daily in patients with accelerated phase chronic myeloid leukemia was sponsored and promoted by the Italian Cooperative Study Group on Chronic Myeloid Leukemia in 2001. RESULTS: One hundred and eleven patients were enrolled; the median follow-up of the 41 living patients is 82 months (range, 73-87). One hundred and seven patients (96%) returned to chronic phase and 79 patients (71%) achieved a complete hematologic response. Cumulative best rates of major cytogenetic response and complete cytogenetic response were 30% and 21%, respectively. All responses were maintained for a minimum of 4 weeks. At last follow-up, four patients were alive in complete remission after allogeneic transplant, 16 patients (14%) had switched to a second generation tyrosine kinase inhibitor and 21 patients (19%) were alive on imatinib therapy. No late toxicities were observed. Progression-free survival and event-free survival rates were 36.5% and 15%, respectively, at 7 years. The median survival time was 37 months, and was significantly associated with the achievement of a complete hematologic response or a complete cytogenetic response. CONCLUSIONS: Imatinib may induce durable responses, associated with prolonged survival, in patients with accelerated phase chronic myeloid leukemia.
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- 2009
11. Long-term outcome of complete cytogenetic responders after imatinib 400 mg in late chronic phase, philadelphia-positive chronic myeloid leukemia: the GIMEMA Working Party on CML
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Palandri, Francesca, Iacobucci, Ilaria, Martinelli, Giovanni, Amabile, Marilina, Poerio, Angela, Testoni, Nicoletta, Soverini, Simona, Castagnetti, Fausto, De Vivo, Antonio, Breccia, Massimo, Specchia, Giorgina, Abruzzese, Elisabetta, Martino, Bruno, Cilloni, Daniela, Saglio, Giuseppe, Pane, Fabrizio, Liberati, Anna Marina, Rosti, Gianantonio, Baccarani, Michele, GIMEMA CML Working Party, Bocchia, Monica, Francesca, Palandri, Ilaria, Iacobucci, Giovanni, Martinelli, Marilina, Amabile, Angela, Poerio, Nicoletta, Testoni, Simona, Soverini, Fausto, Castagnetti, Antonio De, Vivo, Massimo, Breccia, Giorgina, Specchia, Elisabetta, Abruzzese, Bruno, Martino, Daniela, Cilloni, Giuseppe, Saglio, Pane, Fabrizio, Anna Marina, Liberati, Gianantonio, Rosti, Michele, Baccarani, G. I., M., Palandri F, Iacobucci I, Martinelli G, Amabile M, Poerio A, Testoni N, Soverini S, Castagnetti F, De Vivo A, Breccia M, Specchia G, Abruzzese E, Martino B, Cilloni D, Saglio G, Pane F, Liberati AM, Rosti G, Baccarani M, and GIMEMA Working Party on CML.
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Male ,Cancer Research ,Time Factors ,Messenger ,Drug Resistance ,Fusion Proteins, bcr-abl ,Gastroenterology ,Piperazines ,80 and over ,FAILURE ,Prospective Studies ,RNA, Neoplasm ,Chronic ,Prospective cohort study ,Proto-Oncogene Proteins c-abl ,BCR-ABL ,MOLECULAR RESPONSE ,Aged, 80 and over ,Leukemia ,CHRONIC MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,Middle Aged ,Prognosis ,Survival Rate ,Treatment Outcome ,Oncology ,Cohort ,Benzamides ,Proto-Oncogene Proteins c-bcr ,Imatinib Mesylate ,Female ,medicine.drug ,MESYLATE THERAPY ,FOLLOW-UP ,INTERFERON-ALPHA ,SURVIVAL BENEFIT ,BLAST CRISIS ,MANAGEMENT ,Adult ,medicine.medical_specialty ,Alpha interferon ,Antineoplastic Agents ,Aged ,Drug Resistance, Neoplasm ,Humans ,Interferon-alpha ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Pyrimidines ,RNA, Messenger ,COMPLETE CYTOGENETIC RESPONDERS (CCR) ,Internal medicine ,medicine ,IMATINIB MESYLATE (IM) ,Survival rate ,business.industry ,LATE CHRONIC PHASE (LCP) ,Fusion Proteins ,Imatinib ,medicine.disease ,Surgery ,Imatinib mesylate ,Neoplasm ,RNA ,BCR-ABL Positive ,business ,Chronic myelogenous leukemia ,Myelogenous - Abstract
Purpose Imatinib mesylate (IM) has rapidly become the front-line treatment of Philadelphia-positive (Ph-pos) chronic myeloid leukemia, but the number of patients who were treated and are being treated with IM second-line is still substantial. Patients and Methods We have monitored and analyzed the cytogenetic and molecular response to IM 400 mg/d in a cohort of 277 late chronic phase (LCP) patients who were resistant or intolerant to interferon-α and were observed for 48 to 79 months (median, 72 months). Results One hundred fifty-three patients (55%) achieved a complete cytogenetic response (CCgR). Seventy-seven percent of them were still in CCgR after 5 years. The rate of response loss did not increase over time. The 6-year progression-free survival and overall survival of these 153 complete cytogenetic responders were 90% and 91%, respectively. Molecular response was less than major in 21%, major in 78%, and complete in one patient only. Conclusion These data confirm that, in LCP the CCgR rate to IM is 50% to 60%, and show that CCgR is stable and is associated with a prolonged survival, even if leukemia continues to be molecularly detectable.
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- 2008
12. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party
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Rosti, Gianantonio, Iacobucci, Ilaria, Bassi, Simona, Castagnetti, Fausto, Amabile, Marilina, Cilloni, Daniela, Poerio, Angela, Soverini, Simona, Palandri, Francesca, Rege Cambrin, Giovanna, Iuliano, Franco, Alimena, Giuliana, Latagliata, Roberto, Testoni, Nicoletta, Pane, Fabrizio, Saglio, Giuseppe, Baccarani, Michele, Martinelli, Giovanni, GIMEMA CML Working Party, Bocchia, Monica, Rosti G, Iacobucci I, Bassi S, Castagnetti F, Amabile M, Cilloni D, Poerio A, Soverini S, Palandri F, Rege Cambrin G, Iuliano F, Alimena G, Latagliata R, Testoni N, Pane F, Saglio G, Baccarani M, Martinelli G., Rosti, G, Iacobucci, I, Bassi, S, Castagnetti, F, Amabile, M, Cilloni, D, Poerio, A, Soverini, S, Palandri, F, REGE CAMBRIN, G, Iuliano, F, Alimena, G, Latagliata, R, Testoni, N, Pane, Fabrizio, Saglio, G, Baccarani, M, and Martinelli, G.
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Adult ,Male ,medicine.medical_specialty ,Aging ,Adolescent ,Phases of clinical research ,Antineoplastic Agents ,Disease-Free Survival ,Piperazines ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,80 and over ,Age Factors ,Aged ,Aged, 80 and over ,Benzamides ,Female ,Humans ,Imatinib Mesylate ,Middle Aged ,Pyrimidines ,Treatment Outcome ,Chronic ,Adverse effect ,Hematology ,Leukemia ,business.industry ,Myeloid leukemia ,Imatinib ,chronic myeloid leukemia ,imatinib ,older age ,medicine.disease ,Surgery ,Clinical trial ,Imatinib mesylate ,BCR-ABL Positive ,business ,medicine.drug ,Myelogenous - Abstract
To assess the effect of age on response and compliance to treatment in patients with chronic myeloid leukemia (CML) we performed a sub-analysis within a phase II trial of the GIMEMA CML Working Party (CML/002/STI571). Since the WHO cut-off age to define an older patient is 65 years, among the 284 patients considered, we identified 226 (80%) younger patients (below 65 years) and 58 (20%) older patients (above 65 years) before starting imatinib. Response rates (hematologic and cytogenetic) were lower in the older age group but the probabilities of progression-free survival and overall survival (median observation time 3 years) were the same. Moreover, among complete cytogenetic responders, no differences were found in the level of molecular response between the two age groups. As might be expected, older patients experienced more adverse events, both hematologic and non-hematologic: this worsened compliance did not, however, prevent a long-term outcome similar to that of younger patients.
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- 2007
13. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia
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SOVERINI, SIMONA, COLAROSSI, SABRINA, GNANI, ALESSANDRA, ROSTI, GIANANTONIO, CASTAGNETTI, FAUSTO, POERIO, ANGELA, IACOBUCCI, ILARIA, AMABILE, MARILINA, BACCARANI, MICHELE, MARTINELLI, GIOVANNI, Abruzzese E, Orlandi E, Radaelli F, Ciccone F, Tiribelli M, di Lorenzo R, Caracciolo C, Izzo B, Pane F, Saglio G, on behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia, Soverini, S, Colarossi, S, Gnani, A, Rosti, G, Castagnetti, F, Poerio, A, Iacobucci, I, Amabile, M, Abruzzese, E, Orlandi, E, Radaelli, F, Ciccone, F, Tiribelli, M, DI LORENZO, R, Caracciolo, C, Izzo, Barbara, Pane, Fabrizio, Saglio, G, Baccarani, M, Martinelli, G., Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, Iacobucci I, Amabile M, Abruzzese E, Orlandi E, Radaelli F, Ciccone F, Tiribelli M, di Lorenzo R, Caracciolo C, Izzo B, Pane F, Saglio G, Baccarani M, Martinelli G, and on behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML)
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Adult ,Cancer Research ,Myeloid ,Adolescent ,DNA Mutational Analysis ,Antineoplastic Agents ,Genes, abl ,Biology ,IMATINIB ,Piperazines ,Myelogenous ,Gene Frequency ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Chromatography, High Pressure Liquid ,Aged ,Neoplasm Staging ,CHRONIC MYELOID LEUKEMIA ,ABL ,MUTATIONS ,Myeloid leukemia ,Imatinib ,Middle Aged ,medicine.disease ,Hematologic Response ,Protein Structure, Tertiary ,Leukemia ,Pyrimidines ,Imatinib mesylate ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,ABL KINASE DOMAIN ,Benzamides ,Mutation ,Imatinib Mesylate ,Cancer research ,Protein Kinases ,RESISTANCE ,medicine.drug - Abstract
Purpose: ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients. Experimental Design: Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib. Results: Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis. Conclusions: We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.
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- 2007
14. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia
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Soverini, Simona, Martinelli, Giovanni, Rosti, Gianantonio, Bassi, Simona, Amabile, Marilina, Poerio, Angela, Giannini, Barbara, Trabacchi, Elena, Castagnetti, Fausto, Testoni, Nicoletta, Luatti, Simona, De Vivo, Antonio, Cilloni, Daniela, Izzo, Barbara, Fava, Milena, Abruzzese, Elisabetta, Alberti, Daniele, Pane, Fabrizio, Saglio, Giuseppe, Baccarani, Michele, GIMEMA CML Working Party, Bocchia, Monica, Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A, Giannini B, Trabacchi E, Castagnetti F, Testoni N, Luatti S, de Vivo A, Cilloni D, Izzo B, Fava M, Abruzzese E, Alberti D, Pane F, Saglio G, Baccarani M., Soverini, S, Martinelli, G, Rosti, G, Bassi, S, Amabile, M, Poerio, A, Giannini, B, Trabacchi, E, Castagnetti, F, Testoni, N, Luatti, S, DE VIVO, A, Cilloni, D, Izzo, Barbara, Fava, M, Abruzzese, E, Alberti, D, Pane, Fabrizio, Saglio, G, and Baccarani, M.
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Myeloid ,Male ,Oncology ,Cancer Research ,DNA Mutational Analysis ,Drug Resistance ,TYROSINE KINASE ,Piperazines ,hemic and lymphatic diseases ,BCR-ABL ,Chromatography, High Pressure Liquid ,Chromatography ,Leukemia ,ABL ,CLINICAL RESISTANCE ,Reverse Transcriptase Polymerase Chain Reaction ,Statistics ,CHRONIC MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.anatomical_structure ,High Pressure Liquid ,Benzamides ,Cytogenetic Analysis ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,POSITIVE CELLS ,Antineoplastic Agents ,Genes, abl ,Statistics, Nonparametric ,Internal medicine ,medicine ,Humans ,Point Mutation ,Nonparametric ,PERFORMANCE LIQUID-CHROMATOGRAPHY ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,KINASE INHIBITOR BMS-354825 ,I DOSE-ESCALATION ,DOMAIN MUTATIONS ,Aged ,Chi-Square Distribution ,business.industry ,Point mutation ,abl ,Imatinib ,medicine.disease ,Survival Analysis ,Pyrimidines ,Imatinib mesylate ,Genes ,Drug Resistance, Neoplasm ,Immunology ,Neoplasm ,ABL MUTATIONS ,Chronic-Phase ,Bone marrow ,Blast Crisis ,business - Abstract
Purpose Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. Patients and Methods Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. Results Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). Conclusion Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.
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- 2005
15. In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants.
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Soverini, Simona, De Benedittis, Caterina, Castagnetti, Fausto, Gugliotta, Gabriele, Mancini, Manuela, Bavaro, Luana, Polakova, Katerina Machova, Linhartova, Jana, Iurlo, Alessandra, Russo, Domenico, Pane, Fabrizio, Saglio, Giuseppe, Rosti, Gianantonio, Cavo, Michele, Baccarani, Michele, Martinelli, Giovanni, and Machova Polakova, Katerina
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MYELOID leukemia ,LEUKEMIA treatment ,PROTEIN-tyrosine kinase inhibitors ,NUCLEOTIDE sequencing ,NILOTINIB ,DRUG resistance ,DISEASE relapse ,GENETIC mutation ,THERAPEUTICS ,PROTEIN kinase inhibitors ,DRUG resistance in cancer cells ,GENETIC polymorphisms ,PROTEINS ,CHRONIC myeloid leukemia ,SEQUENCE analysis - Abstract
Background: Imatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR-ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR-ABL1 KD mutants predicting for an impending relapse.Methods: a total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%(IS) transcript levels were used to define whether the patient had 'optimal response', 'warning' or 'failure' at the time of first mutation detection by DS.Results: DS was able to backtrack dasatinib- or nilotinib-resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5-17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1-9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as 'Warning' (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as 'Optimal response' in one case, as 'Failure' in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with 'warning' at various timepoints, that later turned into optimal responders with no treatment changes.Conclusions: DS enables a larger window of detection of emerging BCR-ABL1 KD mutations predicting for an impending relapse. A 'Warning' response may represent a rational trigger, besides 'Failure', for DS-based mutation screening in CML patients undergoing second-line TKI therapy. [ABSTRACT FROM AUTHOR]- Published
- 2016
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16. Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia
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Baccarani, Michele, Martinelli, Giovanni, Rosti, Gianantonio, Trabacchi, Elena, Testoni, Nicoletta, Bassi, Simona, Amabile, Marilina, Soverini, Simona, Castagnetti, Fausto, Cilloni, Daniela, Izzo, Barbara, De Vivo, Antonio, Messa, Emanuela, Bonifazi, Francesca, Poerio, Angela, Luatti, Simona, Giugliano, Emilia, Alberti, Daniele, Fincato, Gianluca, Russo, Domenico, Pane, Fabrizio, Saglio, Giuseppe, GIMEMA CML Working Party, Bocchia, Monica, Baccarani, M, Martinelli, G, Rosti, G, Trabacchi, E, Testoni, N, Bassi, S, Amabile, M, Soverini, S, Castagnetti, F, Cilloni, D, Izzo, Barbara, DE VIVO, A, Messa, E, Bonifazi, F, Poerio, A, Luatti, S, Giugliano, E, Alberti, D, Fincato, G, Russo, D, Pane, Fabrizio, Saglio, G, GIMEMA WORKING PARTY ON CHRONIC MYELOID, L. E. U. K. E. M. I. A., BACCARANI M., MARTINELLI G., ROSTI G., TRABACCHI E., TESTONI N., BASSI S., AMABILE M., SOVERINI S., CASTAGNETTI F., CILLONI D., IZZO B., DE VIVO A., MESSA E., BONIFAZI F., POERIO A., LUATTI S., GIUGLIANO E., ALBERTI D., FINCATO G., RUSSO D., PANE F., SAGLIO G., and GIMEMA WORKING PARTY ON CHRONIC MYELOID LEUKEMIA
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Male ,PHILADELPHIA-CHROMOSOME ,Biochemistry ,Gastroenterology ,Piperazines ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Chronic ,BCR-ABL ,Leukemia ,CLINICAL RESISTANCE ,CHRONIC MYELOGENOUS LEUKEMIA ,Myeloid leukemia ,TYROSINE KINASE INHIBITOR ,ABL-POSITIVE CELLS ,SEQUENCE BINDING-PROTEIN ,FUSION GENE TRANSCRIPTS ,CYTOGENETIC RESPONSES ,ANTILEUKEMIC AGENTS ,Hematology ,Middle Aged ,Recombinant Proteins ,Toxicity ,Benzamides ,Imatinib Mesylate ,Female ,Drug ,medicine.drug ,Adult ,medicine.medical_specialty ,Immunology ,Alpha interferon ,Interferon alpha-2 ,Dose-Response Relationship ,chronic myeloid leukemia ,Aged ,Dose-Response Relationship, Drug ,Humans ,Interferon-alpha ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Pyrimidines ,Internal medicine ,medicine ,Adverse effect ,business.industry ,Imatinib ,Cell Biology ,medicine.disease ,Imatinib mesylate ,imatinib ,BCR-ABL Positive ,recombinant alpha2b interferon ,business ,Chronic myelogenous leukemia ,Myelogenous - Abstract
Since interferon-α and imatinib (IM; STI571, Glivec, Gleevec) are effective for the treatment of chronic myeloid leukemia (CML), and their mechanisms of action are different, we designed an exploratory study investigating the effects of a standard IM dose (400 mg/d) and a variable pegylated interferon-α (PegIFN) dose (50 μg/wk, 100 μg/wk, and 150 μg/wk). The criteria for dose adjustment were designed so as to ensure the delivery of the IM dose and to protect life quality. There were 76 patients with previously untreated Philadelphia (Ph)–positive CML enrolled in the study. There were 3 patients who discontinued IM and 45 patients who discontinued PegIFN. The severity of adverse events increased with increasing PegIFN dose. The IM dose could be administered to the patients who were assigned to receive 50 μg/wk or 100 μg/wk PegIFN but not to those who were assigned to receive 150 μg/wk. The median administered dose of PegIFN ranged between 32 μg/wk and 36 μg/wk. The cytogenetic response was 70% complete (Ph-neg 100%) and 83% major (Ph-neg > 65%). The BCR/ABL transcript was reduced by at least 3 logs in 68% of complete cytogenetic responders. These data of toxicity, compliance, and efficacy may assist in the design and preparation of prospective studies.
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- 2004
17. Present and future of molecular monitoring in chronic myeloid leukaemia.
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Soverini, Simona, De Benedittis, Caterina, Mancini, Manuela, and Martinelli, Giovanni
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MYELOID leukemia ,DISEASE remission ,HEALTH outcome assessment ,PATIENT monitoring ,DISEASE management ,PATIENTS - Abstract
Currently, physicians treating chronic myeloid leukaemia ( CML) patients can rely on a wide spectrum of therapeutic options: the best use of such options is essential to achieve excellent clinical outcomes and, possibly, treatment-free remission ( TFR). To accomplish this, proper integration of expert clinical and laboratory monitoring of CML patients is fundamental. Molecular response ( MR) monitoring of patients at defined time points has emerged as an important success factor for optimal disease management and BCR- ABL1 kinase domain mutation screening is useful to guide therapeutic reassessment in patients who do not achieve optimal responses to tyrosine kinase inhibitor therapy. Deeper MRs might be associated with improved long-term survival outcomes. More importantly, they are considered a gateway to TFR. In molecular biology, novel procedures and technologies are continually being developed. More sophisticated molecular tools and automated analytical solutions are emerging as CML treatment endpoints and expectations become more and more ambitious. Here we provide a critical overview of current and novel methodologies, present their strengths and pitfalls and discuss what their present and future role might be. [ABSTRACT FROM AUTHOR]
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- 2016
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18. 14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist chibby 1 in Chronic Myeloid Leukemia.
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Mancini, Manuela, Leo, Elisa, Takemaru, Ken-Ichi, Campi, Virginia, Castagnetti, Fausto, Soverini, Simona, De Benedittis, Caterina, Rosti, Gianantonio, Cavo, Michele, Santucci, Maria Alessandra, and Martinelli, Giovanni
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CATENINS ,MYELOID leukemia ,STEM cells ,HEMATOPOIESIS ,PROMOTERS (Genetics) - Abstract
The down-modulation of the β-catenin antagonist Chibby 1 (CBY1) associated with the BCR-ABL1 fusion gene of chronic myeloid leukemia (CML) contributes to the aberrant activation of β-catenin, particularly in leukemic stem cells (LSC) resistant to tyrosine kinase (TK) inhibitors. It is, at least partly, driven by transcriptional events and gene promoter hyper-methylation. Here we demonstrate that it also arises from reduced protein stability upon binding to 14-3-3σ adapter protein. CBY1/14-3-3σ interaction in BCR-ABL1+ cells is mediated by the fusion protein TK and AKT phosphorylation of CBY1 at critical serine 20, and encompasses the 14-3-3σ binding modes I and II involved in the binding with client proteins. Moreover, it is impaired by c-Jun N-terminal kinase (JNK) phosphorylation of 14-3-3σ at serine 186, which promotes dissociation of client proteins. The ubiquitin proteasome system UPS participates in reducing stability of CBY1 bound with 14-3-3σ through enhanced SUMOylation. Our results open new routes towards the research on molecular pathways promoting the proliferative advantage of leukemic hematopoiesis over the normal counterpart. [ABSTRACT FROM AUTHOR]
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- 2015
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19. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia.
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Kantarjian, Hagop M., Martinelli, Giovanni, Jabbour, Elias J., Quintás‐Cardama, Alfonso, Ando, Kiyoshi, Bay, Jacques‐Olivier, Wei, Andrew, Gröpper, Stefanie, Papayannidis, Cristina, Owen, Kate, Pike, Laura, Schmitt, Nicola, Stockman, Paul K., and Giagounidis, Aristoteles
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MYELOID leukemia , *NEUTROPHILS , *BLOOD platelets , *CYTARABINE , *FEBRILE neutropenia , *PATIENTS - Abstract
BACKGROUND In this phase 2 study, the authors evaluated the efficacy, safety, and tolerability of the Aurora B kinase inhibitor barasertib compared with low-dose cytosine arabinoside (LDAC) in patients aged ≥60 years with acute myeloid leukemia (AML). METHODS Patients were randomized 2:1 to receive either open-label barasertib 1200 mg (as a 7-day intravenous infusion) or LDAC 20 mg (subcutaneously twice daily for 10 days) in 28-day cycles. The primary endpoint was the objective complete response rate (OCRR) (complete responses [CR] plus confirmed CRs with incomplete recovery of neutrophils or platelets [CRi] according to Cheson criteria [also requiring reconfirmation of CRi ≥21 days after the first appearance and associated with partial recovery of platelets and neutrophils]). Secondary endpoints included overall survival (OS) and safety. RESULTS In total, 74 patients (barasertib, n = 48; LDAC, n = 26) completed ≥1 cycle of treatment. A significant improvement in the OCRR was observed with barasertib (35.4% vs 11.5%; difference, 23.9%; 95% confidence interval, 2.7%-39.9%; P < .05). Although the study was not formally sized to compare OS data, the median OS with barasertib was 8.2 months versus 4.5 months with LDAC (hazard ratio, 0.88; 95% confidence interval, 0.49-1.58; P = .663). Stomatitis and febrile neutropenia were the most common adverse events with barasertib versus LDAC (71% vs 15% and 67% vs 19%, respectively). CONCLUSIONS Barasertib produced a significant improvement in the OCRR versus LDAC and had a more toxic but manageable safety profile, consistent with previous studies. Cancer 2013;119:2611-2619. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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20. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107).
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Amadori, Sergio, Stasi, Roberto, Martelli, Alberto M., Venditti, Adriano, Meloni, Giovanna, Pane, Fabrizio, Martinelli, Giovanni, Lunghi, Monia, Pagano, Livio, Cilloni, Daniela, Rossetti, Elena, Di Raimondo, Francesco, Fozza, Claudio, Annino, Luciana, Chiarini, Francesca, Ricci, Francesca, Ammatuna, Emanuele, La Sala, Edoardo, Fazi, Paola, and Vignetti, Marco
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OLDER patients ,MYELOID leukemia ,IMMUNOSUPPRESSIVE agents ,DRUGS ,SALVAGE therapy ,THERAPEUTICS - Abstract
Summary The mammalian target of rapamycin (mTOR) signalling pathway has emerged as an important therapeutic target for acute myeloid leukaemia (AML). This study assessed the combination of temsirolimus, an mTOR inhibitor, and lower-dose clofarabine as salvage therapy in older patients with AML. Induction consisted of clofarabine 20 mg/m
2 on days 1-5 and temsirolimus 25 mg (flat dose) on days 1, 8 and 15. Patients achieving complete remission with (CR) or without (CRi) full haematological recovery could receive monthly temsirolimus maintenance. In 53 evaluable patients, the overall remission rate (ORR) was 21% (8% CR, 13% CRi). Median disease-free survival was 3·5 months, and median overall survival was 4 months (9·1 months for responders). The most common non-haematological severe adverse events included infection (48%), febrile neutropenia (34%) and transaminitis (11%). The 30-d all-cause induction mortality was 13%. Laboratory data from 25 patients demonstrated that a >50% in vivo inhibition of S6 ribosomal protein phosphorylation was highly correlated with response rate (75% with inhibition versus 0% without inhibition; P = 0·0001), suggesting that targeting the mTOR pathway is clinically relevant. The acceptable safety profile and the predictive value of target inhibition encourage further investigation of this novel regimen. [ABSTRACT FROM AUTHOR]- Published
- 2012
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21. A simple prognostic scoring system for newly diagnosed cytogenetically normal acute myeloid leukemia: retrospective analysis of 530 patients.
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Malagola, Michele, Skert, Cristina, Vignetti, Marco, Piciocchi, Alfonso, Martinelli, Giovanni, Alimena, Giuliana, Mecucci, Cristina, Testoni, Nicoletta, Iacobucci, Ilaria, Clavio, Marino, Gobbi, Marco, Candoni, Anna, Damiani, Daniela, Bocchia, Monica, Lauria, Francesco, Zaccaria, Alfonso, Mazza, Patrizio, Visani, Giuseppe, Peli, Annalisa, and Colombi, Chiara
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MYELOID leukemia ,TUMOR markers ,BIOMARKERS ,LEUCOCYTES ,BONE marrow diseases - Abstract
We retrospectively analyzed the data of 337 patients with cytogenetically normal (CN) acute myeloid leukemia (AML), aged ≤ 65 years (training set). A prognostic index score (PIS) was calculated by totaling the score derived from the regression coefficients of each clinical variable, significantly associated with prognosis by multivariate analysis. The variables that were independent prognostic factors for event-free survival (EFS) and overall survival (OS) in the training set were: age ≥ 50 years, secondary AML and white blood cell count (WBC) ≥ 20 × 10
9 /L. The patients of the training set were stratified into three groups: low-, intermediate- and high-risk. The median EFS was 25, 12 and 7 months in the low-, intermediate- and high-risk groups (p < 0.0001), respectively. The median OS was not reached in the low-risk group and was 19 and 10 months in the intermediate- and high-risk groups (p < 0.0001). This PIS was validated in a series of 193 patients with CN-AML. The median EFS was 66, 16, and 3 months (p < 0.0001) and the median OS was 66, 16, and 5 months in the three risk groups, respectively (p < 0.0001). This PIS may be useful for clinical decision-making in CN-AML and may be prospectively integrated with the newest biological markers which at present are not routinely assessed and need prognostic validation. [ABSTRACT FROM AUTHOR]- Published
- 2011
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22. Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia.
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Latagliata, Roberto, Breccia, Massimo, Fazi, Paola, Iacobelli, Simona, Martinelli, Giovanni, Di Raimondo, Francesco, Sborgia, Marco, Fabbiano, Francesco, Pirrotta, Maria Teresa, Zaccaria, Alfonso, Amadori, Sergio, Caramatti, Cecilia, Falzetti, Franca, Candoni, Anna, Mattei, Daniele, Morselli, Monica, Alimena, Giuliana, Vignetti, Marco, Baccarani, Michele, and Mandelli, Franco
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MYELOID leukemia ,BONE marrow diseases ,MEDICAL research ,MEDICAL experimentation on humans ,CLINICAL trials - Abstract
This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m
2 days 1–3) or DNX (80 mg/m2 days 1–3) plus cytarabine (AraC; 100 mg/m2 days 1–7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51·0%) achieved CR, 55 (35·9%) were resistant and 20 (13·1%) died during induction. Among 148 patients in the DNX arm, 73 (49·3%) achieved CR, 47 (31·8%) were resistant and 28 (18·9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12·5% vs. 2·6% at 6 months, P = 0·053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0·064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses. [ABSTRACT FROM AUTHOR]- Published
- 2008
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23. Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway.
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Bortul, Roberta, Tazzari, Pier Luigi, Billi, Anna Maria, Tabellini, Giovanna, Mantovani, Irina, Cappellini, Alessandra, Grafone, Tiziana, Martinelli, Giovanni, Conte, Roberto, and Martelli, Alberto M.
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LEUKEMIA ,PHOSPHOINOSITIDES ,CANCER cells ,CHEMICAL reactions ,MYELOID leukemia ,ANTINEOPLASTIC agents - Abstract
Activation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its downregulation, by means of PI3K inhibitors, lowers resistance to various types of therapy in tumour cell lines. Recently, it has been reported that deguelin, a naturally occurring rotenoid, is a powerful inhibitor of PI3K. We investigated whether or not deguelin could enhance the sensitivity to chemotherapeutic drugs of human U937 leukaemia cells and acute myeloid leukaemia (AML) blasts with an activated PI3K/Akt network. Deguelin (10 nmol/l) induced S phase arrest with interference of progression to G2/M, and at 100 nmol/l significantly increased apoptotic cell death of U937. At 10–100 nmol/l concentrations, deguelin downregulated Akt phosphorylation of leukaemia cells and markedly increased sensitivity of U937 cells to etoposide or cytarabine. A 10 nmol/l concentration of deguelin did not negatively affect the survival rate of human cord blood CD34
+ cells, whereas it increased sensitivity of AML blasts to cytarabine. Deguelin was less toxic than wortmannin on erythropoietin- and stem cell factor-induced erythropoiesis from CD34+ progenitor cells. Overall, our results indicate that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukaemia cells with an active PI3K/Akt signalling network. [ABSTRACT FROM AUTHOR]- Published
- 2005
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24. First experience with gemtuzumab ozogamicin plus cytarabine as continuous infusion for elderly acute myeloid leukaemia patients
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Piccaluga, Pier Paolo, Martinelli, Giovanni, Rondoni, Michela, Malagola, Michele, Gaitani, Stavroula, Visani, Giuseppe, and Baccarani, Michele
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ACUTE myeloid leukemia , *MONOCLONAL antibodies , *MYELOID leukemia , *MOLECULAR cloning - Abstract
Gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody conjugated to calicheamicin, is effective as single agent in the treatment of poor risk acute myeloid leukaemia (AML) patients. We treated with GO in combination with cytarabine as continuous perfusion nine elderly AML patients, either untreated (five cases), or with relapsed/refractory disease (four cases). Five patients achieved a complete remission (CR), four were resistant. One patient died while in CR due to CNS haemorrhage, two relapsed and two are still in CR. The median CR duration was 10 months. The median overall survival was 6 months (1–19 months). The most common adverse event was myelosuppression, as expected. No hepatic veno-occlusive disease was recorded. Notably, in four cases we observed a grade III/IV bleeding, including gasto-intestinal bleeding, epistaxis, CNS haemorrhage, and ocular bleeding. Larger prospective studies are now warranted in order to better define the possible role of this regimen in the treatment of elderly AML patients. [Copyright &y& Elsevier]
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- 2004
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25. No Preferential Sensitivity of t(8;21) Acute Myeloid Leukemias to Cytosine Arabinoside in Vitro: Is Intensity of Therapy or High Dose Ara-C Crucial for Response?
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Visani, Giuseppe, Isidori, Alessandro, Grafone, Tiziana, Tosi, Patrizia, Santinic, Valeria, Malagola, Michele, Martinelli, Giovanni, Piccaluga, Pier Paolo, Gaziev, Djavid, Ottaviani, Emanuela, Sparaventi, Giovanni, and Tura, Sante
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MYELOID leukemia ,DNA ,DOSE-response relationship in biochemistry ,KARYOTYPES ,APOPTOSIS ,DRUG therapy - Abstract
Acute myeloid leukemia (AML) patients with core binding factor abnormalities [inv(16) or t(8;21)] have a relatively good prognosis, especially patients with inv(16) when treated with high-dose cytosine arabinoside (AraC) containing regimens, whereas in the case of t(8;21) evidences in favor of such regimen are contrasting. We previously demonstrated that blast cells from inv(16)-positive AML patients are characterized by an increased sensitivity to AraC with higher incorporation of 3 H AraC into DNA and the increase of induced apoptosis in vitro . In the present study we tested the sensitivity of leukemic cells from 15 t(8;21)-positive AML patients to AraC and compared it with the results obtained from cells of 74 patients with inv(16), "intermediate" or "unfavourable" karyotype at diagnosis (for a total of 89 patients). The incorporation of 3 H AraC into DNA in cells with t(8;21) was significantly lower than in cells with inv(16) ( P = 0.02) or normal karyotype ( P = 0.04). Interestingly, the incorporation of the drug into DNA in t(8;21) cells was similar to those with "unfavourable" karyotype. Furthermore, AraC induced apoptosis in t(8;21)-positive AML cells was not increased. These data suggest that the mechanism of response to chemotherapy for t(8;21)-positive cells is probably different then in AML cells with inv(16), underlining the possible importance for patients carrying the t(8;21) of repeated high-dose regimens and not necessarily of high-dose AraC based ones. [ABSTRACT FROM AUTHOR]
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- 2004
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26. Quantitative Evaluation of BCR-ABL Amount of Transcript Post Mobilization with G-CSF of....
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Martinelli, Giovanni
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MYELOID leukemia , *THERAPEUTIC use of interferons , *STEM cells , *GRANULOCYTE-colony stimulating factor , *PATIENTS - Abstract
Evaluates the cytogenetic response of patients with chronic myeloid leukemia treated with alpha-interferon. Feasibility of peripheral blood stem cell mobilization induced by granulocyte-colony stimulating factor (G-CSF); Patient tolerance for G-CSF; Number of patients who achieved karyotypic remission before mobilization.
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- 2000
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27. Second chronic phase before transplantation is crucial for improving survival of blastic phase chronic myeloid leukaemia.
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Visani, Giuseppe, Rosti, Gianantonio, Bandini, Giuseppe, Tosi, Patrizia, Isidori, Alessandro, Malagola, Michele, Stanzani, Marta, Martinelli, Giovanni, Piccaluga, Pierpaolo, Testoni, Nicoletta, Ricci, Paolo, and Tura, Sante
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MYELOID leukemia ,LEUKEMIA - Abstract
Because successful outcome after transplantation seems to depend in acute myeloid leukaemia (AML) and in chronic phase chronic myeloid leukaemia (CML) on disease status at the time of transplantation, we investigated whether FLAN (fludarabine, cytosine arabinoside, mitoxantrone) induction before allogeneic stem cell transplantation (allo-SCT) may be useful in blastic phase (BP)-CML. Twenty patients with BP-CML were studied: 10 patients received FLAN induction chemotherapy before proceeding to early allo-SCT, whereas 10 patients were submitted to bone marrow transplantation (BMT) without remission induction. Eight out of 10 (80%) patients achieved second chronic phase after one course of therapy with FLAN and seven patients (six in second chronic phase and one with partial response) were then submitted to allo-SCT. Of the six patients transplanted in the second chronic phase, all achieved molecular remission, four are still in second chronic phase, with intervals ranging from 10 to 54 months, whereas one patient died from infection having relapsed 14 months after SCT and one died of transplant-related complications in the second chronic phase. Mean durations of second chronic phase and survival after allo-SCT were both significantly longer than in the group of 10 BP-CML patients submitted to allo-SCT without FLAN remission induction treatment [22·4 (range 1–61) vs. 3·5 months (range 1–10) with FLAN and 22·7 (range 2–61) vs. 6·4 (range 1–16) months without FLAN]. We conclude that FLAN induction therapy followed by early allo-SCT appears to be effective in the treatment of BP-CML and could provide a curative possibility for BP-CML patients. [ABSTRACT FROM AUTHOR]
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- 2000
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28. All‐trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia.
- Author
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Visani, Giuseppe, Gugliotta, Luigi, Tosi, Patrizia, Catani, Lucia, Vianelli, Nicola, Martinelli, Giovanni, Ottaviani, Emanuela, Testoni, Nicoletta, Nocentini, Franco, Pastano, Rocco, Piccaluga, Pierpaolo, Isidori, Alessandro, Grafone, Tiziana, and Tura, Sante
- Subjects
TRETINOIN ,MYELOID leukemia ,LEUKEMIA treatment ,HEMORRHAGIC diseases ,THERAPEUTICS - Abstract
Early hemorrhagic death (within the first 10 d of treatment [EHD]) is reported as the main cause of death during induction therapy for acute promyelocytic leukemia (APL). In order to evaluate possible differences in the incidence of EHD during induction regimens based on all‐trans retinoic acid (ATRA), we retrospectively analyzed a consecutive series of 86 APL patients, diagnosed and treated at our Institution from 1982. Forty‐three patients received combination chemotherapy with anthracyclines and cytosine arabinoside (January 1982 to December 1991), while induction of the remaining 43 was based on ATRA alone or on a combination of ATRA and anthracyclines (January 1992 to October 1996). There were significantly less induction deaths in the ATRA group [9 (chemotherapy group‐CT) vs. 2 (ATRA group‐RA) overall and 8(CT) vs. 1(RA) of EHD; p=0.01]. Hemostatic evaluations showed an earlier reduction of d‐dimer in the ATRA group. No cases of morphological resistance were observed in the ATRA group after induction. In addition, the number of relapses occurring in the first 24 months from the achievement of complete remission (CR) was significantly lower in the ATRA group (15 vs. 7; p=0.01), with a disease free survival at 2 yr of 67% vs. 31%. In conclusion, ATRA appears to be able to significantly reduce the incidence of EHD, increasing the number of possible long‐term remissions. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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29. Selective expansion of normal haemopoietic progenitors from chronic myelogenous leukaemia marrow.
- Author
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Fogli, Miriam, Amabile, Marilina, Martinelli, Giovanni, Fortuna, Alessandra, Rondelli, Damiano, Ratta, Marina, Curti, Antonio, Tura, Sante, and Lemoli, Roberto M.
- Subjects
MYELOID leukemia ,HEMATOPOIESIS - Abstract
CD34
+ and CD34+ DR- cells from the bone marrow (BM) of chronic-phase chronic myelogenous leukaemia (CML) patients at diagnosis were tested for their colony-forming ability in response to early and intermediate-late colony stimulating factors (CSFs). Molecular analysis revealed that 55.6 ± 9% SD of CD34+ DR- colonies, in which actin and ABL mRNA were detectable, expressed the product of the BCR-ABL gene. The percentage and the clonogenic efficiency of CML DR- cells were significantly lower than those of comparable DR- cells from normal donors. However, clonogenic assays using recombinant human CSFs demonstrated a remarkable proliferation of CML cells when stimulated by SCF, IL-11 and IL-3, used as single factors in the presence of erythropoietin (EPO) and was almost entirely due to erythroid progenitors. Conversely, optimal stimulation of CD34+ DR- cells from normal donors required co-incubation with three or more CSFs. Stroma-noncontact long-term cultures were then established in the presence of exogenous CSFs and human irradiated allogeneic stromal layers or the murine stromal cell line M2-10B4, engineered to produce G-CSF and IL-3. In these cultures the combination of SCF and IL-3 induced a 25.4 ± 5 SD, 40 ± 6 SD and 20.5 ± 6 SD fold increase of colony-forming unit cells (CFU-C), at weeks 2, 4 and 5, respectively. At the same time-points the number of primitive long-term culture initiating cells (LTC-IC) showed a 4 ± 2 SD, 3.3 ± 1.5 SD and 2.3 ± 1 SD fold increase compared to baseline values. BCR-ABL mRNA analysis of single colonies demonstrated that 27 ± 9% SD and 7 ± 3% SD CFU-C at weeks 4 and 5, respectively, expressed the fusion gene, whereas leukaemic LTC-IC disappeared from the culture by week 2. These results suggest that leukaemic CD34+ DR- cells have a different pattern of response to CSFs... [ABSTRACT FROM AUTHOR]- Published
- 1998
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30. DNA hypermethylation promotes the low expression of pro-apoptotic BCL2L11 associated with BCR - ABL1 fusion gene of chronic myeloid leukaemia.
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Leo, Elisa, Mancini, Manuela, Aluigi, Michela, Castagnetti, Fausto, Martinelli, Giovanni, Barbieri, Enza, and Santucci, Maria A.
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DNA methylation ,MYELOID leukemia ,GENE expression ,GENE fusion ,POLYMERASE chain reaction ,IMMUNOPRECIPITATION ,CPG nucleotides - Abstract
The article informs about a study based on promoting the low expression of pro-apoptotic BCL2L11 gene associated with BCR-ABL1 fusion gene of chronic myeloid leukemia through DNA hypermethylation. It mentions that polymerase chain reaction and immunoprecipitation methods are used in the study. It adds that DNA methyltransferase (DNMT) 1 recruitment and 5 methylcytosine (5mC) excess was found to be involved in the aberrant DNA methylation at promoter-associated CpG islands of several genes.
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- 2012
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31. Patient with ataxia telangiectasia who developed acute myeloid leukemia.
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Brioli, Annamaria, Parisi, Sarah, Iacobucci, Ilaria, Cavo, Michele, Papayannidis, Cristina, Anna Zannetti, Beatrice, Martinelli, Giovanni, and Baccarani, MicheLe
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MYELOID leukemia ,ATAXIA telangiectasia ,IMMUNOGLOBULINS ,IMMUNODEFICIENCY ,DRUG therapy ,PATIENTS - Abstract
The article discusses the development of acute myeloid leukemia in patient with ataxia telangiectasia (AT). It is noted that two-thirds of patients with AT experience severe to moderate immunodeficiency while more than 50 percent show compartmental immunoglobulin deficit. The author also highlights the need for more information to determine the appropriate dosages of chemotherapy to reduce toxicities and remission rates in AT patients with myeloid leukemia.
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- 2011
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32. Letter to the Editor Dose increase of imatinib mesylate may overcome acquired resistance in bcr/abl-positive acute lymphoid leukaemia.
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Piccaluga, Pier Paolo, Malagola, Michele, Rondoni, Michela, Amabile, Marilina, Paolini, Stefania, Soverini, Simona, Gaitani, Stavroula, Visani, Giuseppe, Baccarani, Michele, and Martinelli, Giovanni
- Subjects
LYMPHOCYTIC leukemia ,LETTERS to the editor ,MYELOID leukemia ,CANCER ,THERAPEUTICS ,IMATINIB - Abstract
Presents letters to the editors related to the dose increase of imatinib mesylate may overcome acquired resistance in bcr/abl-positive acute lymphoid leukemia. Principal mechanisms by which resistance to imatinib can develop; Indication on the increase of imatinib in chronic myelogenous leukemia; Inclusion of the complete hemtologic, cytogenetic and molecular remission with standard induction therapy.
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- 2004
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33. ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol
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Luca Maurillo, Adriano Venditti, Maria Teresa Voso, Paolo de Fabritiis, Giovanni Martinelli, Marco Vignetti, Gabriella Storti, Mario Luppi, Francesco Buccisano, Francesco Lanza, Valentina Arena, Giovangiacinto Paterno, Lorella Melillo, Prassede Salutari, Roberto Cairoli, Serena Lavorgna, Paola Fazi, Anna Candoni, Tiziana Ottone, Alfonso Piciocchi, Maria Antonietta Irno Consalvo, Saveria Capria, Raffaele Palmieri, Maria Ilaria Del Principe, William Arcese, Valeria Calafiore, Buccisano, F, Palmieri, R, Piciocchi, A, Arena, V, Candoni, A, Melillo, L, Calafiore, V, Cairoli, R, de Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Luppi, M, Capria, S, Maurillo, L, Del Principe, M, Paterno, G, Consalvo, M, Ottone, T, Lavorgna, S, Voso, M, Fazi, P, Vignetti, M, Arcese, W, Venditti, A, Buccisano, Francesco, Palmieri, Raffaele, Piciocchi, Alfonso, Arena, Valentina, Candoni, Anna, Melillo, Lorella, Calafiore, Valeria, Cairoli, Roberto, de Fabritiis, Paolo, Storti, Gabriella, Salutari, Prassede, Lanza, Francesco, Martinelli, Giovanni, Luppi, Mario, Capria, Saveria, Maurillo, Luca, Del Principe, Maria Ilaria, Paterno, Giovangiacinto, Irno Consalvo, Maria Antonietta, Ottone, Tiziana, Lavorgna, Serena, Voso, Maria Teresa, Fazi, Paola, Vignetti, Marco, Arcese, William, and Venditti, Adriano
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medicine.medical_specialty ,Humans ,Neoplasm, Residual ,Prognosis ,Prospective Studies ,Risk Assessment ,Transplantation, Homologous ,autologous stem cell transplantation ,post hoc analysi ,overall survival ,Article ,remission ,male ,allogeneic stem cell transplantation ,MED/15 - MALATTIE DEL SANGUE ,Internal medicine ,medicine ,Overall survival ,Mutational status ,human ,outcome assessment ,business.industry ,cytogenetic ,adult ,flow cytometry ,Complete remission ,Myeloid leukemia ,Hematology ,prediction ,Settore MED/15 ,major clinical study ,female ,Acute myeloid leukemia, gimema aml1310, outcome prediction, risk stratification ,Risk stratification ,survival analysi ,minimal residual disease ,treatment outcome ,Population study ,Risk categorization ,business ,Outcome prediction ,intermediate risk patient ,prospective study - Abstract
The 2017 version of the European LeukemiaNet (ELN) recommendations, by integrating cytogenetics and mutational status of specific genes, divides patients with acute myeloid leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR), and adverse (ELN2017-AR). We performed a post hoc analysis of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive an autologous stem cell transplant (auto-SCT) if categorized as favorable risk or an allogeneic stem cell transplant (allo-SCT) if adverse risk. Intermediate-risk patients were to receive auto-SCT or allo-SCT based on the postconsolidation levels of measurable residual disease as measured by using flow cytometry. Risk categorization was originally conducted according to the 2009 National Comprehensive Cancer Network recommendations. Among 500 patients, 445 (89%) were reclassified according to the ELN2017 criteria: ELN2017-FR, 186 (41.8%) of 455; ELN2017-IR, 179 (40.2%) of 445; and ELN2017-AR, 80 (18%) of 455. In 55 patients (11%), ELN2017 was not applicable. Two-year overall survival (OS) was 68.8%, 51.3%, 45.8%, and 42.8% for the ELN2017-FR, ELN2017-IR, ELN2017-not classifiable, and ELN2017-AR groups, respectively (P < .001). When comparing the 2 different transplant strategies in each ELN2017 risk category, a significant benefit of auto-SCT over allo-SCT was observed among ELN2017-FR patients (2-year OS of 83.3% vs 66.7%; P = .0421). The 2 transplant procedures performed almost equally in the ELN2017-IR group (2-year OS of 73.9% vs 70.8%; P = .5552). This post hoc analysis of the GIMEMA AML1310 trial confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies. This trial was registered as EudraCT number 2010-023809-36 and at www.clinicaltrials.gov as #NCT01452646.
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- 2021
34. Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations
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Samantha Bruno, Andrea Ghelli Luserna di Rorà, Anna Maria Ferrari, Giovanni Marconi, Rossella De Tommaso, Carlo Mengucci, Maria Teresa Bochicchio, Cristina Papayannidis, Margherita Perricone, Antonella Padella, Francesco Capozzi, Claudio Delpino, Torsten Haferlach, Jacopo Nanni, Emanuela Ottaviani, Emanuela Scarpi, Martina Pazzaglia, Gastone Castellani, Eugenia Franchini, Giovanni Martinelli, Gianfranco Picone, Martina Ghetti, Annalisa Astolfi, Maria Chiara Fontana, Ilaria Iacobucci, Giorgia Simonetti, Michele Cavo, Roberta Napolitano, Viviana Guadagnuolo, Michela Tebaldi, Eugenio Fonzi, Daniel Remondini, Carmen Baldazzi, Simonetti, Giorgia, Mengucci, Carlo, Padella, Antonella, Fonzi, Eugenio, Picone, Gianfranco, Delpino, Claudio, Nanni, Jacopo, De Tommaso, Rossella, Franchini, Eugenia, Papayannidis, Cristina, Marconi, Giovanni, Pazzaglia, Martina, Perricone, Margherita, Scarpi, Emanuela, Fontana, Maria Chiara, Bruno, Samantha, Tebaldi, Michela, Ferrari, Anna, Bochicchio, Maria Teresa, Ghelli Luserna Di Rorà, Andrea, Ghetti, Martina, Napolitano, Roberta, Astolfi, Annalisa, Baldazzi, Carmen, Guadagnuolo, Viviana, Ottaviani, Emanuela, Iacobucci, Ilaria, Cavo, Michele, Castellani, Gastone, Haferlach, Torsten, Remondini, Daniel, Capozzi, Francesco, and Martinelli, Giovanni
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0301 basic medicine ,Male ,Cancer Research ,Chromosomal Proteins, Non-Histone ,Metabolic alteration ,Cell Cycle Proteins ,medicine.disease_cause ,0302 clinical medicine ,hemic and lymphatic diseases ,Cancer genomics ,Genomic subgroup ,Purine metabolism ,Aged, 80 and over ,Mutation ,Myeloid leukemia ,Nuclear Proteins ,Hematology ,Genomics ,Middle Aged ,Prognosis ,Cancer metabolism ,Chromatin ,3. Good health ,Metabolic cluster ,Leukemia, Myeloid, Acute ,Oncology ,030220 oncology & carcinogenesis ,Molecular classification ,Female ,Nucleophosmin ,Adult ,NPM1 ,congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,DNA damage ,Metabolomic ,Biology ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,Young Adult ,Metabolomics ,medicine ,Metabolome ,Humans ,Aged ,030104 developmental biology ,Cancer research ,DNA Damage - Abstract
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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- 2021
35. Therapeutic Targeting of Acute Myeloid Leukemia by Gemtuzumab Ozogamicin
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Davide Nappi, Francesco Lanza, Andrea Ghelli Luserna di Rorà, Antonella Padella, Maria Benedetta Giannini, Alessandra Sperotto, Marianna Norata, Claudio Cerchione, Giovanni Martinelli, Giorgia Simonetti, Michele Gottardi, Gerardo Musuraca, Gottardi, Michele, Simonetti, Giorgia, Sperotto, Alessandra, Nappi, Davide, Ghelli Luserna di Rorà, Andrea, Padella, Antonella, Norata, Marianna, Giannini, Maria Benedetta, Musuraca, Gerardo, Lanza, Francesco, Cerchione, Claudio, and Martinelli, Giovanni
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Oncology ,Cancer Research ,medicine.medical_specialty ,Gemtuzumab ozogamicin ,Daunorubicin ,CD33 ,Review ,acute myeloid leukemia ,Therapeutic targeting ,Internal medicine ,hemic and lymphatic diseases ,Medicine ,gemtuzumab ozogamicin ,RC254-282 ,business.industry ,Myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,biomarkers ,Minimal residual disease ,Multiple drug resistance ,Cytarabine ,biomarker ,business ,medicine.drug - Abstract
Simple Summary Gemtuzumab Ozogamicin (GO) is a drug approved for the treatment of acute myeloid leukemia (AML). It targets leukemic cells that express the CD33 molecule on their surface and brings the toxic agent calicheamicin inside the cell to kill it. Several studies have shown that AML patients can benefit of the addition of GO to chemotherapy during induction regimens, pre- and post-transplantation. Moreover, some disease features have been addressed or are under investigation for their capacity to predict response to GO, with the future aim of selecting AML patients that can mostly benefit of GO treatment. Abstract Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.
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- 2021
36. Treatment of Chronic Myelogenous Leukemia by Blocking Cytokine Alterations Found in Normal Stem and Progenitor Cells.
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Welner, Robert S., Amabile, Giovanni, Bararia, Deepak, Czibere, Akos, Yang, Henry, Zhang, Hong, Pontes, Lorena Lobo De Figueiredo, Ye, Min, Levantini, Elena, Di Ruscio, Annalisa, Martinelli, Giovanni, and Tenen, Daniel G.
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CYTOKINES , *PROGENITOR cells , *LEUKEMIA treatment , *MYELOID leukemia , *HEMATOPOIETIC stem cells , *INTERLEUKIN-6 - Abstract
Summary Leukemic cells disrupt normal patterns of blood cell formation, but little is understood about the mechanism. We investigated whether leukemic cells alter functions of normal hematopoietic stem and progenitor cells. Exposure to chronic myelogenous leukemia (CML) caused normal mouse hematopoietic progenitor cells to divide more readily, altered their differentiation, and reduced their reconstitution and self-renewal potential. Interestingly, the normal bystander cells acquired gene expression patterns resembling their malignant counterparts. Therefore, much of the leukemia signature is mediated by extrinsic factors. Indeed, IL-6 was responsible for most of these changes. Compatible results were obtained when human CML were cultured with normal human hematopoietic progenitor cells. Furthermore, neutralization of IL-6 prevented these changes and treated the disease. [ABSTRACT FROM AUTHOR]
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- 2015
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37. The hidden genomic landscape of acute myeloid leukemia: subclonal structure revealed by undetected mutations.
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Bodini, Margherita, Ronchini, Chiara, Giacò, Luciano, Russo, Anna, Melloni, Giorgio E. M., Lucilla Luzi, Sardella, Domenico, Volorio, Sara, Hasan, Syed K., Ottone, Tiziana, Lavorgna, Serena, Lo-Coco, Francesco, Candoni, Anna, Fanin, Renato, Toffoletti, Eleonora, lacobucci, Maria, Martinelli, Giovanni, Cignetti, Alessandro, Tarella, Corrado, and Bernard, Loris
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BIOINFORMATICS , *MYELOID leukemia , *BONE marrow diseases , *GENETIC polymorphisms , *SINGLE nucleotide polymorphisms - Abstract
The analyses carried out using two different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 Acute Myeloid Leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these two variant-calling pipelines on 20 leukemia samples from our series (19 primary AMLs and one secondary AML). By validating many of the predicted somatic variants (variant allele frequencies ranging from 100% to 5%), we observed significantly different calling efficiencies. In particular, despite relatively high specificity, sensitivity was poor in both pipelines resulting in a high rate of false negatives. Our findings raise the possibility that landscapes of AML genomes might be more complex than previously reported and characterized by the presence of hundreds of genes mutated at low variant allele frequency, suggesting that the application of genome sequencing to the clinic requires a careful and critical evaluation. We think that improvements in technology and workflow standardization, through the generation of clear experimental and bioinformatics guidelines, are fundamental to translate the use of Next generation sequencing from research to the clinic and to transform genomic information into better diagnosis and outcomes for the patient. [ABSTRACT FROM AUTHOR]
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- 2015
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38. Ponatinib treatment in chronic myeloid leukemia cell lines targets aurora kinase A/FOXM1 axis
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Gabriele Gugliotta, Gianantonio Rosti, Sara De Santis, Manuela Mancini, Fausto Castagnetti, Simona Soverini, Giovanni Martinelli, Cecilia Monaldi, Michele Cavo, Maria Alessandra Santucci, Luana Bavaro, Margherita Martelli, Mancini, Manuela, De Santis, Sara, Monaldi, Cecilia, Bavaro, Luana, Martelli, Margherita, Gugliotta, Gabriele, Castagnetti, Fausto, Rosti, Gianantonio, Santucci, Maria Alessandra, Martinelli, Giovanni, Cavo, Michele, and Soverini, Simona
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Cancer Research ,Apoptosis ,chemistry.chemical_compound ,Aurora kinase ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Tumor Cells, Cultured ,Medicine ,Humans ,Protein Kinase Inhibitors ,Aurora Kinase A ,Cell Proliferation ,business.industry ,Ponatinib ,Forkhead Box Protein M1 ,Imidazoles ,Myeloid leukemia ,Hematology ,General Medicine ,Gene Expression Regulation, Neoplastic ,Pyridazines ,Oncology ,chemistry ,Ponatinib,chronic myeloid leukemia, cell lines targets, aurora kinase ,Cell culture ,Drug Resistance, Neoplasm ,Cancer research ,FOXM1 ,business - Abstract
No abstract available
- Published
- 2020
39. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: The NEXT-in-CML study
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Anna Serra, Antonio Percesepe, Gabriele Gugliotta, Caterina Musolino, Gianni Binotto, Elisabetta Abruzzese, Immacolata Attolico, Gianantonio Rosti, Mario Annunziata, Rosaria Sancetta, Mariella Girasoli, Fabrizio Pane, Maria Antonella Laginestra, Sara Galimberti, Alessandra Iurlo, Stefania Stella, Sabrina Coluzzi, Simona Sica, Monica Bocchia, Marzia Salvucci, Francesca Lunghi, Fabio Stagno, Nicola Orofino, Stefano Pileri, Federica Sorà, Santa Errichiello, Elisabetta Calistri, Paolo Vigneri, Fausto Castagnetti, Michele Baccarani, Luana Bavaro, Michele Cavo, Eros Di Bona, Francesco Di Raimondo, Claudia Baratè, Margherita Martelli, Simona Soverini, Antonella Russo Rossi, Francesco Albano, Mariella D'Adda, Fabio Ciceri, Flavio Mignone, Elena Tenti, Caterina De Benedittis, Giuseppe Saglio, Isabella Capodanno, Giovanni Martinelli, Massimiliano Bonifacio, Luigi Scaffidi, Soverini, S., Bavaro, L., de Benedittis, C., Martelli, M., Iurlo, A., Orofino, N., Sica, S., Sora, F., Lunghi, F., Ciceri, F., Galimberti, S., Barate, C., Bonifacio, M., Scaffidi, L., Castagnetti, F., Gugliotta, G., Albano, F., Rossi, A. V. R., Stagno, F., di Raimondo, F., D'Adda, M., di Bona, E., Abruzzese, E., Binotto, G., Sancetta, R., Salvucci, M., Capodanno, I., Girasoli, M., Coluzzi, S., Attolico, I., Musolino, C., Calistri, E., Annunziata, M., Bocchia, M., Stella, S., Serra, A., Errichiello, S., Saglio, G., Pane, F., Vigneri, P., Mignone, F., Laginestra, M. A., Pileri, S. A., Percesepe, A., Tenti, E., Rosti, G., Baccarani, M., Cavo, M., Martinelli, G., Soverini, Simona, Bavaro, Luana, De Benedittis, Caterina, Martelli, Margherita, Iurlo, Alessandra, Orofino, Nicola, Sica, Simona, Sora, Federica, Lunghi, Francesca, Ciceri, Fabio, Galimberti, Sara, Baratè, Claudia, Bonifacio, Massimiliano, Scaffidi, Luigi, Castagnetti, Fausto, Gugliotta, Gabriele, Albano, Francesco, Russo Rossi, Antonella Vita, Stagno, Fabio, Di Raimondo, Francesco, D'Adda, Mariella, Di Bona, Ero, Abruzzese, Elisabetta, Binotto, Gianni, Sancetta, Rosaria, Salvucci, Marzia, Capodanno, Isabella, Girasoli, Mariella, Coluzzi, Sabrina, Attolico, Immacolata, Musolino, Caterina, Calistri, Elisabetta, Annunziata, Mario, Bocchia, Monica, Stella, Stefania, Serra, Anna, Errichiello, Santa, Saglio, Giuseppe, Pane, Fabrizio, Vigneri, Paolo G, Mignone, Flavio, Laginestra, Maria Antonella, Pileri, Stefano A, Percesepe, Antonio, Tenti, Elena, Rosti, Gianantonio, Baccarani, Michele, Cavo, Michele, and Martinelli, Giovanni
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Oncology ,Male ,Mutation rate ,bcr-abl ,Drug Resistance ,Fusion Proteins, bcr-abl ,Gene mutation ,medicine.disease_cause ,Settore MED/01 - STATISTICA MEDICA ,Biochemistry ,Adult ,Aged ,Aged, 80 and over ,Drug Resistance, Neoplasm ,Female ,High-Throughput Nucleotide Sequencing ,Humans ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Middle Aged ,Mutation ,Mutation Rate ,Prospective Studies ,Protein Kinase Inhibitors ,hemic and lymphatic diseases ,80 and over ,cml mutation ,BCR-ABL mutations ,Chronic ,Prospective cohort study ,Sanger sequencing ,Leukemia ,Chronic myeloid leukemia ,Myeloid leukemia ,Hematology ,TKI ,NGS ,symbols ,Human ,medicine.medical_specialty ,Immunology ,symbols.namesake ,CML, TKIs, BCR-ABL1 ,Chronic myeloid leukemia,TKI,BCR-ABL mutations,Sanger Sequencing,NGS ,Internal medicine ,medicine ,business.industry ,Fusion Proteins ,Cell Biology ,medicine.disease ,Clinical trial ,Prospective Studie ,Sanger Sequencing ,Neoplasm ,BCR-ABL Positive ,business ,Myelogenous - Abstract
In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.
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- 2020
40. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy
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Manuela Mancini, Michele Cavo, Giovanni Martinelli, Simona Soverini, Luana Bavaro, Soverini, Simona, Mancini, Manuela, Bavaro, Luana, Cavo, Michele, and Martinelli, Giovanni
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,Population ,Resistance ,Tyrosine kinase inhibitor ,Protein Kinase Inhibitor ,Drug resistance ,Review ,Biology ,lcsh:RC254-282 ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,education ,Protein Kinase Inhibitors ,Tyrosine kinase ,Tyrosine kinase inhibitors ,education.field_of_study ,Animal ,Myeloid leukemia ,Cancer ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,BCR-ABL1 ,030104 developmental biology ,Imatinib mesylate ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Imatinib Mesylate ,Molecular Medicine ,Magic bullet ,Human ,Signal Transduction - Abstract
Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed. Electronic supplementary material The online version of this article (10.1186/s12943-018-0780-6) contains supplementary material, which is available to authorized users.
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- 2018
41. Chibby 1: a new component of β-catenin-signaling in chronic myeloid leukemia
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Maria Alessandra Santucci, Simona Soverini, Manuela Mancini, Michele Cavo, Gabriele Gugliotta, Giovanni Martinelli, Gianantonio Rosti, Fausto Castagnetti, Mancini, Manuela, Soverini, Simona, Gugliotta, Gabriele, Santucci, MARIA ALESSANDRA, Rosti, Gianantonio, Cavo, Michele, Martinelli, Giovanni, and Castagnetti, Fausto
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0301 basic medicine ,autophagy ,SUMO protein ,Review ,ß-catenin ,Biology ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Epigenetics ,β-catenin ,chibby1 ,Nuclear export signal ,Genetics ,Chronic myeloid leukemia ,breakpoint cluster region ,Myeloid leukemia ,BCR-ABL1 ,Fusion protein ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Unfolded protein response ,ER stre ,ER stress ,Tyrosine kinase - Abstract
// Manuela Mancini 1 , Simona Soverini 1 , Gabriele Gugliotta 1 , Maria Alessandra Santucci 1 , Gianantonio Rosti 1 , Michele Cavo 1 , Giovanni Martinelli 1 and Fausto Castagnetti 1 1 Department of Experimental Diagnostic and Specialty Medicine, DIMES–Institute of Hematology “L. and A. Seragnoli”, University of Bologna Medical School, Bologna, Italy Correspondence to: Manuela Mancini, email: mancini_manu@yahoo.com Keywords: chibby1, s-catenin, ER stress, autophagy, BCR-ABL1 Received: March 31, 2017 Accepted: August 04, 2017 Published: September 22, 2017 ABSTRACT Chibby 1 (CBY1) is a small and evolutionarily conserved protein, which act as β-catenin antagonist. CBY1 is encoded by C22orf2 (22q13.1) Its antagonistic function on β-catenin involves the direct interaction with: The C-terminal activation domain of β-catenin, which hinders β-catenin binding with Tcf/Lef transcription factors hence repressing β-catenin transcriptional activation. 14-3-3 scaffolding proteins (σ or ξ), which drive CBY1 nuclear export into a stable tripartite complex with β-catenin. The relative proximity of C22orf2 gene encoding for CBY1 to the BCR breakpoint on chromosome 22q11, whose translocation and rearrangement with the c-ABL is the causative event of chronic myeloid leukemia (CML), suggested that gene haploinsufficiency may play a role in the disease pathogenesis and progression. We found CBY1 down-modulation associated with the BCR-ABL1 , promoted by transcriptional mechanisms (promoter hyper-methylation) and post-transcriptional events, addressing the protein towards proteasome-dependent degradation through SUMOylation. CBY1 reduced expression in clonal progenitors and, more importantly, in leukemic stem cells (LSC), is contingent upon the tyrosine kinase (TK) activity of BCR-ABL1 fusion protein. Accordingly, its induction by Imatinib (IM) and second generation TK inhibitors contributes to β-catenin inactivation through multiple events encompassing the activation of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) and autophagy, eventually leading to apoptotic death. These findings support the advantage of combined regimens including drugs targeting DNA epigenetics and/or proteasome to eradicate the BCR-ABL1+ hematopoiesis.
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- 2017
42. Genome integrity of myeloproliferative neoplasms in chronic phase and during disease progression.
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Klampfl, Thorsten, Harutyunyan, Ashot, Berg, Tiina, Gisslinger, Bettina, Schalling, Martin, Bagienski, Klaudia, Olcaydu, Damla, Passamonti, Francesco, Rumi, Elisa, Pietra, Daniela, Jager, Roland, Pieri, Lisa, Guglielmelli, Paola, lacobucci, lana, Martinelli, Giovanni, Cazzola, Mario, Vannucchi, Alessandro M., Gisslinger, Heinz, and Kralovics, Robert
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MYELOPROLIFERATIVE neoplasms , *TUMORS , *GENOMES , *CHROMOSOMES , *DISEASE progression , *MYELOID leukemia - Abstract
Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are clonal myelold disorders with Increased production of terminally differentiated cells. The disease course is generaiiy chronic, but some patients show disease progression (secondary myeiofibrosis or accelerated phase) and/or leukemic transformation. We investigated chromosomal aberrations in 408 MPN samples using high-resolution single-nucleotide polymorphism microarrays to identify diseaseassociated somatic lessions. Of 408 samples, 37.5% had a wild-type karyotype and 62.5% harbored at least 1 chromosomal aberration. We Identified 25 recurrent aberrations that were found in 3 or more samples. An Increased number of chromosomal lessions was significantly associated with patient age, as well as with disease progression and leukemic transformation, but no association was observed with MPN subtypes, Janus klnase 2 (JAK2) mutational status, or disease duration. Aberrations of chromosomes 1 q and 9p were positively associated with disease progression to secondary myelofibrosis or accelerated phase. Changes of chromosomes 1 q, 7q, 5q, 6p, 7p, 19q, 22q, and 3q were positively associated with postMPN acute myeloid leukemia. We mapped commonly affected regions to single target genes on chromosomes 3p (forkhead box P1 (FOXP1]), 4q (tet oncogene family member 2 [TET2]), 7p (IKAROS family zinc finger 1 [IKZFI]), 7q (cut-like homeobox 1 [CUX1]), 12p (ets variant 6 [ETV6]), and 21q (runtrelated transcription factor 1 [RUNXI]). Our data provide insight into the genetic complexity of MPNs and Implicate new genes Involved in disease progression. [ABSTRACT FROM AUTHOR]
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- 2011
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43. Novel FLT3 point mutation in acute myeloid leukaemia
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Piccaluga, Pier Paolo, Bianchini, Michele, and Martinelli, Giovanni
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COMPARATIVE studies , *HIGH performance liquid chromatography , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *PROTEINS , *RESEARCH , *TRANSFERASES , *EVALUATION research , *MYELOID leukemia , *ACUTE diseases - Published
- 2003
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44. Chk2 drives late G1/early S phase arrest of clonal myeloid progenitors expressing the p210 BCR-ABL tyrosine kinase in response to STI571.
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Mazzacurati, Lucia, Pattacini, Laura, Brusa, Gianluca, Mancini, Manuela, Benvenuti, Michela, Barbieri, Enza, Martinelli, Giovanni, Baccarani, Michele, Greenberger, Joel S., and Santucci, Maria Alessandra
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MYELOID leukemia , *PROTEIN-tyrosine kinases , *TYROSINE , *MYELOID metaplasia , *MOUSE leukemia , *GENETIC mutation - Abstract
STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G1/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.The Hematology Journal (2004) 5, 168-177. doi:10.1038/sj.thj.6200365 [ABSTRACT FROM AUTHOR]
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- 2004
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45. Endoplasmic reticulum stress initiates apoptotic death induced by STI571 inhibition of p210 bcr–abl tyrosine kinase
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Pattacini, Laura, Mancini, Manuela, Mazzacurati, Lucia, Brusa, Gianluca, Benvenuti, Michela, Martinelli, Giovanni, Baccarani, Michele, and Santucci, Maria Alessandra
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ENDOPLASMIC reticulum , *PROTEINS , *APOPTOSIS , *MYELOID leukemia - Abstract
The endoplasmic reticulum (ER) is the site where proteins destined to either secretion or different subcellular compartments assemble and the major storage of intracellular Ca2+. The ER stress resulting from a variety of toxic insults leads to apoptosis. Here, we showed that the apoptotic death triggered by STI571, an inhibitor of the p210 bcr–abl tyrosine kinase, in murine myeloid progenitors transducing the p210 bcr–abl tyrosine kinase of Chronic Myeloid Leukemia (CML) proceeds from ER stress. The Bcl-2 dowmodulation and inactivation induced by the binding to its antagonist: Bad, the release of caspase 12 from the ER membranes in its active form and of Ca2+ from the ER pool addressed towards ER a sensor of STI571-induced pro-apoptotic signal. [Copyright &y& Elsevier]
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- 2004
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46. Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery
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Elisa Ficarra, Ilaria Iacobucci, Carmen Baldazzi, Giorgia Simonetti, Elisa Zuffa, Emanuela Ottaviani, Jesús M. Hernández, Antonella Padella, Stefania Paolini, Eugenia Franchini, Federica Zanotti, Giovanni Martinelli, Peter Vandenberghe, Anna Maria Ferrari, Samantha Bruno, Marco Sazzini, Torsten Haferlach, Nicoletta Testoni, Gastone Castellani, Marco Manfrini, Annalisa Astolfi, Simona Bernardi, Italo Faria do Valle, Maria Antonella Laginestra, Jan Cools, Maria Chiara Fontana, Cristina Papayannidis, Giovanni Marconi, Eugenio Fonzi, Daniel Remondini, Michele Cavo, Viviana Guadagnuolo, Lars Bullinger, Simonetti, Giorgia, Padella, Antonella, do Valle, Italo Farìa, Fontana, Maria Chiara, Fonzi, Eugenio, Bruno, Samantha, Baldazzi, Carmen, Guadagnuolo, Viviana, Manfrini, Marco, Ferrari, Anna, Paolini, Stefania, Papayannidis, Cristina, Marconi, Giovanni, Franchini, Eugenia, Zuffa, Elisa, Laginestra, Maria Antonella, Zanotti, Federica, Astolfi, Annalisa, Iacobucci, Ilaria, Bernardi, Simona, Sazzini, Marco, Ficarra, Elisa, Hernandez, Jesus Maria, Vandenberghe, Peter, Cools, Jan, Bullinger, Lar, Ottaviani, Emanuela, Testoni, Nicoletta, Cavo, Michele, Haferlach, Torsten, Castellani, Gastone, Remondini, Daniel, and Martinelli, Giovanni
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Male ,Cancer Research ,Hematologic Malignancies ,Gene Dosage ,Aneuploidy ,medicine.disease_cause ,whole exome sequencing ,genomic ,acute myeloid leukemia, aneuploidy, cell cycle, genomics, mutation, ubiquitination, whole exome sequencing ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene Regulatory Networks ,030212 general & internal medicine ,Aged, 80 and over ,Mutation ,Gene Expression Regulation, Leukemic ,Myeloid leukemia ,bioinformatics ,Middle Aged ,Cell cycle ,3. Good health ,Leukemia, Myeloid, Acute ,Oncology ,030220 oncology & carcinogenesis ,Female ,Original Article ,cell cycle ,Erratum ,Adult ,acute myeloid leukemia ,aneuploidy ,genomics ,mutation ,ubiquitination ,Cancer Research, bioinformatics ,DNA repair ,Protein degradation ,NO ,Young Adult ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Aged ,business.industry ,Gene Expression Profiling ,Original Articles ,medicine.disease ,Protein ubiquitination ,Chromosome Banding ,Rad50 ,Proteolysis ,Cancer research ,Disease Site ,business - Abstract
Background Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. Methods To understand the molecular bases of aneuploid acute myeloid leukemia (A‐AML), this study examined the genomic profile in 42 A‐AML cases and 35 euploid acute myeloid leukemia (E‐AML) cases. Results A‐AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E‐AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A‐AML, which was associated with a 3‐gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A‐AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E‐AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. Conclusions These findings indicate that aneuploidy‐related and leukemia‐specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets., Aneuploid acute myeloid leukemia (A‐AML) is associated with genomic and transcriptional alterations in the cell cycle and protein degradation pathways. The upregulation of PLK1 and CDC20 and the downregulation of RAD50 and of a p53‐related signature are hallmarks of A‐AML.
- Published
- 2019
47. The human Smoothened inhibitor PF-04449913 induces exit from quiescence and loss of multipotentDrosophilahematopoietic progenitor cells
- Author
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Marilena Barraco, Giorgia Simonetti, Angela Giangrande, Giorgia Giordani, Viviana Guadagnuolo, Roberto Bernardoni, Giovanni Perini, Giovanni Martinelli, University of Bologna, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), University of Huddersfield, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Giordani, Giorgia, Barraco, Marilena, Giangrande, Angela, Martinelli, Giovanni, Guadagnuolo, Viviana, Simonetti, Giorgia, Perini, Giovanni, Bernardoni, Roberto, University of Bologna/Università di Bologna, and Cattenoz, Pierre
- Subjects
Smoothened inhibitor ,0301 basic medicine ,medicine.medical_specialty ,Prohemocyte ,[SDV]Life Sciences [q-bio] ,Cellular differentiation ,Biology ,03 medical and health sciences ,prohemocytes ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Homeostasis ,Humans ,Hematology ,Multipotent Stem Cells ,Phenylurea Compounds ,leukemia ,Myeloid leukemia ,Cell Differentiation ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Smoothened Receptor ,PF-04449913 ,Hedgehog signaling pathway ,3. Good health ,[SDV] Life Sciences [q-bio] ,Leukemia ,Haematopoiesis ,Drosophila melanogaster ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Benzimidazoles ,Drosophila ,Bone marrow ,Smoothened ,Research Paper - Abstract
// Giorgia Giordani 1, 5, * , Marilena Barraco 1, 6, * , Angela Giangrande 2 , Giovanni Martinelli 3 , Viviana Guadagnuolo 3 , Giorgia Simonetti 3 , Giovanni Perini 1, 4 , Roberto Bernardoni 1, 4 1 Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy 2 Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP 67404 Illkirch, France 3 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Hematology "L. e A. Seragnoli", University of Bologna, Bologna, Italy 4 Health Sciences and Technology - Interdepartmental Center for Industrial Research (HST-ICIR), University of Bologna, Ozzano Emilia, Italy 5 Present address: Department of Biological Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, UK 6 Present address: Institute of Hematology, “L e A Seragnoli”, S. Orsola-Malpighi Hospital, Bologna, Italy * These authors contributed equally to this work Correspondence to: Roberto Bernardoni, email: roberto.bernardoni@unibo.it Giovanni Perini, email: giovanni.perini@unibo.it Keywords: PF-04449913, Smoothened inhibitor, leukemia, Drosophila, prohemocytes Received: December 09, 2015 Accepted: June 26, 2016 Published: July 28, 2016 ABSTRACT The efficient treatment of hematological malignancies as Acute Myeloid Leukemia, myelofibrosis and Chronic Myeloid Leukemia, requires the elimination of cancer-initiating cells and the prevention of disease relapse through targeting pathways that stimulate generation and maintenance of these cells. In mammals, inhibition of Smoothened, the key mediator of the Hedgehog signaling pathway, reduces Chronic Myeloid Leukemia progression and propagation. These findings make Smo a candidate target to inhibit maintenance of leukemia-initiating cells. In Drosophila melanogaster the same pathway maintains the hematopoietic precursor cells of the lymph gland, the hematopoietic organ that develops in the larva. Using Drosophila as an in vivo model, we investigated the mode of action of PF-04449913, a small-molecule inhibitor of the human Smo protein. Drosophila larvae fed with PF-04449913 showed traits of altered hematopoietic homeostasis. These include the development of melanotic nodules, increase of circulating hemocytes, the size increase of the lymph gland and accelerated differentiation of blood cells likely due to the exit of multi-potent precursors from quiescence. Importantly, the Smo inhibition can lead to the complete loss of hematopoietic precursors. We conclude that PF-04449913 inhibits Drosophila Smo blocking the Hh signaling pathway and causing the loss of hematopoietic precursor cells. Interestingly, this is the effect expected in patients treated with PF-04449913: number decrease of cancer initiating cells in the bone marrow to reduce the risk of leukemia relapse. Altogether our results indicate that Drosophila comprises a model system for the in vivo study of molecules that target evolutionary conserved pathways implicated in human hematological malignancies.
- Published
- 2016
48. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients
- Author
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Katerina Machova Polakova, Fausto Castagnetti, Marzia Salvucci, Simona Soverini, Giovanni Martinelli, Domenico Russo, Gabriele Gugliotta, Michele Cavo, Hana Klamova, Michele Baccarani, Cristina Papayannidis, Gianantonio Rosti, Francesco Albano, Alessandra Iurlo, Monica Crugnola, Manuela Mancini, Jana Linhartova, Caterina De Benedittis, Soverini, Simona, De Benedittis, Caterina, Polakova, Katerina Machova, Linhartova, Jana, Castagnetti, Fausto, Gugliotta, Gabriele, Papayannidis, Cristina, Mancini, Manuela, Klamova, Hana, Salvucci, Marzia, Crugnola, Monica, Iurlo, Alessandra, Albano, Francesco, Russo, Domenico, Rosti, Gianantonio, Cavo, Michele, Baccarani, Michele, and Martinelli, Giovanni
- Subjects
0301 basic medicine ,Oncology ,Male ,Pathology ,DNA Mutational Analysis ,Dasatinib ,Fusion Proteins, bcr-abl ,Tyrosine kinase inhibitor ,medicine.disease_cause ,Tyrosine-kinase inhibitor ,0302 clinical medicine ,hemic and lymphatic diseases ,tyrosine kinase inhibitors ,Sanger sequencing ,Mutation ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,Acute lymphoblastic leukemia ,BCR-ABL1 ,Chronic myeloid leukemia ,Next generation sequencing ,Tyrosine kinase inhibitors ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,030220 oncology & carcinogenesis ,symbols ,Imatinib Mesylate ,Female ,medicine.drug ,Research Paper ,Adult ,medicine.medical_specialty ,medicine.drug_class ,acute lymphoblastic leukemia ,DNA sequencing ,03 medical and health sciences ,symbols.namesake ,chronic myeloid leukemia ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,business.industry ,Imatinib ,030104 developmental biology ,Imatinib mesylate ,Drug Resistance, Neoplasm ,Next-generation sequencing ,business - Abstract
In chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) patients who fail imatinib treatment, BCR-ABL1 mutation profiling by Sanger sequencing (SS) is recommended before changing therapy since detection of specific mutations influences second-generation tyrosine kinase inhibitor (2GTKI) choice. We aimed to assess i) in how many patients who relapse on second-line 2GTKI therapy next generation sequencing (NGS) may track resistant mutations back to the sample collected at the time of imatinib resistance, before 2GTKI start (switchover sample) and ii) whether low level mutations identified by NGS always undergo clonal expansion. To this purpose, we used NGS to retrospectively analyze 60 imatinib-resistant patients (CML, n = 45; Ph+ ALL, n = 15) who had failed second-line 2GTKI therapy and had acquired BCR-ABL1 mutations (Group 1) and 25 imatinib-resistant patients (CML, n = 21; Ph+ ALL, n = 4) who had responded to second-line 2GTKI therapy, for comparison (Group 2). NGS uncovered that in 26 (43%) patients in Group 1, the 2GTKI-resistant mutations that triggered relapse were already detectable at low levels in the switchover sample (median mutation burden, 5%; range 1.1%–18.4%). Importantly, none of the low level mutations detected by NGS in switchover samples failed to expand whenever the patient received the 2GTKI to whom they were insensitive. In contrast, no low level mutation that was resistant to the 2GTKI the patients subsequently received was detected in the switchover samples from Group 2. NGS at the time of imatinib failure reliably identifies clinically relevant mutations, thus enabling a more effective therapeutic tailoring.
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- 2016
49. Chromothripsis in acute myeloid leukemia: Biological features and impact on survival
- Author
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Michele Cavo, Zdenek Racil, Viviana Guadagnuolo, Antonella Padella, Maria Chiara Fontana, Michael Steurer, Michael Doubek, Emanuela Ottaviani, Nicoletta Testoni, Giovanni Marconi, Marco Manfrini, Torsten Haferlach, Carmen Baldazzi, Stefania Paolini, Simona Soverini, Andrea Ghelli Luserna di Rorà, Vincenza Solli, Robert Kralovics, Anna Maria Ferrari, Eugenio Fonzi, Cristina Papayannidis, Eugenia Franchini, Giovanni Martinelli, Lukáš Semerád, Ilaria Iacobucci, Jelena D. Milosevic Feenstra, Giorgia Simonetti, Fontana, Maria Chiara, Marconi, Giovanni, Feenstra, Jelena D. Milosevic, Fonzi, Eugenio, Papayannidis, Cristina, Ghelli Luserna Di Rorá, Andrea, Padella, Antonella, Solli, Vincenza, Franchini, Eugenia, Ottaviani, Emanuela, Ferrari, Anna, Baldazzi, Carmen, Testoni, Nicoletta, Iacobucci, Ilaria, Soverini, Simona, Haferlach, Torsten, Guadagnuolo, Viviana, Semerad, Luka, Doubek, Michael, Steurer, Michael, Racil, Zdenek, Paolini, Stefania, Manfrini, Marco, Cavo, Michele, Simonetti, Giorgia, Kralovics, Robert, and Martinelli, Giovanni
- Subjects
0301 basic medicine ,Genome instability ,Oncology ,Adult ,Male ,medicine.medical_specialty ,NPM1 ,Cancer Research ,Adolescent ,Ring chromosome ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Young Adult ,Internal medicine ,Chromosome instability ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Humans ,Genetic Predisposition to Disease ,Ring Chromosomes ,In Situ Hybridization, Fluorescence ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Chromothripsis ,Hematology ,business.industry ,Myeloid leukemia ,Adult Acute Myeloid Leukemia ,Middle Aged ,Prognosis ,3. Good health ,Chromosome Banding ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Treatment Outcome ,Anesthesiology and Pain Medicine ,Mutation ,Female ,business ,Nucleophosmin - Abstract
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix??) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p???=???0.002), ELN high risk (HR) (p?????0.001), lower white blood cell (WBC) count (p???=???0.040), TP53 loss, and/or mutations (p?????0.001) while FLT3 (p???=???0.025), and NPM1 (p???=???0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p?????0.001) compared with HR patients (p???=???0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.
- Published
- 2017
50. Inverse regulation of bridging integrator 1 and BCR-ABL1 in chronic myeloid leukemia
- Author
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Maria Teresa Bochicchio, Luciana De Luca, Gabriella Bianchino, Giovanni Martinelli, Vittorio Simeon, Annalisa Morano, Elisabetta Signorino, Gianantonio Rosti, Giuseppe Pietrantuono, Pellegrino Musto, Luigi Del Vecchio, Claudia Venturi, Francesco La Rocca, Vitina Grieco, Ilaria Laurenzana, Stefania Trino, Alberto Fragasso, Antonella Caivano, Daniela Cilloni, Trino, Stefania, De Luca, Luciana, Simeon, Vittorio, Laurenzana, Ilaria, Morano, Annalisa, Caivano, Antonella, La Rocca, Francesco, Pietrantuono, Giuseppe, Bianchino, Gabriella, Grieco, Vitina, Signorino, Elisabetta, Fragasso, Alberto, Bochicchio, Maria Teresa, Venturi, Claudia, Rosti, Gianantonio, Martinelli, Giovanni, Del Vecchio, Luigi, Cilloni, Daniela, and Musto, Pellegrino
- Subjects
0301 basic medicine ,Cytoplasm ,Cancer Research ,Bridging integrator 1 ,Fusion Proteins, bcr-abl ,Bone Marrow Cells ,Real-Time Polymerase Chain Reaction ,Endocytosis ,Receptor tyrosine kinase ,03 medical and health sciences ,Downregulation and upregulation ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Humans ,AXL ,BCR-ABL1 ,Chronic myeloid leukemia ,Rab interactor 1 ,Adaptor Proteins, Signal Transducing ,biology ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,Receptor Protein-Tyrosine Kinases ,Myeloid leukemia ,Imatinib ,General Medicine ,Axl Receptor Tyrosine Kinase ,Up-Regulation ,Cell biology ,Gene Expression Regulation, Neoplastic ,HEK293 Cells ,030104 developmental biology ,Drug Resistance, Neoplasm ,Leukocytes, Mononuclear ,biology.protein ,Cancer research ,Rab ,K562 Cells ,Tyrosine kinase ,Signal Transduction ,medicine.drug ,K562 cells - Abstract
Endocytosis is the major regulator process of tyrosine kinase receptor (RTK) functional activities. Bridging integrator 1 (BIN1) is a key protein involved in RTK intracellular trafficking. Here, we report, by studying 34 patients with chronic myeloid leukemia (CML) at diagnosis, that BIN1 gene is downregulated in CML as compared to healthy controls, suggesting an altered endocytosis of RTKs. Rab interactor 1 (RIN1), an activator of BIN1, displayed a similar behavior. Treatment of 57 patients by tyrosine kinase inhibitors caused, along with BCR-ABL1 inactivation, an increase of BIN1 and RIN1 expression, potentially restoring endocytosis. There was a significant inverse correlation between BIN1-RIN1 and BCR-ABL1 expression. In vitro experiments on both CML and nontumorigenic cell lines treated with Imatinib confirmed these results. In order to provide another proof in favor of BIN1 and RIN1 endocytosis function in CML, we demonstrated that Imatinib induced, in K562 cell line, BIN1-RIN1 upregulation accompanied by a parallel AXL receptor internalization into cytoplasmic compartment. This study shows a novel deregulated mechanism in CML patients, indicating BIN1 and RIN1 as players in the maintenance of the abnormal RTK signaling in this hematological disease.
- Published
- 2015
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