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1. Morgana acts as an oncosuppressor in chronic myeloid leukemia.

Author

Di Savino A, Panuzzo C, Rocca S, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A, and Brancaccio M

Subjects
Animals, Apoptosis, Blotting, Western, Bone Marrow metabolism, Bone Marrow pathology, Cell Proliferation, Flow Cytometry, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, Immunoenzyme Techniques, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Chaperones, Protein Kinase Inhibitors pharmacology, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, rho-Associated Kinases genetics, rho-Associated Kinases metabolism, Benzamides pharmacology, Carrier Proteins physiology, Drug Resistance, Neoplasm genetics, Fusion Proteins, bcr-abl metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Philadelphia Chromosome, Piperazines pharmacology, Pyrimidines pharmacology, rho-Associated Kinases antagonists & inhibitors
Abstract

We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed., (© 2015 by The American Society of Hematology.)

Published
2015
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2. 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.

Author

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, and Rosti G

Subjects
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Benzamides, Cytogenetic Analysis, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Imatinib Mesylate, In Situ Hybridization, Fluorescence, Italy, Kaplan-Meier Estimate, Leukemia, Myeloid, Chronic-Phase mortality, Logistic Models, Male, Maximum Tolerated Dose, Middle Aged, Multivariate Analysis, Piperazines adverse effects, Probability, Prognosis, Prospective Studies, Pyrimidines adverse effects, Reference Values, Reverse Transcriptase Polymerase Chain Reaction, Risk Assessment, Severity of Illness Index, Statistics, Nonparametric, Survival Analysis, Treatment Outcome, Young Adult, Chromosomes, Human, Pair 9 genetics, Gene Deletion, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase genetics, Piperazines administration & dosage, Pyrimidines administration & dosage
Abstract

Purpose: Deletions of the derivative chromosome 9 [der(9)] have been associated with a poor prognosis in chronic myeloid leukemia (CML) across different treatment modalities. In the imatinib era, the prognostic impact of der(9) deletions has been evaluated mainly in patients with late chronic-phase (CP) CML, giving partially conflicting results. Few data are available in the early CP setting. For this reason, in 2006, the European LeukemiaNet recommendations still considered der(9) deletions as a candidate adverse prognostic factor and required a careful monitoring of the patient., Patients and Methods: To investigate the prognostic value of der(9) deletions in early CP CML, we performed an analysis of three prospective imatinib trials of the Italian Group for Hematological Malignancies of the Adult (GIMEMA) CML Working Party., Results: A fluorescent in situ hybridization (FISH) analysis of bone marrow cells was performed at diagnosis; der(9) deletions were detected in 60 (12%) of 521 evaluable patients. At 60 months, the cumulative incidence of complete cytogenetic response and major molecular response-and the probability of event-free survival, failure-free survival, progression-free survival, and overall survival-in patients with and without deletions were not statistically different., Conclusion: Our data strongly support the notion that, when investigated by FISH, der(9) deletions are not a poor prognostic factor in patients with early CP CML treated with imatinib.

Published
2010
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3. Sustained molecular remissions are achievable with tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia and additional cytogenetic clonal evolution.

Author

Falchi L, Rege-Cambrin G, Fava C, Donti E, Luzi D, Giugliano E, Gubbiotti M, Schippa M, and Liberati AM

Subjects
Adult, Benzamides, Female, Humans, Imatinib Mesylate, Karyotyping, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Male, Middle Aged, Remission Induction, Treatment Outcome, Clone Cells drug effects, Clone Cells pathology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use
Abstract

Little is known regarding the activity of tyrosine kinase inhibitors (TKis) on chronic myeloid leukemia (CML) clonal evolution (CE). We treated 10 CE CML patients in either hematologic chronic (8 cases) or accelerated (2 cases) phase with imatinib or second generation TKi. Additional chromosomal abnormalities appeared during the course of disease in seven cases, being present at diagnosis in three. A total of 6/10 (60%) patients achieved complete cytogenetic remission (CCyR) with imatinib in 3-14 months. Major or complete molecular remission (CMR) was obtained in four CCyR patients after 21, 25, 22, and 12 months, as well as in a fifth patient who started nilotinib because of suboptimal response after 75 months of imatinib treatment. One patient received nilotinib due to imatinib intolerance after 56 months of therapy while on CMR, and maintained such status. After a median follow-up of 82 months (range, 3-116), six patients are alive, five of which are in continuous CCyR while one patient is in his third CCyR on dasatinib after relapsing on imatinib and nilotinib. Five patients are in complete (four) or major (one) molecular remission, ongoing at 3, 48, 61, 95, and 96 months, on imatinib (three) or nilotinib (two). Although a small number of patients was studied, our results suggest that long-term cytogenetic and molecular remission can be achieved in CML CE patients with TKis treatment., (Copyright 2010 Elsevier Inc. All rights reserved.)

Published
2010
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4. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study.

Author

Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S, Tiribelli M, Buccisano F, Testoni N, Gottardi E, de Vivo A, Giugliano E, Iacobucci I, Paolini S, Soverini S, Rosti G, Rancati F, Astolfi C, Pane F, Saglio G, and Martinelli G

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Benzamides, Female, Gene Rearrangement, Humans, Hypereosinophilic Syndrome drug therapy, Imatinib Mesylate, Male, Middle Aged, Oncogene Proteins, Fusion metabolism, Prospective Studies, Protein-Tyrosine Kinases antagonists & inhibitors, Receptor, Platelet-Derived Growth Factor alpha metabolism, Treatment Outcome, mRNA Cleavage and Polyadenylation Factors metabolism, Antineoplastic Agents therapeutic use, Hypereosinophilic Syndrome genetics, Oncogene Proteins, Fusion genetics, Piperazines therapeutic use, Pyrimidines therapeutic use, Receptor, Platelet-Derived Growth Factor alpha genetics, mRNA Cleavage and Polyadenylation Factors genetics
Abstract

Background and Objectives: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate., Design and Methods: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily., Results: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months., Interpretation and Conclusions: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.

Published
2007
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5. The NF-kappaB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance.

Author

Cilloni D, Messa F, Arruga F, Defilippi I, Morotti A, Messa E, Carturan S, Giugliano E, Pautasso M, Bracco E, Rosso V, Sen A, Martinelli G, Baccarani M, and Saglio G

Subjects
Apoptosis drug effects, Benzamides, Binding Sites, Blotting, Western, Bone Marrow Cells drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Cells, Cultured, Combined Modality Therapy, DNA metabolism, Enzyme-Linked Immunosorbent Assay, Humans, Imatinib Mesylate, In Vitro Techniques, K562 Cells, NF-kappa B metabolism, Tumor Stem Cell Assay methods, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Heterocyclic Compounds, 3-Ring pharmacology, I-kappa B Kinase antagonists & inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, NF-kappa B antagonists & inhibitors, Piperazines therapeutic use, Pyridines pharmacology, Pyrimidines therapeutic use
Abstract

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappaB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-kappaB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.

Published
2006
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6. Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia.

Author

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, and Saglio G

Subjects
Adult, Aged, Antineoplastic Combined Chemotherapy Protocols toxicity, Benzamides, Dose-Response Relationship, Drug, Female, Humans, Imatinib Mesylate, Interferon alpha-2, Interferon-alpha toxicity, Male, Middle Aged, Piperazines toxicity, Pyrimidines toxicity, Recombinant Proteins, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Interferon-alpha administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Piperazines administration & dosage, Pyrimidines administration & dosage
Abstract

Since interferon-alpha 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-alpha (PegIFN) dose (50 microg/wk, 100 microg/wk, and 150 microg/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 microg/wk or 100 microg/wk PegIFN but not to those who were assigned to receive 150 microg/wk. The median administered dose of PegIFN ranged between 32 microg/wk and 36 microg/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.

Published
2004
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7. Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.

Author

Cilloni D, Messa F, Gottardi E, Fava M, Arruga F, Defilippi I, Carturan S, Messa E, Morotti A, Giugliano E, Rege-Cambrin G, Alberti D, Baccarani M, and Saglio G

Subjects
Animals, Apoptosis, Benzamides, COS Cells, Chlorocebus aethiops, Drug Resistance, Neoplasm, Follow-Up Studies, Fusion Proteins, bcr-abl genetics, Humans, Imatinib Mesylate, In Vitro Techniques, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative metabolism, Prognosis, Protein-Tyrosine Kinases antagonists & inhibitors, RNA, Neoplasm genetics, Reverse Transcriptase Polymerase Chain Reaction, Transfection, WT1 Proteins antagonists & inhibitors, WT1 Proteins metabolism, Antineoplastic Agents therapeutic use, Bone Marrow pathology, Gene Expression Regulation, Neoplastic, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Piperazines therapeutic use, Pyrimidines therapeutic use, RNA, Messenger analysis, WT1 Proteins genetics
Abstract

Background: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib., Methods: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis., Results: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines., Conclusions: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients., (Copyright 2004 American Cancer Society.)

Published
2004
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8. Chromosome abnormalities additional to the Philadelphia chromosome at the diagnosis of chronic myelogenous leukemia: pathogenetic and prognostic implications

Author

Zaccaria, A, Testoni, N, Valenti, Am, Luatti, S, Tonelli, M, Marzocchi, G, Cipriani, R, Baldazzi, C, Giannini, B, Stacchini, M, Gamberini, C, Castagnetti, F, Rosti, G, Azzena, A, Cavazzini, Francesco, Cianciulli, Am, Dalsass, A, Donti, E, Giugliano, E, Gozzetti, A, Grimoldi, Mg, Ronconi, S, Santoro, A, Spedicato, F, Zanatta, L, Baccarani, M, GIMEMA Working Party on, C. M. L., Zaccaria A, Testoni N, Valenti AM, Luatti S, Tonelli M, Marzocchi G, Cipriani R, Baldazzi C, Giannini B, Stacchini M, Gamberini C, Castagnetti F, Rosti G, Azzena A, Cavazzini F, Cianciulli AM, Dalsass A, Donti E, Giugliano E, Gozzetti A, Grimoldi MG, Ronconi S, Santoro A, Spedicato F, Zanatta L, and Baccarani M

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Biology, Philadelphia chromosome, Gastroenterology, Piperazines, NO, Myelogenous, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Internal medicine, Aged, Aged, 80 and over, Benzamides, Female, Humans, Imatinib Mesylate, Karyotyping, Middle Aged, Protein-Tyrosine Kinases, Pyrimidines, Remission Induction, Treatment Outcome, Chromosome Aberrations, Philadelphia Chromosome, Molecular Biology, Genetics, 80 and over, medicine, Chronic, Leukemia, Karyotype, Imatinib, medicine.disease, Imatinib mesylate, Immunology, BCR-ABL Positive, Sokal Score, Chronic myelogenous leukemia, medicine.drug
Abstract

Additional chromosome abnormalities (ACAs) occur in less than 10% of cases at diagnosis of Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). In some cases, on the basis of the persistence of the ACAs in Ph-negative cells after response to imatinib, a secondary origin of the Ph chromosome has been demonstrated. In this study, the possible prognostic value of this phenomenon was evaluated. Thirty-six Ph-positive CML patients were included in the study. In six patients, ACAs persisted after the disappearance of the Ph. A complete cytogenetic response (CCR) was obtained in five of these six patients, and five of six also had a high Sokal score. In all the other cases, ACAs disappeared together (in cases of response to therapy with imatinib) or persisted with the Ph (in cases of no response to imatinib). In the former cases, the primary origin of the Ph was demonstrated. CCR was obtained in 22 cases (17 with low to intermediate Sokal scores), while no response was observed in 8 patients (5 with a high Sokal score). Sokal score seems to maintain its prognostic value for patients in whom the Ph occurs as a primary event, but not in those in whom it occurs as a secondary one.

Published
2010

9. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFR -positive hypereosinophilic syndrome. Results of a multicenter prospective study

Author

Michele Baccarani, Enrico Gottardi, Michela Rondoni, Nicoletta Testoni, Emanuela Ottaviani, Cinzia Astolfi, Mario Tiribelli, Emilia Giugliano, Fabrizio Pane, Daniela Cilloni, Francesco Buccisano, Francesca Rancati, Serena Merante, Ilaria Iacobucci, Giovanni Martinelli, Gianantonio Rosti, Stefania Paolini, Francesca Messa, Giuseppe Saglio, Simona Soverini, Antonio De Vivo, Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S, Tiribelli M, Buccisano F, Testoni N, Gottardi E, de Vivo A, Giugliano E, Iacobucci I, Paolini S, Soverini S, Rosti G, Rancati F, Astolfi C, Pane F, Saglio G, Martinelli G., Baccarani, M, Cilloni, D, Rondoni, M, Ottaviani, E, Messa, F, Merante, S, Tiribelli, M, Buccisano, F, Testoni, N, Gottardi, E, DE VIVO, A, Giugliano, E, Iacobucci, I, Paolini, S, Soverini, S, Rosti, G, Rancati, F, Astolfi, C, Pane, Fabrizio, Saglio, G, and Martinelli, G.

Subjects
Male, Receptor, Platelet-Derived Growth Factor alpha, Oncogene Proteins, Fusion, FIP1L1-PDGFRA FUSION, TYROSINE KINASE, THERAPY, Gastroenterology, Piperazines, Tyrosine-kinase inhibitor, Prospective Studies, FIP1L1-PDGFRALPHA, BCR-ABL, Aged, 80 and over, Gene Rearrangement, HYPEREOSINOPHILIC SYNDROME, Hematology, Hypereosinophilic syndrome, Middle Aged, Protein-Tyrosine Kinases, EOSINOPHILIC DISORDERS, Treatment Outcome, CHRONIC MYELOPROLIFERATIVE DISORDERS, Benzamides, Imatinib Mesylate, GROWTH, Female, Tyrosine kinase, medicine.drug, Adult, medicine.medical_specialty, Adolescent, medicine.drug_class, Antineoplastic Agents, CHRONIC MYELOID-LEUKEMIA, FACTOR RECEPTOR-BETA, MOLECULAR REMISSION, IMATINIB, TYROSINE, Internal medicine, medicine, Humans, Aged, mRNA Cleavage and Polyadenylation Factors, Chronic eosinophilic leukemia, business.industry, EOSINOPHILS, Imatinib, medicine.disease, Pyrimidines, Imatinib mesylate, Fusion transcript, Cancer research, business, Settore MED/15 - Malattie del Sangue
Abstract

BACKGROUND AND OBJECTIVES: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate. DESIGN AND METHODS: A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily. RESULTS: Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months. INTERPRETATION AND CONCLUSIONS: All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.

Published
2007
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10. 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

Author

Castagnetti, Fausto, Testoni, Nicoletta, Luatti, Simona, Marzocchi, Giulia, Mancini, Marco, Kerim, Simonetta, Giugliano, Emilia, Albano, Francesco, Cuneo, Antonio, Abruzzese, Elisabetta, Martino, Bruno, Palandri, Francesca, Amabile, Marilina, Iacobucci, Ilaria, Alimena, Giuliana, Pane, Fabrizio, Martinelli, Giovanni, Saglio, Giuseppe, Baccarani, Michele, Rosti, Gianantonio, GIMEMA CML working party, Bocchia, Monica, Castagnetti, F., Testoni, N., Luatti, S., Marzocchi, G., Mancini, M., Kerim, S., Giugliano, E., Albano, F., Cuneo, A., Abruzzese, E., Martino, B., Palandri, F., Amabile, M., Iacobucci, I., Alimena, G., Pane, Fabrizio, Martinelli, G., Saglio, G., Baccarani, M., Rosti, G., Castagnetti F, Testoni N, Luatti S, Marzocchi G, Mancini M, Kerim S, Giugliano E, Albano F, Cuneo A, Abruzzese E, Martino B, Palandri F, Amabile M, Iacobucci I, Alimena G, Pane F, Martinelli G, Saglio G, Baccarani M, Rosti G, Castagnetti, F, Testoni, N, Luatti, S, Marzocchi, G, Mancini, M, Kerim, S, Giugliano, E, Albano, F, Cuneo, A, Abruzzese, E, Martino, B, Palandri, F, Amabile, M, Iacobucci, I, Alimena, G, Martinelli, G, Saglio, G, and Baccarani, M

Subjects
Oncology, poor-prognosis, Myeloid, Male, Cancer Research, Kaplan-Meier Estimate, Severity of Illness Index, Piperazines, European LeukemiaNet, fusion gene transcripts, Reference Values, hemic and lymphatic diseases, 80 and over, Prospective Studies, stem-cell transplantation, In Situ Hybridization, In Situ Hybridization, Fluorescence, Aged, 80 and over, Adolescent, Adult, Age Factors, Aged, Benzamides, Chromosomes, Human, Pair 9, Cytogenetic Analysis, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Imatinib Mesylate, Italy, Leukemia, Myeloid, Chronic-Phase, Logistic Models, Maximum Tolerated Dose, Middle Aged, Multivariate Analysis, Probability, Prognosis, Pyrimidines, Reverse Transcriptase Polymerase Chain Reaction, Risk Assessment, Statistics, Nonparametric, Survival Analysis, Treatment Outcome, Young Adult, Gene Deletion, Medicine (all), Leukemia, philadelphia-chromosome, Statistics, Myeloid leukemia, chronic myelogenous leukemia, medicine.anatomical_structure, abl tyrosine kinase, bcr expression, cytogenetic responses, minimal-residual-disease, patients receiving imatinib, Drug, medicine.drug, Human, Pair 9, medicine.medical_specialty, Derivative chromosome, Chromosomes, Fluorescence, Dose-Response Relationship, chronic myeloid leukemia, Internal medicine, medicine, Nonparametric, business.industry, Imatinib, medicine.disease, Imatinib mesylate, Immunology, Chronic-Phase, Bone marrow, business
Abstract

Purpose Deletions of the derivative chromosome 9 [der(9)] have been associated with a poor prognosis in chronic myeloid leukemia (CML) across different treatment modalities. In the imatinib era, the prognostic impact of der(9) deletions has been evaluated mainly in patients with late chronic-phase (CP) CML, giving partially conflicting results. Few data are available in the early CP setting. For this reason, in 2006, the European LeukemiaNet recommendations still considered der(9) deletions as a candidate adverse prognostic factor and required a careful monitoring of the patient. Patients and Methods To investigate the prognostic value of der(9) deletions in early CP CML, we performed an analysis of three prospective imatinib trials of the Italian Group for Hematological Malignancies of the Adult (GIMEMA) CML Working Party. Results A fluorescent in situ hybridization (FISH) analysis of bone marrow cells was performed at diagnosis; der(9) deletions were detected in 60 (12%) of 521 evaluable patients. At 60 months, the cumulative incidence of complete cytogenetic response and major molecular response—and the probability of event-free survival, failure-free survival, progression-free survival, and overall survival—in patients with and without deletions were not statistically different. Conclusion Our data strongly support the notion that, when investigated by FISH, der(9) deletions are not a poor prognostic factor in patients with early CP CML treated with imatinib.

Published
2010

11. Imatinib and pegylated human recombinant interferon-alpha2b in early chronic-phase chronic myeloid leukemia

Author

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

Subjects
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.

Published
2004

12. Morgana acts as an oncosuppressor in chronic myeloid leukemia

Author

Sabrina Crivellaro, Ubaldo Familiari, Mara Brancaccio, Emilia Turco, Alessandro Morotti, Giovanna Carrà, Emilia Giugliano, Rocco Piazza, Mauro Papotti, Juan Carlos Cutrin, Federica Fusella, Cristina Panuzzo, Emilio Hirsch, Carlo Gambacorti-Passerini, Giuseppe Saglio, Giovanna Rege-Cambrin, Lorenzo Silengo, Guido Tarone, Pier Paolo Pandolfi, Roberta Ferretti, Annalisa Camporeale, Irene Franco, Augusta Di Savino, Stefania Rocca, Barbara Miniscalco, Di Savino, A, Panuzzo, C, Rocca, S, Familiari, U, Piazza, R, Crivellaro, S, Carrà, G, Ferretti, R, Fusella, F, Giugliano, E, Camporeale, A, DE FRANCO, I, Miniscalco, B, Cutrin, J, Turco, E, Silengo, L, Hirsch, E, Rege Cambrin, G, GAMBACORTI PASSERINI, C, Pandolfi, P, Papotti, M, Saglio, G, Tarone, G, Morotti, A, and Brancaccio, M

Subjects
Fusion Proteins, bcr-abl, Immunoenzyme Technique, Apoptosis, Medicina Clínica, Biochemistry, Piperazines, Immunoenzyme Techniques, Mice, Bone Marrow, hemic and lymphatic diseases, rho-Associated Kinase, Tumor Cells, Cultured, Philadelphia Chromosome, Mice, Knockout, rho-Associated Kinases, Hematology, Reverse Transcriptase Polymerase Chain Reaction, Medicine (all), Myeloid leukemia, Flow Cytometry, Leukemia, ROCK INHIBITORS, Benzamides, Imatinib Mesylate, Atypical chronic myeloid leukemia, medicine.drug, Human, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Blotting, Western, Immunology, Protein Kinase Inhibitor, Biology, Philadelphia chromosome, Real-Time Polymerase Chain Reaction, MORGANA, Benzamide, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Animals, Humans, CENTROSOME, Centrosome duplication, Hematología, RNA, Messenger, Protein Kinase Inhibitors, neoplasms, Piperazine, Cell Proliferation, CHRONIC MYELOID LEUKEMIA, Animal, Apoptosi, Imatinib, Cell Biology, medicine.disease, Molecular biology, Mice, Inbred C57BL, Pyrimidines, Imatinib mesylate, Pyrimidine, Drug Resistance, Neoplasm, Carrier Proteins, Carrier Protein, Molecular Chaperones
Abstract

We recently described morgana as an essential protein able to regulate centrosome du- plication and genomic stability, by inhibiting ROCK. Here we show that morgana 1/2 mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome am- plification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph1 CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph1 CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplifi- cation and cytogenetic abnormalities, and (2) in Ph1 CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibitionin the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underex- pressed. Fil: Di Savino, Augusta. Universitã â Di Torino; Italia Fil: Panuzzo, Cristina. Universitã â Di Torino; Italia Fil: Rocca, Stefania. Universitã â Di Torino; Italia Fil: Familiari, Ubaldo. Universitã â Di Torino; Italia Fil: Piazza, Rocco. Universita Degli Studi Di Milano; Italia Fil: Crivellaro, Sabrina. Universitã â Di Torino; Italia Fil: Carrà, Giovanna. Universitã â Di Torino; Italia Fil: Ferretti, Roberta. Universitã â Di Torino; Italia Fil: Fusella, Federica. Universitã â Di Torino; Italia Fil: Giugliano, Emilia. Universitã â Di Torino; Italia Fil: Camporeale, Annalisa. Universitã â Di Torino; Italia Fil: Franco, Irene. Universitã â Di Torino; Italia Fil: Miniscalco, Barbara. Harvard Medical School; Estados Unidos Fil: Cutrin, Juan Carlos. Universitã â Di Torino; Italia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Cardiológicas (i); Argentina Fil: Turco, Emilia. Universita di Torino; Italia Fil: Silengo, Lorenzo. Universita di Torino; Italia Fil: Hirsch, Emilio. Universita di Torino; Italia Fil: Rege Cambrin, Giovanna. Universita di Torino; Italia Fil: Gambacorti Passerin, Carlo. Universita Degli Studi Di Milano; Italia Fil: Pandolfi, Pier Paolo. Universita di Torino; Italia. Harvard Medical School; Estados Unidos Fil: Papotti, Mauro. Universita di Torino; Italia Fil: Saglio, Giuseppe. Universita di Torino; Italia Fil: Tarone, Guido. Universita di Torino; Italia Fil: Morotti, Alessandro. Universita di Torino; Italia Fil: Brancaccio, Mara. Universita di Torino; Italia

Published
2015

13. The NF-κB pathway blockade by the IKK inhibitor PS1145 can overcome Imatinib resistance

Author

Alessandro Morotti, Michele Baccarani, A Sen, Rosso, G. Saglio, Enrico Bracco, Daniela Cilloni, Francesca Arruga, Ilaria Defilippi, Emanuela Messa, Giovanni Martinelli, Sonia Carturan, Marisa Pautasso, Emilia Giugliano, Francesca Messa, Cilloni D, Messa F, Arruga F, Defilippi I, Morotti A, Messa E, Carturan S, Giugliano E, Pautasso M, Bracco E, Rosso V, Sen A, Martinelli G, Baccarani M, and Saglio G.

Subjects
Cancer Research, Cell Survival, Pyridines, Blotting, Western, Antineoplastic Agents, Apoptosis, Bone Marrow Cells, Enzyme-Linked Immunosorbent Assay, Drug resistance, In Vitro Techniques, Pharmacology, Piperazines, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Humans, Medicine, neoplasms, Cells, Cultured, Tumor Stem Cell Assay, Cell Proliferation, Binding Sites, business.industry, Kinase, NF-kappa B, Imatinib, DNA, Hematology, medicine.disease, Combined Modality Therapy, I-kappa B Kinase, Blockade, Leukemia, Pyrimidines, Imatinib mesylate, Oncology, Drug Resistance, Neoplasm, Benzamides, Imatinib Mesylate, K562 Cells, business, Heterocyclic Compounds, 3-Ring, medicine.drug, K562 cells
Abstract

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-kappaB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Rel-blocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-kappaB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.

Published
2005
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14. Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation

Author

Milena Fava, Enrico Gottardi, Giovanna Rege-Cambrin, Giuseppe Saglio, Francesca Arruga, Emanuela Messa, Ilaria Defilippi, Daniela Cilloni, Francesca Messa, Sonia Carturan, Emilia Giugliano, Daniele Alberti, Alessandro Morotti, Michele Baccarani, CILLONI D, MESSA F, GOTTARDI E, FAVA M, ARRUGA F, DEFILIPPI I, CARTURAN S, MESSA E, MOROTTI A, GIUGLIANO E, REGE-CAMBRIN G, ALBERTI D, BACCARANI M., and SAGLIO G.

Subjects
Cancer Research, Fusion Proteins, bcr-abl, Antineoplastic Agents, Apoptosis, In Vitro Techniques, Transfection, Philadelphia chromosome, IMATINIB, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative, Piperazines, Bone Marrow, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, Chlorocebus aethiops, medicine, Animals, Humans, RNA, Messenger, RNA, Neoplasm, WT1 Proteins, CML, neoplasms, ABL, Reverse Transcriptase Polymerase Chain Reaction, business.industry, breakpoint cluster region, Wilms' tumor, Imatinib, Protein-Tyrosine Kinases, Prognosis, medicine.disease, WT1, Gene Expression Regulation, Neoplastic, Pyrimidines, Real-time polymerase chain reaction, Oncology, Drug Resistance, Neoplasm, Benzamides, COS Cells, Imatinib Mesylate, Cancer research, business, Tyrosine kinase, Follow-Up Studies, Chronic myelogenous leukemia, medicine.drug
Abstract

BACKGROUND The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 μM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients. Cancer 2004. © 2004 American Cancer Society.

Published
2004
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