113 results on '"Luigiana Luciano"'
Search Results
2. P671: USE OF RT-QPCR VERSUS DIGITAL DROPLET PCR AND EVALUATION OF CD26+ CELLS IN LONG TFR PATIENTS WITH CHRONIC MYELOID LEUKEMIA
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Laura De Fazio, Raffaella Reina, Raffella Iannotta, Martina Lamagna, Dario Lisi, Giuseppe Gaeta, Andrea Cacace, Alessandra Potenza, Santa Erricchiello, Barbara Izzo, Donatella Raspadori, Monica Bocchia, Fabrizio Pane, and Luigiana Luciano
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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3. P686: REAL-WORLD EFFICACY PROFILE OF ASCIMINIB IN AN ITALIAN, MULTI-RESISTANT CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENT POPULATION
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Massimo Breccia, Antonella Russo Rossi, Valentina Giai, Bruno Martino, Carmen Fava, Mario Annunziata, Elisabetta Abruzzese, Gianni Binotto, Claudia Baratè, Aurelio Pio Nardozza, Alessandra Misto, Paola Coco, Valeria Calafiore, Maria Cristina Carraro, Federica Cattina, Francesco Cavazzini, Maria Teresa Corsetti, Lara Crucitti, Monica Crugnola, Paolo Ditonno, Ambra DI Veroli, Anna Ermacora, Felicetto Ferrara, Angelo Genua, Antonella Gozzini, Stefana Impera, Alessandra Iurlo, Luciano Levato, Luigiana Luciano, Maria Cristina Miggiano, Marco De Gobbi, Marco Santoro, Barbara Scappini, Anna Rita Scortechini, Andrea Patriarca, Serena Rosati, Sabina Russo, Rosaria Sancetta, Grazia Sanpaolo, Teresa Maria Santeramo, Silvia Sibilla, Federica Sorà, Paolo Sportoletti, Fabio Stagno, Elena Trabacchi, and Fausto Castagnetti
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells
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Paola Pacelli, Adele Santoni, Anna Sicuranza, Elisabetta Abruzzese, Valentina Giai, Monica Crugnola, Mario Annunziata, Sara Galimberti, Alessandra Iurlo, Luigiana Luciano, Federica Sorà, Carmen Fava, Elena Bestoso, Cristina Marzano, Alessandra Cartocci, Marzia Defina, Vincenzo Sammartano, Emanuele Cencini, Donatella Raspadori, and Monica Bocchia
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chronic myelogenous leukemia ,treatment free remission ,CD26+ ,leukemia stem cell ,TKI ,flow cytometry ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR.Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation.Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss.Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of “fluctuating” values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs “burden” playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs’ ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.
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- 2023
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5. Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study
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Alessandra Iurlo, Daniele Cattaneo, Silvia Artuso, Dario Consonni, Elisabetta Abruzzese, Gianni Binotto, Monica Bocchia, Massimiliano Bonifacio, Fausto Castagnetti, Sara Galimberti, Antonella Gozzini, Miriam Iezza, Roberto Latagliata, Luigiana Luciano, Alessandro Maggi, Maria Cristina Miggiano, Patrizia Pregno, Giovanna Rege-Cambrin, Sabina Russo, Anna Rita Scortechini, Agostino Tafuri, Mario Tiribelli, Carmen Fava, Gianantonio Rosti, Robin Foa, Massimo Breccia, and Giuseppe Saglio
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chronic myeloid leukemia ,tyrosine kinase inhibitors (TKI) ,treatment-free remission (TFR) ,low dose ,adverse event (AE) ,real life ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs.
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- 2022
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6. Pro-Inflammatory and Pro-Oxidative Changes During Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)
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Anna Sicuranza, Ilaria Ferrigno, Elisabetta Abruzzese, Alessandra Iurlo, Sara Galimberti, Antonella Gozzini, Luigiana Luciano, Fabio Stagno, Antonella Russo Rossi, Nicola Sgherza, Daniele Cattaneo, Corrado Zuanelli Brambilla, Cristina Marzano, Carmen Fava, Olga Mulas, Emanuele Cencini, Adele Santoni, Vincenzo Sammartano, Alessandro Gozzetti, Luca Puccetti, and Monica Bocchia
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CML ,TKI ,cytokines ,AOEs ,cardiovascular risk (CV risk) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an “inflammatory status” during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.
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- 2022
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7. Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper
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Simona Soverini, Elisabetta Abruzzese, Monica Bocchia, Massimiliano Bonifacio, Sara Galimberti, Antonella Gozzini, Alessandra Iurlo, Luigiana Luciano, Patrizia Pregno, Gianantonio Rosti, Giuseppe Saglio, Fabio Stagno, Mario Tiribelli, Paolo Vigneri, Giovanni Barosi, and Massimo Breccia
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Next-generation sequencing ,Chronic myeloid leukemia ,Sanger sequencing ,BCR-ABL1 mutation ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract BCR-ABL1 kinase domain (KD) mutation status is considered to be an important element of clinical decision algorithms for chronic myeloid leukemia (CML) patients who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs). Conventional Sanger sequencing is the method currently recommended to test BCR-ABL1 KD mutations. However, Sanger sequencing has limited sensitivity and cannot always discriminate between polyclonal and compound mutations. The use of next-generation sequencing (NGS) is increasingly widespread in diagnostic laboratories and represents an attractive alternative. Currently available data on the clinical impact of NGS-based mutational testing in CML patients do not allow recommendations with a high grade of evidence to be prepared. This article reports the results of a group discussion among an ad hoc expert panel with the objective of producing recommendations on the appropriateness of clinical decisions about the indication for NGS, the performance characteristics of NGS platforms, and the therapeutic changes that could be applied based on the use of NGS in CML. Overall, these recommendations might be employed to inform clinicians about the practical use of NGS in CML.
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- 2019
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8. Prognostic Factors for Overall Survival In Chronic Myeloid Leukemia Patients: A Multicentric Cohort Study by the Italian CML GIMEMA Network
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Giorgina Specchia, Patrizia Pregno, Massimo Breccia, Fausto Castagnetti, Chiara Monagheddu, Massimiliano Bonifacio, Mario Tiribelli, Fabio Stagno, Giovanni Caocci, Bruno Martino, Luigiana Luciano, Michele Pizzuti, Antonella Gozzini, Anna Rita Scortechini, Francesco Albano, Micaela Bergamaschi, Isabella Capodanno, Andrea Patriarca, Carmen Fava, Giovanna Rege-Cambrin, Federica Sorà, Sara Galimberti, Monica Bocchia, Gianni Binotto, Giovanni Reddiconto, Paolo DiTonno, Alessandro Maggi, Grazia Sanpaolo, Maria Stella De Candia, Valentina Giai, Elisabetta Abruzzese, Maria Cristina Miggiano, Gaetano La Barba, Giuseppe Pietrantuono, Anna Guella, Luciano Levato, Olga Mulas, Fabio Saccona, Gianantonio Rosti, Pellegrino Musto, Francesco Di Raimondo, Fabrizio Pane, Michele Baccarani, Giuseppe Saglio, and Giovannino Ciccone
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chronic myeloid leukemia ,tyrosine kinase inhibitors ,prognostic factors ,ELTs ,Sokal score ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2nd generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p
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- 2021
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9. Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis
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Novella Pugliese, Claudia Giordano, Davide Nappi, Luigiana Luciano, Claudio Cerchione, Mario Annunziata, Beniamino Casale, Elena Crisà, Maria Rosaria Villa, Luca Pezzullo, Maria Iovine, Marco Picardi, Francesco Grimaldi, Fabrizio Pane, and Vincenzo Martinelli
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hydroxyurea ,Janus kinase (JAK) inhibitors ,primary myelofibrosis ,ruxolitinib ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease‐related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi‐center study enrolled 20 adult patients with intermediate‐ or high‐risk primary MF, post‐ polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib‐hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow‐up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF.
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- 2019
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10. Frontline Dasatinib Treatment in a 'Real-Life' Cohort of Patients Older than 65 Years with Chronic Myeloid Leukemia
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Roberto Latagliata, Fabio Stagno, Mario Annunziata, Elisabetta Abruzzese, Alessandra Iurlo, Attilio Guarini, Carmen Fava, Antonella Gozzini, Massimiliano Bonifacio, Federica Sorà, Sabrina Leonetti Crescenzi, Monica Bocchia, Monica Crugnola, Fausto Castagnetti, Isabella Capodanno, Sara Galimberti, Costanzo Feo, Raffaele Porrini, Patrizia Pregno, Manuela Rizzo, Agostino Antolino, Endri Mauro, Nicola Sgherza, Luigiana Luciano, Mario Tiribelli, Antonella Russo Rossi, Malgorzata Trawinska, Paolo Vigneri, Massimo Breccia, Gianantonio Rosti, and Giuliana Alimena
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a “real-life” cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.
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- 2016
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11. Residual Peripheral Blood CD26+ Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission
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Monica Bocchia, Anna Sicuranza, Elisabetta Abruzzese, Alessandra Iurlo, Santina Sirianni, Antonella Gozzini, Sara Galimberti, Lara Aprile, Bruno Martino, Patrizia Pregno, Federica Sorà, Giulia Alunni, Carmen Fava, Fausto Castagnetti, Luca Puccetti, Massimo Breccia, Daniele Cattaneo, Marzia Defina, Olga Mulas, Claudia Baratè, Giovanni Caocci, Simona Sica, Alessandro Gozzetti, Luigiana Luciano, Monica Crugnola, Mario Annunziata, Mario Tiribelli, Paola Pacelli, Ilaria Ferrigno, Emilio Usala, Nicola Sgherza, Gianantonio Rosti, Alberto Bosi, and Donatella Raspadori
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chronic myeloid leukemia ,CD26 ,leukemic stem cells ,TKI ,minimal residual disease ,flow cytometry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Chronic myeloid leukemia (CML) patients in sustained “deep molecular response” may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34+/CD38− LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26+ LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45+/CD34+/CD38− stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26+ LSCs (median 19.20/μL, range 0.27–698.6). PB CD26+ LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012–0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006–0.76). Notably, no correlation between BCR-ABL/ABLIS ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that “circulating” CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26+ LSCs during TKI treatment and the role of a “stem cell response” threshold to achieve and maintain TFR are ongoing.
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- 2018
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12. DDX3X-MLLT10 fusion in adults with NOTCH1 positive T-cell acute lymphoblastic leukemia
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Lucia Brandimarte, Roberta La Starza, Valentina Gianfelici, Gianluca Barba, Valentina Pierini, Danika Di Giacomo, Jan Cools, Loredana Elia, Antonella Vitale, Luigiana Luciano, Antonella Bardi, Sabina Chiaretti, Caterina Matteucci, Giorgina Specchia, and Cristina Mecucci
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2014
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13. Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors
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Antonella Russo Rossi, Massimo Breccia, Elisabetta Abruzzese, Fausto Castagnetti, Luigiana Luciano, Antonella Gozzini, Mario Annunziata, Bruno Martino, Fabio Stagno, Francesco Cavazzini, Mario Tiribelli, Giuseppe Visani, Patrizia Pregno, Pellegrino Musto, Carmen Fava, Nicola Sgherza, Francesco Albano, Gianantonio Rosti, Giuliana Alimena, and Giorgina Specchia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.
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- 2013
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14. Charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment compliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib
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Massimo Breccia, Roberto Latagliata, Fabio Stagno, Luigiana Luciano, Antonella Gozzini, Fausto Castagnetti, Carmen Fava, Francesco Cavazzini, Mario Annunziata, Antonella Russo Rossi, Patrizia Pregno, Elisabetta Abruzzese, Paolo Vigneri, Giovanna Rege-Cambrin, Simona Sica, Fabrizio Pane, Valeria Santini, Giorgina Specchia, Gianantonio Rosti, and Giuliana Alimena
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data.Design and Methods We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment.Results We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3–5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0–1 and 69% of patients with score 2–3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non-hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions.Conclusions In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities.
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- 2011
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15. Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells
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Pacelli, Paola, Santoni, Adele, Sicuranza, Anna, Elisabetta, Abruzzese, Valentina, Giai, Monica, Crugnola, Mario, Annunziata, Sara, Galimberti, Alessandra, Iurlo, Luigiana, Luciano, Federica, Sorà, Carmen, Fava, Elena, Bestoso, Cristina, Marzano, Cartocci, Alessandra, Marzia, Defina, Sammartano, Vincenzo, Emanuele, Cencini, Donatella, Raspadori, and Bocchia, Monica
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Pharmacology ,Pharmacology (medical) - Abstract
Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR.Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation.Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss.Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of “fluctuating” values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs “burden” playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs’ ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.
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- 2023
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16. Choice of Tyrosine Kinase Inhibitor and Early Events during the First Year of Therapy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia (CML) Patients with Concomitant Diabetes: A 'Campus CML' Study
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Isabella Capodanno, Mario Tiribelli, Maria Cristina Miggiano, Cristina Bucelli, Francesco Cavazzini, Sabrina Leonetti Crescenzi, Sabina Russo, Emilia Scalzulli, Andrea Bernardelli, Luigiana Luciano, Olga Mulas, Giuseppina Loglisci, Chiara Elena, Umberto Pizzano, Immacolata Attolico, Gianni Binotto, Elena Crisà, Paolo Sportoletti, Ambra Di Veroli, Anna Rita Scortechini, Annapaola Leporace, Maria Basile, Monica Crugnola, Fabio Stagno, Pamela Murgano, Davide Rapezzi, Debora Luzi, Alessandra Iurlo, Monica Bocchia, Carmen Fava, Alessandra Malato, Sara Galimberti, Iolanda Donatella Vincelli, Malgorzata Monika Trawinska, Michele Pizzuti, Giovanni Caocci, Massimiliano Bonifacio, Giuseppe Saglio, Giorgina Specchia, Massimo Breccia, and Roberto Latagliata
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. In Search of Drivers of CD34+/CD38-/CD26+ Leukemia Stem Cells Persistence in CML Patients
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Paola Pacelli, Elena Bestoso, Anna Sicuranza, Elisabetta Abruzzese, Luigiana Luciano, Alessandra Iurlo, Marzia Defina, Sara Fredducci, Monica Crugnola, Valentina Giai, Federica Sorà, Sara Galimberti, Donatella Raspadori, and Monica Bocchia
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. COVID-19 infection in chronic myeloid leukaemia after oneyear of the pandemic in Italy. A Campus CML report
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Elisabetta Abruzzese, Sabina Russo, Carmen Fava, Francesca Lunghi, Sabrina Leonetti Crescenzi, Chiara Elena, Vincenzo Accurso, Fausto Castagnetti, Debora Luzi, Giovanni Caocci, Elena Crisà, Maria Cristina Miggiano, Massimo Breccia, Antonella Gozzini, Giuseppina Loglisci, Giovanna Rege-Cambrin, Monica Bocchia, Immacolata Attolico, Massimiliano Bonifacio, Luigiana Luciano, Gaetano La Barba, Gianantonio Rosti, Maria Stella De Candia, Roberto Latagliata, Gabriele Gugliotta, Francesco Cavazzini, Rosaria Sancetta, Micaela Bergamaschi, Anna Rita Scortechini, Sara Galimberti, Tamara Intermesoli, Federica Sorà, Luciano Levato, Paolo Sportoletti, Monica Crugnola, Mario Tiribelli, Isabella Capodanno, Giuseppe Saglio, Davide Rapezzi, Robin Foà, Alessandra Iurlo, Alessandro Lucchesi, Michele Pizzuti, Sara Barulli, Fabio Stagno, Patrizia Pregno, Alessandra Malato, Gianni Binotto, Agostino Tafuri, Breccia M., Abruzzese E., Accurso V., Attolico I., Barulli S., Bergamaschi M., Binotto G., Bocchia M., Bonifacio M., Caocci G., Capodanno I., Castagnetti F., Cavazzini F., Crisa E., Crugnola M., Stella De Candia M., Elena C., Fava C., Galimberti S., Gozzini A., Gugliotta G., Intermesoli T., Iurlo A., La Barba G., Latagliata R., Leonetti Crescenzi S., Levato L., Loglisci G., Lucchesi A., Luciano L., Lunghi F., Luzi D., Malato A., Cristina Miggiano M., Pizzuti M., Pregno P., Rapezzi D., Rege-Cambrin G., Rosti G., Russo S., Sancetta R., Rita Scortechini A., Sora F., Sportoletti P., Stagno F., Tafuri A., Tiribelli M., Foa R., and Saglio G.
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Male ,Tyrosine-kinase inhibitor ,law.invention ,law ,Retrospective Studie ,Pandemic ,Chronic ,Covid‐19 ,Leukemia ,Mortality rate ,Hematology ,Middle Aged ,Intensive care unit ,Research Papers ,Survival Rate ,Italy ,covid-19 ,Hematologic Neoplasms ,Cohort ,Female ,prognosi ,Human ,Research Paper ,chronic myeloid leukemia, Covid-19, prognosis, mortality ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,medicine.drug_class ,chronic myeloid leukemia ,prognosis, mortality ,Chronic myeloid leukaemia ,Disease-Free Survival ,NO ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Covid-19 ,mortality ,prognosis ,Aged ,Humans ,Retrospective Studies ,COVID-19 ,Pandemics ,SARS-CoV-2 ,medicine ,business.industry ,Concomitant ,Commentary ,BCR-ABL Positive ,business ,Myelogenous - Abstract
Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18years). Twenty-one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.
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- 2022
19. Long term follow-up of frontline Dasatinib in older patients with chronic myeloid leukemia in chronic phase treated outside clinical trials: a real-life cohort observational study
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Gioia Colafigli, Monica Crugnola, Ida Carmosino, Nicola Sgherza, Mario Tiribelli, Federica Sorà, Sara Galimberti, Cristina Bucelli, Fabio Stagno, Mario Annunziata, Roberto Latagliata, Alessandra Iurlo, Antonella Russo Rossi, Malgorzata Monika Trawinska, Luigiana Luciano, Carmen Fava, Costanzo Feo, Antonella Gozzini, Francesco Di Raimondo, Sabrina Leonetti Crescenzi, Massimiliano Bonifacio, Gianantonio Rosti, Attilio Guarini, Massimo Breccia, Endri Mauro, Gabriele Gugliotta, and Elisabetta Abruzzese
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Oncology ,medicine.medical_specialty ,older CML patients ,Dasatinib ,hemic and lymphatic diseases ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,80 and over ,Humans ,Radiology, Nuclear Medicine and imaging ,Chronic ,Chronic myeloid leukemia ,CML therapy ,dasatinib ,imatinib ,nilotinib ,Aged ,Aged, 80 and over ,Follow-Up Studies ,Imatinib Mesylate ,Retrospective Studies ,Treatment Outcome ,Protein Kinase Inhibitors ,Leukemia ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,General Medicine ,Clinical trial ,Nilotinib ,Cohort ,Observational study ,BCR-ABL Positive ,business ,Tyrosine kinase ,medicine.drug ,Myelogenous - Abstract
A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged75 years treated frontline with second-generation tyrosine kinase inhibitors.To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS).Median age was 78.4 years (range 75-89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 - 63.3).Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 - 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 - 80.0) and 82.3% (95%, CI 70.3-94.3), respectively.These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged75 years) affected by CP-CML with acceptable toxicity.
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- 2021
20. Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis
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Maria Rosaria Villa, Francesco Grimaldi, Davide Nappi, Mario Annunziata, Elena Crisà, Fabrizio Pane, Luigiana Luciano, L Pezzullo, Claudia Giordano, Novella Pugliese, Beniamino Casale, Marco Picardi, Maria Iovine, Claudio Cerchione, Vincenzo Martinelli, Pugliese, N., Giordano, C., Nappi, D., Luciano, L., Cerchione, C., Annunziata, M., Casale, B., Crisa, E., Villa, M. R., Pezzullo, L., Iovine, M., Picardi, M., Grimaldi, F., Pane, F., and Martinelli, V.
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Male ,0301 basic medicine ,Cancer Research ,Ruxolitinib ,ruxolitinib ,Biochemistry ,Gastroenterology ,hydroxyurea ,Polycythemia vera ,0302 clinical medicine ,hemic and lymphatic diseases ,Leukocytosis ,Original Research ,Aged, 80 and over ,primary myelofibrosi ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Janus kinase (JAK) inhibitor ,Optimal management ,Oncology ,030220 oncology & carcinogenesis ,primary myelofibrosis ,Janus kinase (JAK) inhibitors ,Drug Therapy, Combination ,Female ,medicine.symptom ,medicine.drug ,Adult ,medicine.medical_specialty ,Combination therapy ,Dose ,Immunology ,Antineoplastic Agents ,lcsh:RC254-282 ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Humans ,Janus Kinase Inhibitors ,Radiology, Nuclear Medicine and imaging ,Adverse effect ,Myelofibrosis ,Aged ,Retrospective Studies ,Cytopenia ,Thrombocytosis ,business.industry ,Clinical Cancer Research ,Cell Biology ,medicine.disease ,Pyrimidines ,030104 developmental biology ,Pyrazoles ,business ,Biomarkers ,030215 immunology - Abstract
Background Ruxolitinib (Ruxo), an orally bioavailable and selective inhibitor of JAK1 and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea (HU) might improve hematological response. Aims: To evaluate the efficacy and safety of Ruxo and HU combination. Methods This observational multicenter study, conducted from April 2012 to April 2017, enrolled 20 adult patients with a confirmed diagnosis of primary myelofibrosis (PMF), post-polycythemia vera (PPV-MF), or post-essential thrombocythemia (PET-MF) with hyperproliferative manifestations of the disease not controlled by Ruxo therapy. All patients we enrolled into the study had received Ruxo at a starting dose based on baseline platelet count. Patients were included into the study when Ruxo proved to be unable to reduce WBC and/or platelet count to within normal range (WBC Results The addition of HU was started after a median time of ruxolitinib monotherapy of 6.5 months (range 1-49.6 months): 17 patients (85%) started HU treatment due to lack of WBC control, whereas the remaining 3 patients (15%) started for the lack of platelet control. While on Ruxo monotherapy, ten patients (50%) needed a dose reduction due to hematological toxicity and three patients temporarily discontinued Ruxo due to severe thrombocytopenia (15%). After 14.5 months (range 2-195) median time of combination therapy in 8 patients the Ruxo daily doses increased (mean increase = 5.1 mg BID), in 9 the dose was unchanged despite the addition of HU, and only in three cases the ruxolitinib dose had to be reduced (mean reduction = 3.4 mg BID). Overall, the mean daily dose of Ruxo administered to the whole cohort of patients increased by 1.8 mg BID (P=.013), and only one patient had to discontinue Ruxo, due to severe thrombocytopenia. Non-hematological adverse events were not observed. Among the 17 patients who started combination therapy to control WBC count, 14 (82.3%) obtained a WBC response, whereas, among the three patients who started HU in association with Ruxo in order to reduce platelets count, two (66.6%) achieved a platelet response. In addition, 12 patients of the whole study cohort had clinical improvement in MF-associated symptomatic burden, with 9 of them showing spleen and symptoms response and the remaining three only spleen response. Thus, a clinical response of any type was obtained in 8 patients (40%) during Ruxo monotherapy and in 17 patients (85%) during Ruxo-HU combination (P=.003). Of note, all 8 patients in which Ruxo dose was increased during combination had at least one type of drug-related clinical response. Conclusion In conclusion, the combination of HU with Ruxo yielded a high clinical response rate and increased Ruxo exposure in patients with hyperproliferative forms of MF. The association was very well tolerated, and the hematological toxicities mostly and were generally manageable with dose reductions and/or supportive treatment. Disclosures Pane: AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau.
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- 2019
21. Flow Cytometry Assessment of CD26+ Leukemic Stem Cells in Peripheral Blood: A Simple and Rapid New Diagnostic Tool for Chronic Myeloid Leukemia
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Claudia Baratè, Sara Galimberti, Emilio Usala, Anna Sicuranza, Giovanni Caocci, Luigiana Luciano, Monica Bocchia, Elisabetta Abruzzese, Maura Nicolosi, Daniele Cattaneo, Alessandro Gozzetti, Federica Sorà, Donatella Raspadori, Claudio Fozza, Nicola Sgherza, Paola Pacelli, Sabina Russo, Alessandra Iurlo, Mario Annunziata, Antonella Gozzini, Sara Ciofini, M. Liberati, M. M. Trawinska, Patrizia Pregno, and Sabrina Moretti
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0301 basic medicine ,CD26+ ,Myeloid ,Histology ,CD26 + ,chronic myeloid leukemia ,diagnosis ,flow cytometry ,leukemic stem cells ,peripheral blood ,2734 ,Cell Biology ,Dipeptidyl Peptidase 4 ,Population ,CD34 ,CD26 ,+ ,Pathology and Forensic Medicine ,Flow cytometry ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,education ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Myeloid leukemia ,Original Articles ,Haematopoiesis ,Settore MED/15 - MALATTIE DEL SANGUE ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Neoplastic Stem Cells ,Original Article ,Bone marrow ,INGLESE ,business ,Cytometry - Abstract
Background Recent investigations in chronic myeloid leukemia (CML) have focused on the identification and characterization of leukemic stem cells (LSCs). These cells reside within the CD34+ /CD38─ /Lin─ fraction and score positive for CD26 (dipeptidylpeptidase IV) a marker, expressed in both bone marrow (BM) and peripheral blood (PB) samples, that discriminates CML cells from normal hematopoietic stem cells (HSCs) or from LSCs of other myeloid neoplasms. CD26 evaluation could be a useful tool to improve the identification of CML LCSs by using flow-cytometry assay. Methods CD26+ LSCs have been isolated from EDTA PB and BM samples of patients with leucocytosis suspected for CML. Analysis of LSCs CML has been performed by using custom-made lyophilized pre-titrated antibody mixture test and control tube and a CD45+ /CD34+ /CD38- /CD26+ panel as a strict flow cytometric gating strategy. Results The expression of CD26 on CD34+ /CD38- population was detectable in 211/211 PB and 84/84 BM samples of subsequently confirmed BCR-ABL+ CP-CML patients. None of the 32 samples suspicious for CML but scoring negative for circulating CD26+ LSCs were diagnosed as CML after conventional cytogenetic and molecular testing. To validate our results, we checked for PB CD26+ LSCs in patients affected by other hematological disorders and they all scored negative for CD26 expression. Conclusions We propose flow cytometry evaluation of CD26 expression on PB CD34+ /CD38- population as a new rapid, reproducible, and powerful diagnostic tool for the diagnosis of CML. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.
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- 2019
22. Author response for 'Bosutinib in the Real‐Life Treatment of Chronic Myeloid Leukemia Patients Aged > 65 Years Resistant/Intolerant to Previous Tyrosine‐Kinase Inhibitors'
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Giorgina Specchia, Chiara Aguzzi, Massimo Breccia, Endri Mauro, Immacolata Attolico, Giovanni Caocci, Chiara Elena, Debora Luzi, Elena Mariggiò, Roberto Latagliata, Massimiliano Bonifacio, A. Iurlo, Luigi Scaffidi, Nicola Sgherza, Ambra Di Veroli, Daniele Cattaneo, Gianni Binotto, Micaela Bergamaschi, Barbara Monteleone, Mario Annunziata, Federica Sorà, E Abruzzese, I Capodanno, S Galimberti, Monica Crugnola, Claudia Baratè, Antonella Gozzini, Luigiana Luciano, and Malgorzata Monika Trawinska
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business.industry ,Cancer research ,medicine ,Myeloid leukemia ,business ,Tyrosine kinase ,Bosutinib ,medicine.drug - Published
- 2021
23. Eutos long-term survival score discriminates different Sokal score categories in chronic myeloid leukemia patients, showing better survival prediction. Analysis of the {GIMEMA} {CML} observational study
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Giovannino Ciccone, Gaetano La Barba, Giovanni Caocci, Mario Tiribelli, Anna Rita Scortechini, Bruno Martino, Giuseppe Saglio, Massimo Breccia, Antonella Gozzini, Michele Pizzuti, Fausto Castagnetti, Massimiliano Bonifacio, Fabio Stagno, Patrizia Pregno, Luigiana Luciano, Giorgina Specchia, Breccia M., Pregno P., Castagnetti F., Bonifacio M., Tiribelli M., Gozzini A., Scortechini A.R., Luciano L., Martino B., Stagno F., Caocci G., La Barba G., Pizzuti M., Ciccone G., Saglio G., and Specchia G.
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Outcome Assessment ,Prognosi ,Dasatinib ,Severity of Illness Index ,Follow-Up Studie ,Retrospective Studie ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Outcome Assessment, Health Care ,medicine ,Humans ,Prospective Studies ,Chronic ,Prospective cohort study ,Survival rate ,Aged ,Retrospective Studies ,Antineoplastic Combined Chemotherapy Protocol ,Leukemia ,business.industry ,Myeloid leukemia ,Retrospective cohort study ,Hematology ,Middle Aged ,Prognosis ,Survival Rate ,Health Care ,Prospective Studie ,Imatinib mesylate ,Pyrimidines ,Pyrimidine ,Imatinib Mesylate ,Observational study ,Female ,BCR-ABL Positive ,Sokal Score ,business ,medicine.drug ,Human ,Follow-Up Studies ,Myelogenous - Abstract
NA
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- 2021
24. Prognostic Factors for Overall Survival In Chronic Myeloid Leukemia Patients: A Multicentric Cohort Study by the Italian CML GIMEMA Network
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Giovanni Reddiconto, Maria Stella De Candia, Sara Galimberti, Fabrizio Pane, Michele Pizzuti, Luciano Levato, Massimiliano Bonifacio, Massimo Breccia, Anna Rita Scortechini, Elisabetta Abruzzese, Giovanni Caocci, Valentina Giai, Paolo Ditonno, Andrea Patriarca, Federica Sorà, Giuseppe Pietrantuono, Gaetano La Barba, Fabio Stagno, Patrizia Pregno, Antonella Gozzini, Francesco Di Raimondo, Michele Baccarani, Grazia Sanpaolo, Giovannino Ciccone, Micaela Bergamaschi, Gianni Binotto, Alessandro Maggi, Chiara Monagheddu, Giuseppe Saglio, Maria Cristina Miggiano, Monica Bocchia, Pellegrino Musto, Anna Guella, Luigiana Luciano, Giorgina Specchia, Bruno Martino, Francesco Albano, Fabio Saccona, Giovanna Rege-Cambrin, Olga Mulas, Gianantonio Rosti, Carmen Fava, Mario Tiribelli, Fausto Castagnetti, Isabella Capodanno, Specchia G., Pregno P., Breccia M., Castagnetti F., Monagheddu C., Bonifacio M., Tiribelli M., Stagno F., Caocci G., Martino B., Luciano L., Pizzuti M., Gozzini A., Scortechini A.R., Albano F., Bergamaschi M., Capodanno I., Patriarca A., Fava C., Rege-Cambrin G., Sora F., Galimberti S., Bocchia M., Binotto G., Reddiconto G., DiTonno P., Maggi A., Sanpaolo G., De Candia M.S., Giai V., Abruzzese E., Miggiano M.C., La Barba G., Pietrantuono G., Guella A., Levato L., Mulas O., Saccona F., Rosti G., Musto P., Di Raimondo F., Pane F., Baccarani M., Saglio G., and Ciccone G.
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ELT ,chronic myeloid leukemia ,ELTs ,prognostic factors ,Sokal score ,tyrosine kinase inhibitors ,Cancer Research ,medicine.medical_specialty ,Patient characteristics ,Internal medicine ,Overall survival ,Medicine ,Prospective cohort study ,prognostic factor ,RC254-282 ,Original Research ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Myeloid leukemia ,Imatinib ,prognostic factors for overall survival in chronic myeloid leukemia patient a multicentric cohort study ,Settore MED/15 - MALATTIE DEL SANGUE ,Oncology ,Cohort ,business ,Sokal Score ,Cohort study ,medicine.drug - Abstract
An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2nd generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p
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- 2021
25. Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors
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Massimiliano Bonifacio, Chiara Aguzzi, Immacolata Attolico, Sara Galimberti, Debora Luzi, Daniele Cattaneo, Micaela Bergamaschi, Luigi Scaffidi, Elena Mariggiò, Barbara Monteleone, Roberto Latagliata, Chiara Elena, Endri Mauro, Ambra Di Veroli, Massimo Breccia, Elisabetta Abruzzese, Alessandra Iurlo, Malgorzata Monika Trawinska, Monica Crugnola, Nicola Sgherza, Isabella Capodanno, Claudia Baratè, Giovanni Caocci, Gianni Binotto, Federica Sorà, Luigiana Luciano, Giorgina Specchia, Antonella Gozzini, and Mario Annunziata
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Male ,Cancer Research ,medicine.medical_specialty ,real-life clinical experience ,bosutinib ,Gastroenterology ,chronic myeloid leukemia ,elderly people ,Aged ,Aniline Compounds ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Middle Aged ,Nitriles ,Protein Kinase Inhibitors ,Quinolines ,Survival Rate ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Chronic ,Survival rate ,Leukemia ,business.industry ,Myeloid leukemia ,Hematology ,General Medicine ,Discontinuation ,Safety profile ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Cohort ,BCR-ABL Positive ,business ,Bosutinib ,Tyrosine kinase ,030215 immunology ,medicine.drug ,Myelogenous - Abstract
To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.
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- 2021
26. Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib
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Fabio Stagno, Patrizia Pregno, Giovanni Caocci, Gianni Binotto, Robin Foà, Anna Sicuranza, Emilia Scalzulli, Francesca Pirillo, Mario Tiribelli, Isabella Capodanno, Antonella Gozzini, Massimiliano Bonifacio, Rossella Stella, Elisabetta Abruzzese, Massimo Breccia, Claudio Fozza, Gabriele Gugliotta, Giorgio La Nasa, Luigiana Luciano, Olga Mulas, Maria Pina Simula, Daniele Cattaneo, Mario Annunziata, Francesco Albano, Luigi Scaffidi, Fiorenza De Gregorio, Debora Luzi, Claudia Baratè, Malgorzata Monika Trawinska, Immacolata Attolico, Fabio Efficace, Sara Galimberti, Fausto Castagnetti, Monica Bocchia, Bruno Martino, Alessandra Iurlo, Caocci G., Mulas O., Capodanno I., Bonifacio M., Annunziata M., Galimberti S., Luciano L., Tiribelli M., Martino B., Castagnetti F., Binotto G., Pregno P., Stagno F., Abruzzese E., Bocchia M., Gozzini A., Albano F., Fozza C., Luzi D., Efficace F., Simula M.P., Scaffidi L., Barate C., De Gregorio F., Stella R., Gugliotta G., Pirillo F., Trawinska M.M., Sicuranza A., Cattaneo D., Attolico I., Scalzulli E., Iurlo A., Foa R., Breccia M., and La Nasa G.
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Male ,Arterial Occlusive Disease ,Triglyceride ,Gastroenterology ,Antineoplastic Agent ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,80 and over ,Cumulative incidence ,Chronic ,Aged, 80 and over ,Leukemia ,Incidence (epidemiology) ,Chronic myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Lipoproteins, LDL ,Cholesterol ,030220 oncology & carcinogenesis ,Low-density lipoprotein ,Female ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Lipoproteins ,Arterial occlusive event ,Antineoplastic Agents ,Arterial Occlusive Diseases ,Lower risk ,High cholesterol ,LDL ,03 medical and health sciences ,Young Adult ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Triglycerides ,Aged ,Dyslipidemias ,business.industry ,Risk Factor ,Nilotinib ,medicine.disease ,Pyrimidines ,Dyslipidemia ,Pyrimidine ,chemistry ,BCR-ABL Positive ,business ,030215 immunology ,Myelogenous - Abstract
Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200mg/dL and LDL > 70mg/dL 3months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P= 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P< 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P= 0.008; HR = 3.5; 95% CI = 1.4–8.7 and P < 0.001; HR = 4.4; 95% CI = 2–9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins. Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.
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- 2020
27. Author response for 'Favourable outcome of chronic myeloid leukemia co‐expressing e13a2 and e14a2 transcripts, treated with nilotinib'
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Nicola Sgherza, Olga Mulas, Chiara Elena, Bruno Martino, Claudia Baratè, Ester Orlandi, Massimo Breccia, Anna Sicuranza, E Abruzzese, Robin Foà, Emilia Scalzulli, Monica Bocchia, Antonella Gozzini, Massimiliano Bonifacio, Malgorzata Monika Trawinska, S Galimberti, Daniele Cattaneo, Luigiana Luciano, Patrizia Pregno, Giorgio La Nasa, Francesco Albano, Fausto Castagnetti, A. Iurlo, Luigi Scaffidi, Gianni Binotto, Imma Attolico, Claudio Fozza, Mario Annunziata, Fiorenza De Gregorio, Giovanni Caocci, Maria Pina Simula, Gabriele Gugliotta, and Francesca Pirillo
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Oncology ,medicine.medical_specialty ,Nilotinib ,business.industry ,Internal medicine ,Medicine ,Myeloid leukemia ,business ,Outcome (game theory) ,medicine.drug - Published
- 2020
28. Low-dose ponatinib is a good option in chronic myeloid leukemia patients intolerant to previous TKIs
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Anna Rita Scortechini, Elisabetta Abruzzese, Alessandro Maggi, Luigiana Luciano, Emilia Scalzulli, Cristina Bucelli, Bruno Martino, Daniele Cattaneo, Imma Attolico, Patrizia Pregno, Alessandra Malato, Mario Annunziata, Massimo Breccia, Alessandra Iurlo, Antonella Gozzini, Giovanni Caocci, and Vincenzo Accurso
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Myelogenous ,chemistry.chemical_compound ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,Child ,Protein Kinase Inhibitors ,business.industry ,Ponatinib ,Low dose ,Follow up studies ,Imidazoles ,Myeloid leukemia ,Infant ,Hematology ,medicine.disease ,Pyridazines ,Leukemia ,chemistry ,Child, Preschool ,Female ,business ,Follow-Up Studies - Published
- 2020
29. Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors
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Chiara Elena, Alessandra Iurlo, Antonella Gozzini, Giorgio La Nasa, Claudia Baratè, Gabriele Gugliotta, Bruno Martino, Francesca Pirillo, Fiorenza De Gregorio, Fabio Efficace, Monica Bocchia, Massimo Breccia, Claudio Fozza, Elisabetta Abruzzese, Mario Annunziata, Sara Galimberti, Gianni Binotto, Fabio Stagno, Isabella Capodanno, Malgorzata Monika Trawinska, Anna Sicuranza, Maria Pina Simula, Robin Foà, Debora Luzi, Patrizia Pregno, Rossella Stella, Imma Attolico, Luigiana Luciano, Francesco Albano, Giovanni Caocci, Ester Orlandi, Daniele Cattaneo, Olga Mulas, Nicola Sgherza, Luigi Scaffidi, Massimiliano Bonifacio, Emilia Scalzulli, Mario Tiribelli, Fausto Castagnetti, Mulas O., Caocci G., Stagno F., Bonifacio M., Annunziata M., Luciano L., Orlandi E.M., Abruzzese E., Sgherza N., Martino B., Albano F., Galimberti S., Pregno P., Bocchia M., Castagnetti F., Tiribelli M., Binotto G., Gozzini A., Capodanno I., Fozza C., Luzi D., Efficace F., Simula M.P., Scaffidi L., De Gregorio F., Elena C., Trawinska M.M., Cattaneo D., Attolico I., Barate C., Pirillo F., Sicuranza A., Gugliotta G., Stella R., Scalzulli E., Iurlo A., Foa R., Breccia M., and La Nasa G.
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Male ,Myeloid ,Angiotensin-Converting Enzyme Inhibitors ,Gastroenterology ,Cohort Studies ,Renin-Angiotensin System ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,80 and over ,Cumulative incidence ,Chronic ,Aged, 80 and over ,Leukemia ,Arterial occlusive events ,Incidence ,Ponatinib ,Angiotensin Receptor Antagonist ,Chronic myeloid leukemia ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,TKI ,Dasatinib ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Combination ,Hypertension ,Drug Therapy, Combination ,Female ,Survival Analysi ,medicine.drug ,Human ,Renin angiotensin system inhibitors ,Adult ,medicine.medical_specialty ,Arterial occlusive event ,Protein Kinase Inhibitor ,03 medical and health sciences ,Angiotensin Receptor Antagonists ,Drug Therapy ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Artery occlusion ,Protein Kinase Inhibitors ,Aged ,business.industry ,Risk Factor ,Angiotensin-Converting Enzyme Inhibitor ,Thrombosis ,Renin angiotensin system inhibitor ,Survival Analysis ,Blood pressure ,chemistry ,Nilotinib ,BCR-ABL Positive ,Cohort Studie ,business ,030215 immunology ,Myelogenous - Abstract
Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.
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- 2020
30. Favorable outcome of chronic myeloid leukemia co-expressing e13a2 and e14a2 transcripts, treated with nilotinib
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Sara Galimberti, Giovanni Caocci, Ester Orlandi, Mario Annunziata, Gabriele Gugliotta, Emilia Scalzulli, Alessandra Iurlo, Chiara Elena, Elisabetta Abruzzese, Daniele Cattaneo, Bruno Martino, Malgorzata Monika Trawinska, Giorgio La Nasa, Luigi Scaffidi, Francesca Pirillo, Anna Sicuranza, Luigiana Luciano, Fausto Castagnetti, Patrizia Pregno, Monica Bocchia, Nicola Sgherza, Francesco Albano, Robin Foà, Massimo Breccia, Fiorenza De Gregorio, Antonella Gozzini, Massimiliano Bonifacio, Claudia Baratè, Imma Attolico, Maria Pina Simula, Gianni Binotto, Claudio Fozza, Olga Mulas, Mulas O., Caocci G., Annunziata M., Martino B., Luciano L., Castagnetti F., Pregno P., Galimberti S., Albano F., Orlandi E.M., Sgherza N., Iurlo A., Bonifacio M., Binotto G., Gozzini A., Bocchia M., Abruzzese E., Fozza C., Simula M.P., De Gregorio F., Gugliotta G., Pirillo F., Barate C., Attolico I., Elena C., Cattaneo D., Scaffidi L., Sicuranza A., Trawinska M.M., Scalzulli E., Foa R., Breccia M., and La Nasa G.
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Oncology ,Male ,Cancer Research ,Chromosomes, Human, Pair 22 ,bcr-abl ,Messenger ,Fusion Proteins, bcr-abl ,Translocation, Genetic ,80 and over ,Favorable outcome ,RNA, Neoplasm ,Chronic ,Aged, 80 and over ,Leukemia ,Follow up studies ,Myeloid leukemia ,molecular response ,Hematology ,General Medicine ,Middle Aged ,Survival Rate ,outcome ,Female ,Chromosomes, Human, Pair 9 ,medicine.drug ,Human ,Pair 9 ,Adult ,medicine.medical_specialty ,Disease free survival ,transcript type ,MEDLINE ,Translocation ,Disease-Free Survival ,Chromosomes ,Follow-Up Studie ,Text mining ,Genetic ,chronic myeloid leukemia ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,RNA, Messenger ,Survival rate ,nilotinib ,Aged ,Follow-Up Studies ,Pyrimidines ,business.industry ,chronic myeloid leukemia, nilotinib, transcript type, molecular response, outcome ,Fusion Proteins ,Nilotinib ,Pyrimidine ,RNA ,Neoplasm ,BCR-ABL Positive ,Pair 22 ,business ,Myelogenous - Abstract
No abstract available.
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- 2020
31. Low low-density lipoprotein (LDL), cholesterol and triglycerides plasma levels are associated with reduced risk of arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life. A Campus CML study
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Emilia Scalzulli, Fabio Efficace, Giovanni Caocci, Ester Orlandi, Sara Galimberti, Mario Tiribelli, Daniele Cattaneo, Elisabetta Abruzzese, Luigi Scaffidi, Olga Mulas, Immacolata Attolico, Debora Luzi, Massimiliano Bonifacio, Robin Foà, Chiara Elena, Rossella Stella, Fausto Castagnetti, Massimo Breccia, Maria Pina Simula, Claudia Baratè, Luigiana Luciano, Malgorzata Monika Trawinska, Francesco Albano, Fabio Stagno, Patrizia Pregno, Antonella Gozzini, Gianni Binotto, Gabriele Gugliotta, Giorgio La Nasa, Francesca Pirillo, Nicola Sgherza, Mario Annunziata, Alessandra Iurlo, Claudio Fozza, Isabella Capodanno, Fiorenza De Gregorio, Caocci G., Mulas O., Capodanno I., Abruzzese E., Iurlo A., Luciano L., Albano F., Annunziata M., Tiribelli M., Bonifacio M., Galimberti S., Castagnetti F., Sgherza N., Stagno F., Gozzini A., Orlandi E.M., Luzi D., Binotto G., Pregno P., Fozza C., Efficace F., Simula M.P., Trawinska M.M., Cattaneo D., De Gregorio F., Attolico I., Stella R., Scaffidi L., Barate C., Gugliotta G., Scalzulli E., Elena C., Pirillo F., Foa R., Breccia M., and Nasa G.L.
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Adult ,Male ,medicine.medical_specialty ,Antineoplastic Agents ,Arterial Occlusive Diseases ,Gastroenterology ,lcsh:RC254-282 ,chronic myeloid leukemia, TKI, ponatinib, arterial occlusive events ,Article ,chemistry.chemical_compound ,Young Adult ,Myeloproliferative disease ,High-density lipoprotein ,Low low-density lipoprotein, LDL, cholesterol, triglycerides, arterial occlusive events, chronic myeloid leukemia, ponatinib, CML, Campus ,chronic myeloid leukemia ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Medicine ,Humans ,ponatinib ,Artery occlusion ,arterial occlusive events ,Triglycerides ,Aged ,Aged, 80 and over ,business.industry ,Cholesterol ,Ponatinib ,Imidazoles ,Myeloid leukemia ,Hematology ,Middle Aged ,Protective Factors ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,TKI ,Lipoproteins, LDL ,Pyridazines ,Leukemia ,Oncology ,chemistry ,Risk factors ,Low-density lipoprotein ,Female ,business ,Dyslipidemia - Abstract
Not available.
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- 2020
32. Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia
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Simona Sica, Marco Cerrano, Monica Crugnola, Claudia Baratè, Federica Ricci, Nicola Sgherza, Roberto Latagliata, Luigiana Luciano, Sara Galimberti, Monica Bocchia, Camilla Frieri, I Capodanno, Chiara Aguzzi, Emilia Scalzulli, Chiara Elena, Antonella Gozzini, Malgorzata Monika Trawinska, Micaela Bergamaschi, Lara Aprile, Antonia Cagnetta, Federica Sorà, Ida Carmosino, Massimiliano Bonifacio, Laura Cesini, and Massimo Breccia
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Erythrocyte Indices ,Male ,medicine.medical_specialty ,chronic myeloid leukemia ,erythropoietin ,imatinib ,late anemia ,Blood transfusion ,Anemia ,medicine.medical_treatment ,Antineoplastic Agents ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Interquartile range ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,erythropoietin treatment in chronic phase chronic myeloid patients treated with frontline imatinib who developed late anemia ,business.industry ,Myeloid leukemia ,Disease Management ,Retrospective cohort study ,Imatinib ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Settore MED/15 - MALATTIE DEL SANGUE ,Treatment Outcome ,treatment in chronic phase chronic myeloid leukemia ,Erythropoietin ,030220 oncology & carcinogenesis ,Toxicity ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,Disease Susceptibility ,business ,Biomarkers ,030215 immunology ,medicine.drug - Abstract
Background Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. Methods Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. Results Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. Conclusions Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.
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- 2020
33. Predictive Factors for Overall Survival in Chronic Myeloid Leukemia Patients: An Analysis By the Gimema Cml Italian Study
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Maria Cristina Miggiano, Olga Mulas, Fabrizio Pane, Pellegrino Musto, Massimiliano Bonifacio, Robin Foà, Attilio Guarini, Chiara Monagheddu, Giuseppe Pietrantuono, Giovanni Caocci, Gianantonio Rosti, Giuseppe Saglio, Giovanna Rege Cambrin, Valentina Giai, Giovannino Ciccone, Maria Stella De Candia, Fabio Stagno, Gianni Binotto, Patrizia Pregno, Carmen Fava, Giovanni Reddiconto, Luciano Levato, Sara Galimberti, Micaela Bergamaschi, Luigiana Luciano, Giorgina Specchia, Francesco Albano, Alessandro Maggi, Anna Guella, Elisabetta Abruzzese, Fabio Saccona, Bruno Martino, Andrea Patriarca, Fausto Castagnetti, Gaetano La Barba, Michele Baccarani, Antonella Gozzini, Francesco Di Raimondo, Franca Falzetti, Michele Pizzuti, Mario Tiribelli, Monica Bocchia, Isabella Capodanno, Anna Rita Scortechini, Federica Sorà, Grazia Sanpaolo, and Massimo Breccia
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Overall survival ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Introduction Tyrosine kinase inhibitors (TKIs) have dramatically changed the outcome of chronic phase chronic myeloid leukemia patients (CP-CML),improving the long-term outcome; indeed, life expectancy is now very close to that of age matched individuals in the general population. Imatinib (IMA) the first generation TKI, increased the overall survival(OS)by more than 80%. Second-generation TKIs, (2gen TKIs) used in first line dasatinib and nilotinib, induced faster molecular responses, rapidly reducing the disease burden, but did not change the OS of CP-CML newly diagnosed patients. Most of the available data reported were extrapolated from sponsored clinical trials. The aim of this analysis is to detail and analyze the prognostic features influencing the OS in a large Italian CML cohort of patients prospectively enrolled in the GIMEMA CML Italian study. Methods Relevant clinical, demographic, biological and treatment-related information were web-based collected during a multicenter,observational Italian study that enrolled consecutive patients in each disease phase, at 68 Italian hematologic centers belonging to the GIMEMA network from January 2013 to June 2020. We analyzed prognostic factors influencing the OS by Kaplan Meier method and Cox multivariable models. Results A cohort of 1206 patients was prospectively analyzed, 608 of them received frontline IMA and 598 2genTKIs. Median age in the IMA cohort was 69 years (range 58-77) vs 52 years in the 2genTKIs cohort (range 41-63). The male/female ratio was 1.7 in the IMA group and 1.35 in the 2genTKIs cohort. Ninety-eight percent of patients were in CP. Results of molecular analysis of the BCR-ABL transcript at baseline showed: b2a2 in 33.1 % of patients and b3a2 in 59.9%, while an atypical transcript was found in 7%. The cytogenetic analysis at baseline showed major and minor additional aberrations in 5.7% and 1.6% of patients respectively. In the IMA cohort,according to the Sokal score, 27.7%, 57.3% and 15% of patients were stratified as low, intermediate and high risk, whereas according to the ELTS score 51.3%, 35.5% and 13.3%, of patients were classified as low, intermediate and high risk. In the 2genTKIs cohort, according to the Sokal score, 44.8%, 34.5% and 20.8%, were low, intermediate and high risk, respectively, whereas according to the ELTS score, 66.9%, 22% and 11% were assigned to the respective risk groups.The Charlson comorbidity index in the IMA cohort was 2-3 and 4-5 in 74% and 26% of patients respectively; in the 2genTKIs cohort the score was 2-3 in 89% and 4-5 only in 10% of patients. Overall, median follow-up of the whole population was 24.7 months (range 13.3-39.3).Seventy-three patients (6.1%) in the overall population died, the majority of them in the IMA cohort: 56 patients (9.2%), at median age of 80.5 years,11/608 (1.8%) due to CML-related causes. Conversely,in the 2genTKIs cohort only 17 patients (2.8%) died, at a median age of 62 years, 10/598 (1.7%) for CML-related causes. Estimated 60-months OS of the overall population was 86.4% (95% CI 81.3-90.2): 75.8% (95% CI 64.5-84) in the IMA cohort and 93.8% (95% CI 87.5-97) in the 2genTKIs group (p Conclusions In this first analysis of our study different clinical behaviors were observed among Italian hematologists, who prevalently prescribed IMA to older patients,with more comorbidities, as compared to 2genTKIs.These differences explain a better OS for patients treated with 2genTKIs vs IMA, however, the risk of death for CML related causes is quite similar between the two groups, all the differences being attributable to other causes of death.Prognostic baseline features associated to an increased OS confirmed that, in addition to age, the ELTS score and the comorbidities are the main clinical factors that independently influence the long-term OS Disclosures Pregno: Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levato:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Di Raimondo:GILEAD, Incyte: Research Funding; Amgen, Takeda, Novartis: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Pane:Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Foà:Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Roche: Research Funding; Novartis: Research Funding; Ariad: Research Funding.
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- 2020
34. Choice of Frontline Tyrosine-Kinase Inhibitor in Very Elderly Patients with Chronic Myeloid Leukemia: A 'Campus CML' Study
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Sabina Russo, Paolo Sportoletti, Massimo Breccia, Jolanda Donatella Vincelli, Ambra Di Veroli, Mario Tiribelli, Rikard Mullai, Giuseppina Loglisci, Pamela Murgano, Anna Rita Scortechini, Debora Luzi, Monica Bocchia, Sabrina Leonetti Crescenzi, Cristina Bucelli, Fabio Stagno, Alessandro Maggi, Federica Sorà, Mario Annunziata, Massimiliano Bonifacio, Elisabetta Abruzzese, Alessandra Malato, Isabella Capodanno, Annapaola Leporace, Giovanni Caocci, Roberto Latagliata, Giuseppe Saglio, Imma Attolico, Francesco Cavazzini, Luigiana Luciano, Giorgina Specchia, Elena Crisà, Gianni Binotto, Rosaria Sancetta, Chiara Elena, Carmen Fava, Alessandra Iurlo, Maria Cristina Miggiano, Gioia Colafigli, Monica Crugnola, and Davide Rapezzi
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business.industry ,medicine.drug_class ,Immunology ,Cancer research ,Medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry ,Tyrosine-kinase inhibitor - Abstract
Introduction Treatment of chronic phase (CP) chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) proved to be almost equally effective in young and elderly patients. Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based on a combined evaluation of patient's characteristics and expectations, with age usually playing a prominent role. However, to date, few data are available on patterns of TKI selection in very elderly patients. Aim To analyse the use of frontline TKI therapy in a large and unselected cohort of very elderly CP-CML patients Methods We retrospectively evaluated 332 patients aged ≥75 year diagnosed from 1/2012 to 12/2019 at 36 Hematology Centres participating at the "Campus CML" project. Results Clinical features at diagnosis for the whole cohort and according to frontline TKI are reported in Table 1. As to frontline TKI, 285 patients (85.8%) received IM and 47 (14.2%) a 2G-TKI (DAS n=28, 59.5%; NIL n=19, 40.5%). Of the 285 IM-treated patients, 192 (67.3%) started with standard dose (400 mg/day) and 93 (32.7%) with a reduced dose (300 mg/day n=64, 22.5%; Following widespread introduction of generic IM in Italy in early 2018, patients were divided in 2 groups: among 238 patients diagnosed from 2012 to 2017, 198 (83.1%) received IM and 40 (16.9%) a 2G-TKI, while patients diagnosed in 2018-2019 were treated with IM in 87/94 (92.5%) cases and with a 2G-TKI in 7 (7.5%) cases only (p=0.028). Conclusions IM remains the frontline drug of choice in very elderly CML patients, and this trend seems to increase after the introduction of the generic formulation. However, 2G-TKI are used in a small but sizeable group of patients, without a clear correlation with baseline CML features, thus probably reflecting a physician's evaluation of patient's fitness and/or expectation. Efficacy and safety of initial reduced TKIs doses in the setting of very elderly patients warrant further analyses. Figure 1 Figure 1. Disclosures Latagliata: Novartis: Honoraria; BMS Cellgene: Honoraria; Pfizer: Honoraria. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Iurlo: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Abruzzese: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.
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- 2021
35. Pro-Inflammatory and Pro-Oxidative Changes during Nilotinib Treatment in CML Patients: Results of a Prospective Multicenter Front-Line TKIs Study (KIARO Study)
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Monica Bocchia, Anna Sicuranza, Elisabetta Abruzzese, Antonella Russo Rossi, Daniele Cattaneo, Emanuele Cencini, Corrado Zuanelli Brambilla, Cristina Marzano, Carmen Fava, Fabio Stagno, Luca Puccetti, Olga Mulas, Ilaria Ferrigno, Sara Galimberti, Antonella Gozzini, Nicola Sgherza, Alessandro Gozzetti, Luigiana Luciano, and Alessandra Iurlo
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Front line ,Cell Biology ,Hematology ,Oxidative phosphorylation ,Biochemistry ,Nilotinib ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
Background: Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, during treatment with nilotinib, a higher than expected incidence of arterial occlusive events (AOEs) was observed. We retrospectively showed an "inflammatory status" during nilotinib treatment that may explain this increased incidence of AOEs. Here, we report results of a prospective multicenter (KIARO) study including 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib) in which pro/anti-inflammatory cytokines were measured at diagnosis and during treatment, with the aim to investigate potential changes in each patient's inflammatory status possibly favoring AOEs. Aims: The aims of this study are: 1) to analyze prospectively inflammation status during TKI treatment; 2) to record AOEs; 3) to calculate the SCORE and evaluate its predictive role for AOEs; 4) to analyze possible associations of AOEs with altered inflammation status. Methods: Inflammatory status was evaluated by measuring IL6, IL10, TNFα, oxLDL and hs-CRP plasma levels at diagnosis and during treatment (+1, +3, +6, +12 months); additionally, clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. Results: 186 newly-diagnosed CML patients starting either imatinib, nilotinib or dasatinib treatment, entered this study. Regarding the inflammation status, we observed that TNFα and IL6 levels were high at diagnosis and decreased during the first 12 months of treatment regardless the type of TKI; instead, IL10 levels were comparable among the 3 TKI cohorts at baseline, but showed a remarkably different evolution during treatment. In fact, IL10 levels were significantly higher after 6 and 12 months of imatinib (p=0.012 and p=0.009, respectively) and dasatinib (p=0.032 and p=0.014, respectively) compared to nilotinib. Consequently, TNFα/IL10 ratio was significantly higher in nilotinib cohort at 6 and 12 months respect to imatinib (p=0.044 at 6 months and p=0.041 at 12 months) and dasatinib (p=0.040 at 6 months and p=0.044 at 12 months). As well, IL6/IL10 ratio was significantly higher in nilotinib cohort compared to imatinib and dasatinib both at 6 (p=0.042 and p=0.049, respectively) and 12 months (p=0.040 and p=0.041, respectively) (Figure 1). OxLDL levels were similar in the 3 groups for the first 6 months. At 12 months we detected a significant increase of oxLDL levels in the nilotinib cohort (p=0.041), respect to imatinib and dasatinib. We did not find significant differences in hs-CRP levels across the 3 TKIs, although a trend for higher levels was observed in nilotinib cohort. Overall, these results suggest a TKI-driven pro-inflammatory status in nilotinib treated patients. After a median follow-up of 23.3 months of TKI treatment, 10 patients (5.4%) suffered an AOE, specifically: 6 ACS, 2 PAOD, 1 TIA and 1 stroke. 5 events (50%) occurred in patients treated with nilotinib, either in first line (4 patients) or in third line (1 patient, after failure following brief treatment with imatinib and dasatinib). In this subgroup of 10 patients experiencing an AOE, we observed a trend of increased IL6 and TNFα median values both at diagnosis and at each time point, compared with the remaining no-AOE patients. IL10 and oxLDL had similar median concentrations in both AOE and no-AOE cohorts, except for oxLDL at 12 months which resulted higher in patients who experienced AOEs. Moreover, regarding AOEs, nilotinib treatment showed a 3.1 times increased risk compared to other TKIs (HR 3.1, 95% CI 2.6-4.4 p< 0.001), whereas 10-year SCORE was not predictive in the whole cohort (HR 0.6, 95% CI 0.33-0.94 p= 0.094) or in any subgroup (imatinib HR 0.8, 95% CI 0.49-1.03 p= 0.067; nilotinib HR 0.4, 95% CI 0.29-0.76 p= 0.112, dasatinib HR 0.6, 95% CI 0.37-0.92 p= 0.082). Conclusions: Our results showed a pro-inflammatory/oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher IL6/IL10 and TNFα/IL10 ratios, higher levels of oxLDL and a trend for higher hs-CRP only in nilotinib cohort. However, due to the low number of observed events, a formal statistical analysis for any association between AOEs and pro/anti-inflammatory cytokines levels was not possible. Therefore, a longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis. Figure 1 Figure 1. Disclosures Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding.
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- 2021
36. Analysis of Early Events during the First Year of Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase - Chronic Myeloid Leukemia: A 'Campus CML' Study
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Sabrina Leonetti Crescenzi, Elena Crisà, Isabella Capodanno, Carmen Fava, Immacolata Attolico, Gianni Binotto, Debora Luzi, Maria Cristina Miggiano, Andrea Bernardelli, Massimiliano Bonifacio, Maria Basile, Giuseppina Loglisci, Chiara Elena, Fabio Stagno, Anna Rita Scortechini, Olga Mulas, Cristina Bucelli, Roberto Latagliata, Alessandra Malato, Francesco Cavazzini, Giovanni Caocci, Luigiana Luciano, Giuseppe Saglio, Ambra Di Veroli, Paolo Sportoletti, Giorgina Specchia, Monica Bocchia, Umberto Pizzano, Massimo Breccia, Michele Pizzuti, Annapaola Leporace, Emilia Scalzulli, Malgorzata Monika Trawinska, Mario Tiribelli, Sabina Russo, Pamela Murgano, Monica Crugnola, Davide Rapezzi, and Alessandra Iurlo
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business.industry ,medicine.drug_class ,Immunology ,Cancer research ,Medicine ,In patient ,Cell Biology ,Hematology ,Chronic phase chronic myeloid leukemia ,business ,Biochemistry ,Tyrosine-kinase inhibitor - Abstract
Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year. Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations. Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively. Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. Figure 1 Figure 1. Disclosures Elena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.
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- 2021
37. Droplet Digital PCR for BCR–ABL1 Monitoring in Diagnostic Routine: Ready to Start?
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Maria Teresa Bochicchio, Emanuela Ottaviani, Claudia Venturi, Emilia Giugliano, Fabrizio Pane, Luigiana Luciano, Paola Berchialla, Barbara Izzo, Daniela Cilloni, Giovanni Martinelli, Giuseppe Saglio, Giovanna Rege-Cambrin, Santa Errichiello, Jessica Petiti, Gianantonio Rosti, Carmen Fava, Daniele Calistri, Enrico Gottardi, Filomena Daraio, Bochicchio, M. T., Petiti, J., Berchialla, P., Izzo, B., Giugliano, E., Ottaviani, E., Errichiello, S., Rege-Cambrin, G., Venturi, C., Luciano, L., Daraio, F., Calistri, D., Rosti, G., Saglio, G., Martinelli, G., Pane, F., Cilloni, D., Gottardi, E. M., and Fava, C.
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BCR–ABL1 ,Oncology ,treatment-free remission ,Cancer Research ,medicine.medical_specialty ,business.industry ,ddPCR ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Myeloid leukemia ,Minimal residual disease ,Article ,deep molecular response ,Clinical Practice ,Bcr abl1 ,Real-time polymerase chain reaction ,Mrna level ,chronic myeloid leukemia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Digital polymerase chain reaction ,business ,RC254-282 - Abstract
Simple Summary The introduction to clinical practice of a treatment-free remission approach in chronic myeloid leukemia patients with a stable deep molecular response highlighted how crucial it is to monitor the molecular levels of BCR–ABL1 as accurately and precisely as possible. In this context, the droplet digital PCR (ddPCR) presents an alternative methodology for such quantification. To hypothesize the introduction of this technology in routine practice, we performed a multicentric study that compares ddPCR with the standard methodology currently used. Our results demonstrate that the use of ddPCR in clinical practice is feasible and could be beneficial. Abstract BCR–ABL1 mRNA levels represent the key molecular marker for the evaluation of minimal residual disease (MRD) in chronic myeloid leukemia (CML) patients and real-time quantitative PCR (RT-qPCR) is currently the standard method to monitor it. In the era of tyrosine kinase inhibitors (TKIs) discontinuation, droplet digital PCR (ddPCR) has emerged to provide a more precise detection of MRD. To hypothesize the use of ddPCR in clinical practice, we designed a multicentric study to evaluate the potential value of ddPCR in the diagnostic routine. Thirty-seven RNA samples from CML patients and five from healthy donors were analyzed using both ddPCR QXDxTM BCR-ABL %IS Kit and LabNet-approved RT-qPCR methodologies in three different Italian laboratories. Our results show that ddPCR has a good agreement with RT-qPCR, but it is more precise to quantify BCR–ABL1 transcript levels. Furthermore, we did not find differences between duplicate or quadruplicate analysis in terms of BCR–ABL1% IS values. Droplet digital PCR could be confidently introduced into the diagnostic routine as a complement to the RT-qPCR.
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- 2021
38. Low Cholesterol, Low-Density Lipoprotein (LDL) and Triglycerides Plasma Levels Are Associated with Lower Risk of Arterial Occlusive Events in Chronic Myeloid Leukemia Patients Treated with Nilotinib
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Giovanni Caocci, Francesca Pirillo, Massimo Breccia, Emilia Scalzulli, Gabriele Gugliotta, Fabio Stagno, Chiara Elena, Mario Tiribelli, Patrizia Pregno, Alessandra Iurlo, Robin Foà, Bruno Martino, Claudia Baratè, Debora Luzi, Claudio Fozza, Anna Sicuranza, Daniele Cattaneo, Fiorenza De Gregorio, Gianni Binotto, Monica Bocchia, Luigi Scaffidi, Isabella Capodanno, Sara Galimberti, Massimiliano Bonifacio, Olga Mulas, Fausto Castagnetti, Maria Pina Simula, Malgorzata Monika Trawinska, Imma Attolico, Elisabetta Abruzzese, Rossella Stella, Luigiana Luciano, Francesco Albano, Antonella Gozzini, Mario Annunziata, and Giorgio La Nasa
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Lower risk ,medicine.disease ,Biochemistry ,Nilotinib ,Internal medicine ,medicine ,Rosuvastatin ,Cumulative incidence ,Risk factor ,Lipid modification ,Sokal Score ,business ,Dyslipidemia ,medicine.drug - Abstract
Introduction. New guidelines for the management of dyslipidemia and lipid modification in order to reduce the risk of cardiovascular (CV) events have been recently published by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). New recommendations regarding the target value of plasma lipids in very high and high CV risk patients have been provided, in addition to an estimate of the CV risk with a new Systematic Coronary Risk Evaluation (SCORE) chart. Few data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib, and the association with arterial occlusive events (AOEs). We therefore analyzed a large real-life cohort of Italian patients with CML treated with nilotinib outside of clinical trials and evaluated the association between AOEs and plasma lipoproteins levels; moreover, we estimated the prognostic value of the new SCORE chart to predict AOEs. The secondary endpoint was to report the management of dyslipidemia in the clinical practice. Methods. We identified 233 adult patients with CML who were treated in 20 Italian centers with nilotinib. All patients were stratified into low to moderate (SCORE ≤ 5%) or high to very high (SCORE risk >5%) CV risk, according to the new version of the SCORE 2019. We recorded concentration levels of cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL) and triglycerides at diagnosis of CML, before starting ponatinib and therefore after 3, 6 and 12 months of treatment. All AOEs (cerebrovascular, peripheral vascular and CV events excluding hypertension) were considered. Results. The median age was 50 years (range 20-88) and the Sokal score was intermediate-high in 45.5% of patients. The median follow-up was 5 years (range 3.4-10.5). Nilotinib was administered as first line of therapy in (72%) of cases or second or subsequent lines of treatment for inefficacy (20.9%) or intolerance (7.1%). At baseline, nilotinib was administered at the following doses: 800 mg/day in 9.3% of patients, 600 mg/day in 87% of patients, 400 mg/day in 3.1% of patients and 300mg in 0.6% of patients, respectively. The median time of drug exposure was 60 months (range 2-155). The 48-month cumulative incidence rate of AOEs was 14.1±2.7%. Patients with cholesterol plasma levels > 200 mg/dL and LDL >70 mg/dL at baseline and 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (24.5±7.3% vs 11±2.7%, P=0.02 and 22.3±4.9% vs 5.9±2.6, P=0.003, respectively) Figure 1. Patients with triglycerides levels > 200 mg/dL 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (56±20.5% vs 13.3±2.7%, P=0.011) Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (32.8.1±9% vs. 9±1%±2.6%, p=0.001). In multivariate analysis, statistical significance of cholesterol plasma levels > 200 mg/dL and LDL >70 mg/dL after 3 months and high-very-high SCORE was maintained (P=0.018, HR=3.4, 95% CI=1.2-9.4 and P=0.004, HR=3.5, 95% CI=1.5-8.2, respectively). Overall, 46 patients (20.5%) presented dyslipidemia at CML diagnosis and 65 (29%) at the start of treatment with nilotinib. Despite dyslipidemia, only 6 patients were taking statins during the treatment with nilotinib and only 5 started it after 3 months of nilotinib: 3 patients were treated with rosuvastatin and 2 with pravastatin. Conclusions. Our findings suggest that a proper control of dyslipidemia, keeping cholesterol and triglycerides plasma levels ≤ 200 mg/dL and LDL ≤70 mg/dL is associated with reduced risk of AOEs in CML patients treated with nilotinib. An under estimation of the clinical importance of elevated plasma lipids as a risk factor for AOEs events represents a possible issue in the real-life. Figure 1 Disclosures Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galimberti:Incyte: Honoraria; Novartis: Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Gugliotta:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.
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- 2020
39. Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors
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Gabriele Gugliotta, Francesca Pirillo, Bruno Martino, Fausto Castagnetti, Chiara Elena, Antonella Gozzini, Giorgio La Nasa, Massimiliano Bonifacio, Claudia Baratè, Gianni Binotto, Robin Foà, Daniele Cattaneo, Nicola Sgherza, Alessandra Iurlo, Monica Bocchia, Elisabetta Abruzzese, Mario Annunziata, Claudio Fozza, Fiorenza De Gregorio, Matteo Molica, Luigi Scaffidi, Sara Galimberti, Olga Mulas, Giovanni Caocci, Imma Attolico, Ester Orlandi, Maria Pina Simula, Luigiana Luciano, Massimo Breccia, Francesco Albano, Fabio Stagno, Patrizia Pregno, Anna Sicuranza, Malgorzata Monika Trawinska, Caocci G., Mulas O., Annunziata M., Luciano L., Abruzzese E., Bonifacio M., Orlandi E.M., Albano F., Galimberti S., Iurlo A., Pregno P., Sgherza N., Martino B., Binotto G., Castagnetti F., Gozzini A., Bocchia M., Fozza C., Stagno F., Simula M.P., De Gregorio F., Trawinska M.M., Scaffidi L., Elena C., Attolico I., Barate C., Cattaneo D., Pirillo F., Gugliotta G., Sicuranza A., Molica M., La Nasa G., Foa R., and Breccia M.
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Male ,Chronic myeloid leuk ,Dasatinib ,emia ,Long Term Adverse Effects ,Long Term Adverse Effect ,030204 cardiovascular system & hematology ,Antineoplastic Agent ,chemistry.chemical_compound ,0302 clinical medicine ,Cardiovascular Disease ,Cardiovascular toxicity ,Ischemic heart disease ,TKI ,Aged ,Antineoplastic Agents ,Female ,Humans ,Italy ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Life Expectancy ,Mortality ,Protein Kinase Inhibitors ,Risk Adjustment ,Aniline Compounds ,Cardiotoxicity ,Cardiovascular Diseases ,Imidazoles ,Nitriles ,Pyridazines ,Pyrimidines ,Quinolines ,030212 general & internal medicine ,Chronic ,education.field_of_study ,Leukemia ,Mortality rate ,Ponatinib ,Aniline Compound ,a ,Pyridazine ,Cardiology and Cardiovascular Medicine ,Nitrile ,Bosutinib ,Human ,medicine.drug ,medicine.medical_specialty ,Population ,Protein Kinase Inhibitor ,03 medical and health sciences ,Internal medicine ,medicine ,education ,Imidazole ,Survival rate ,business.industry ,Standardized mortality ratio ,Pyrimidine ,Nilotinib ,chemistry ,BCR-ABL Positive ,business ,Myelogenous - Abstract
Background Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) in the real-life practice. Methods We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib. Results The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control. Conclusion. Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.
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- 2019
40. Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention
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Claudio Fozza, Giovanni Caocci, Ester Orlandi, Massimiliano Bonifacio, Chiara Elena, Bruno Martino, Daniele Cattaneo, Mario Annunziata, Luigi Scaffidi, Antonella Gozzini, Sara Galimberti, Olga Mulas, Fabio Stagno, Gianni Binotto, Patrizia Pregno, Giorgio La Nasa, Robin Foà, Fausto Castagnetti, Alessandra Iurlo, Malgorzata Monika Trawinska, Massimo Breccia, Emilia Scalzulli, Luigiana Luciano, Francesco Albano, Claudia Baratè, Elisabetta Abruzzese, Caocci G., Mulas O., Bonifacio M., Abruzzese E., Galimberti S., Orlandi E.M., Iurlo A., Annunziata M., Luciano L., Castagnetti F., Gozzini A., Stagno F., Binotto G., Pregno P., Albano F., Martino B., Fozza C., Scaffidi L., Trawinska M.M., Barate C., Elena C., Cattaneo D., Scalzulli E., La Nasa G., Foa R., and Breccia M.
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Oncology ,Male ,Time Factors ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,0302 clinical medicine ,Recurrent arterial occlusive event ,Recurrence ,Risk Factors ,80 and over ,Secondary Prevention ,Medicine ,Cumulative incidence ,030212 general & internal medicine ,Chronic ,Aged, 80 and over ,Chronic myeloid leukemia ,Secondary prophylaxis ,Leukemia ,Incidence (epidemiology) ,Incidence ,Ponatinib ,Myeloid leukemia ,Middle Aged ,Aged ,Anticoagulants ,Arterial Occlusive Diseases ,Female ,Follow-Up Studies ,Humans ,Italy ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Platelet Aggregation Inhibitors ,Protein Kinase Inhibitors ,Treatment Outcome ,Dasatinib ,Platelet aggregation inhibitor ,Cardiology and Cardiovascular Medicine ,Bosutinib ,medicine.drug ,medicine.medical_specialty ,03 medical and health sciences ,Internal medicine ,business.industry ,chemistry ,Nilotinib ,BCR-ABL Positive ,business ,Myelogenous - Abstract
Background Risk of death is particularly high in patients with a previous history of arterial occlusive events (AOEs) and the probability for a recurrent event is around 20%. Little is known about recurrent AOE and the role of secondary prevention in patients with Chronic Myeloid Leukemia (CML) with previous AOE, treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs), nilotinib, dasatinib, bosutinib and ponatinib. Methods We identified a real-life cohort of 57 consecutive adult CML patients treated with 2ndG/3rdG TKI. All patients had a previous history of AOE. Ongoing use of secondary prevention of AOE (including antiplatelet agents, anticoagulant therapy, and statins) before starting a 2ndG/3rdG TKI was recorded, as well as CV risk factors. Results The 60-month cumulative incidence rate of recurrent AOEs was 47.8 ± 10.9%. Despite a history of AOE, 10 patients (16%) were not receiving secondary preventative measures. Patients treated with nilotinib and ponatinib showed a higher incidence of recurrent AOEs (76.7 ± 14.3% and 64 ± 20.1%, respectively) than those treated with dasatinib and bosutinib (44 ± 24.2% and 30.5 ± 15.5%, respectively) (p = 0.01). Only treatment with a 2ndG/3rdG TKI given as second or subsequent line therapy showed a significant association with an increased incidence of recurrent AOE (p = 0.039). Overall, 17 recurrent AOEs were observed; 3 CV-related deaths were reported. Conclusion CML patients with a previous history of AOE treated with 2ndG/3rdG TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE; individualized treatment is needed to optimize secondary prevention.
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- 2019
41. Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline
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Fabio Stagno, Patrizia Pregno, Alessandra Iurlo, Nicola Orofino, Gianfranco Giglio, Cristina Bucelli, Giovanna Mansueto, Massimiliano Bonifacio, Francesca Celesti, Elisabetta Abruzzese, Ester Orlandi, Antonella Russo-Rossi, Luigiana Luciano, Adam D'Addosio, Sara Galimberti, Dario Ferrero, Elena Crisà, Monica Crugnola, Gabriele Gugliotta, Enrico Montefusco, Gianantonio Rosti, Giovanna Rege Cambrin, Sergio Storti, Roberto Latagliata, Francesco Cavazzini, Fausto Castagnetti, Michele Cedrone, Mario Tiribelli, Endri Mauro, Antonella Gozzini, Gianni Binotto, Carmen Fava, Franca Falzetti, Mario Annunziata, Elisabetta Calistri, Romano Atelda, Federica Sorà, Nicola Sgherza, Isabella Capodanno, Sabina Russo, Malgorzata Monika Trawinska, Monica Bocchia, Massimo Breccia, Alessandro Isidori, Crugnola M., Castagnetti F., Breccia M., Ferrero D., Trawinska M.M., Abruzzese E., Annunziata M., Stagno F., Tiribelli M., Binotto G., Bonifacio M., Fava C., Iurlo A., Bucelli C., Mansueto G., Gozzini A., Falzetti F., Montefusco E., Crisa E., Gugliotta G., Russo S., Cedrone M., RussoRossi A., Pregno P., Isidori A., Mauro E., Atelda R., Giglio G., Celesti F., Sora F., Storti S., D'Addosio A., Galimberti S., Orlandi E., Calistri E., Bocchia M., Cavazzini F., Rege Cambrin G., Orofino N., Luciano L., Sgherza N., Rosti G., Latagliata R., and Capodanno I.
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Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Socio-culturale ,Tyrosine kinase inhibitor ,Blastic Phase ,Tyrosine-kinase inhibitor ,Chronic myeloid leukaemia, Elderly, Outcome, Tyrosine kinase inhibitor ,Chronic myeloid leukaemia ,Elderly ,Outcome ,Disease-Free Survival ,Follow-Up Studie ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,80 and over ,medicine ,Humans ,Chronic ,Survival rate ,Aged ,Aged, 80 and over ,Leukemia ,Hematology ,Settore MED/06 - ONCOLOGIA MEDICA ,business.industry ,Incidence (epidemiology) ,Imatinib ,General Medicine ,Survival Rate ,Female ,Follow-Up Studies ,Imatinib Mesylate ,030220 oncology & carcinogenesis ,Concomitant ,Toxicity ,BCR-ABL Positive ,business ,Myelogenous ,030215 immunology ,medicine.drug ,Human - Abstract
Very elderly (> 75years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians’ judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3–4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤80years and > 80years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80years and > 80years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.
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- 2019
42. Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper
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Sara Galimberti, Fabio Stagno, Patrizia Pregno, Monica Bocchia, Mario Tiribelli, Elisabetta Abruzzese, Giuseppe Saglio, Luigiana Luciano, Alessandra Iurlo, Gianantonio Rosti, Giovanni Barosi, Massimiliano Bonifacio, Massimo Breccia, Antonella Gozzini, Simona Soverini, Paolo Vigneri, Soverini S., Abruzzese E., Bocchia M., Bonifacio M., Galimberti S., Gozzini A., Iurlo A., Luciano L., Pregno P., Rosti G., Saglio G., Stagno F., Tiribelli M., Vigneri P., Barosi G., and Breccia M.
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Cancer Research ,medicine.medical_specialty ,Sanger sequencing ,DNA Mutational Analysis ,Fusion Proteins, bcr-abl ,Computational biology ,Review ,lcsh:RC254-282 ,DNA sequencing ,symbols.namesake ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Medicine ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,Hematology ,business.industry ,lcsh:RC633-647.5 ,Patient Selection ,Chronic myeloid leukemia ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,BCR-ABL1 mutation ,lcsh:Diseases of the blood and blood-forming organs ,Protein-Tyrosine Kinases ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,Protein kinase domain ,Mutation (genetic algorithm) ,Mutation ,symbols ,Mutation testing ,Next-generation sequencing ,Position paper ,business - Abstract
BCR-ABL1 kinase domain (KD) mutation status is considered to be an important element of clinical decision algorithms for chronic myeloid leukemia (CML) patients who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs). Conventional Sanger sequencing is the method currently recommended to test BCR-ABL1 KD mutations. However, Sanger sequencing has limited sensitivity and cannot always discriminate between polyclonal and compound mutations. The use of next-generation sequencing (NGS) is increasingly widespread in diagnostic laboratories and represents an attractive alternative. Currently available data on the clinical impact of NGS-based mutational testing in CML patients do not allow recommendations with a high grade of evidence to be prepared. This article reports the results of a group discussion among an ad hoc expert panel with the objective of producing recommendations on the appropriateness of clinical decisions about the indication for NGS, the performance characteristics of NGS platforms, and the therapeutic changes that could be applied based on the use of NGS in CML. Overall, these recommendations might be employed to inform clinicians about the practical use of NGS in CML.
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- 2019
43. Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart
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Giovanni Caocci, Massimo Breccia, Ester Orlandi, Antonella Gozzini, Robin Foà, Luigiana Luciano, Nicola Sgherza, Francesco Albano, Sara Galimberti, Massimiliano Bonifacio, Elisabetta Abruzzese, Gabriele Gugliotta, Olga Mulas, Daniele Cattaneo, Gianni Binotto, Chiara Elena, Luigi Scaffidi, Claudia Baratè, Fabio Stagno, Patrizia Pregno, Immacolata Attolico, Fiorenza De Gregorio, Emilia Scalzulli, Fausto Castagnetti, Mario Annunziata, Giorgio La Nasa, Alessandra Iurlo, Francesca Pirillo, Malgorzata Monika Trawinska, Claudio Fozza, Caocci G., Mulas O., Abruzzese E., Luciano L., Iurlo A., Attolico I., Castagnetti F., Galimberti S., Sgherza N., Bonifacio M., Annunziata M., Gozzini A., Orlandi E.M., Stagno F., Binotto G., Pregno P., Fozza C., Trawinska M.M., De Gregorio F., Cattaneo D., Albano F., Gugliotta G., Barate C., Scaffidi L., Elena C., Pirillo F., Scalzulli E., La Nasa G., Foa R., and Breccia M.
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Male ,Cancer Research ,Decision Support Systems ,Medical Oncology ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Retrospective Studie ,Original Research Articles ,Epidemiology ,80 and over ,Medicine ,Cumulative incidence ,ponatinib ,Original Research Article ,arterial occlusive event ,Chronic ,Aged, 80 and over ,Aspirin ,Leukemia ,Incidence (epidemiology) ,Incidence ,Ponatinib ,Imidazoles ,Hematology ,General Medicine ,Middle Aged ,Pyridazines ,Treatment Outcome ,Oncology ,Italy ,030220 oncology & carcinogenesis ,Hypertension ,Female ,prophylaxis ,Pyridazine ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,Chronic myeloid leukemia ,Cardiology ,03 medical and health sciences ,Clinical ,Young Adult ,chronic myeloid leukemia ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Risk factor ,Imidazole ,Retrospective Studies ,Aged ,business.industry ,prophylaxi ,Risk Factor ,Coronary Occlusion ,Decision Support Systems, Clinical ,Retrospective cohort study ,Blood pressure ,chemistry ,BCR-ABL Positive ,business ,030215 immunology ,Myelogenous - Abstract
Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28months (range, 3-69months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P 
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- 2019
44. Preliminary Results of CML1214, a Survey on Ponatinib Compassionate Use in Italy By the Gimema CML Working Party
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Giovanni Reddiconto, Carmen Fava, Sara Galimberti, Carlo Gambacorti-Passerini, Monia Lunghi, Giovanni D'Arena, Chiara Elena, Luigiana Luciano, Giorgina Specchia, Paola Boggione, Alessandra Iurlo, Micaela Bergamaschi, Patrizia Pregno, Giuseppe Saglio, Francesca Paoloni, Ester Pungolino, Matteo Dragani, Antonella Gozzini, Franca Falzetti, Elisabetta Abruzzese, Enrico Crea, Claudio Fozza, and Giovanna Rege Cambrin
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Brachial Plexus Neuritis ,Cardiotoxicity ,Pediatrics ,medicine.medical_specialty ,Measles-Mumps-Rubella Vaccine ,business.industry ,medicine.medical_treatment ,Immunology ,Ponatinib ,Compassionate Use ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease ,Biochemistry ,Transplantation ,chemistry.chemical_compound ,chemistry ,medicine ,business - Abstract
Background: Since its introduction ponatinib has proved great efficacy among patients (pts) with chronic myeloid leukemia (CML), representing in some settings like the T315I mutation the only therapeutical choice due to its unique conformation. Its use both in the cohort of heavily pretreated CML and frontline has led to promising results in terms of overall survival (OS) and progression free survival (PFS), as demonstrated in the PACE study (Cortes JE, Blood 2018) and in the single center experience of the MD Anderson (Jain P, Lancet Haematol 2015). The cardiovascular toxicity associated with treatment has been addressed both in protocols and real-life experiences: it is clear that the benefits of ponatinib in terms of molecular response have to be balanced with the possibility of adverse events such as arterial and venous thromboembolism, dyslipidemia and hypertension which have to be managed and, whenever possible, prevented (Dorer JD, Leuk Res 2016; Caocci G, Int J Cardiol 2019). Before the final registration of the drug by AIFA, ponatinib has been available in Italy since October 2011 to March 2015 in compassionate regimen: the results collected here represent a real-life experience on ponatinib use in a cohort of Italian patients mostly heavily pre-treated. Methods: Italian chronic-phase (CP) CML pts treated with ponatinib in compassionate regimen since October 2011 were collected in the GIMEMA retrospective multicenter protocol CML1214 (clinicaltrials.gov NCT02448095). Primary objective of the study was the assessment of the tolerability and safety profile; secondary objectives were the assessment of the OS, PFS, best response, mutational status, rate of dose reductions. Data were collected following the rules of retrospective studies in Italy and all patients signed an informed consent. Results: 34 pts with CP-CML were enrolled. Accelerated phase or blastic phase were considered as exclusion criteria. There were 17 males and 17 females, with a median age of 62 (25-84) years at ponatinib initiation. Sokal score was high in 7 (23.33%), intermediate in 17 (56.67%), low in 6 (20%) and unknown in 4 pts. Regarding previous TKIs, 22 (64.7%) pts had three previous lines of therapy, 10 (29.41%) two lines, 2 (5.8%) only one TKI before ponatinib. Two patients experienced a previous stem cell transplant (SCT) and other 10 (29.4%) harbored a T315I mutation before ponatinib initiation. At baseline none of the 34 patients were in major molecular remission (MMR). The median follow-up on ponatinib was 46.6 months (range 15.2-74.5). Cumulative incidence of MMR was 14.7% at three months, 20.6% at six months, 29.4% at nine months, and 55.5% at 36 months. Rate of OS at 36 months was 80% (Figure 1); the presence of T315I did not affect survival. At last follow-up 17 pts were still on treatment with ponatinib; eight pts died, 3 after SCT, 1 for cardiovascular toxicity, 3 for disease progression; one for unknown reason. The treatment-related vascular adverse events (AEs) represented 20.6% of total AEs reported: 6 of them were cardiovascular, 2 cerebrovascular, 2 peripheral, 3 new-onset hypertension, 2 cardiac failures. Non cardiovascular AEs were mostly due to hematological intolerance, with 43 events of neutropenia/thrombocytopenia out of 73 total collateral effects, followed by 9 reported skin problems (which varied from simple rash or desquamation to one episode of ichthyosis). Conclusions: After a median follow up of 46.6 months, ponatinib provided substantial benefits in a cohort of pts in a timeframe where, after failing 2nd generation TKIs, no other chances were available except transplantation, and T315I positive patients were practically orphan of treatment before ponatinib. Aside from the large prospective PACE trial, results from GIMEMA CML1214 pair with other real-life experiences like the French PEARL (Heiblig M, Exp Hematol 2018) or the Spanish GELMC (Garcia-Gutierrez V, EHA 2016) reports, thus confirming the manageability and the effectiveness of this therapy in challenging clinical situations. Disclosures Fava: Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy. Elena:Pfizer: Consultancy; Novartis: Consultancy. Iurlo:Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.
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- 2019
45. Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis
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Michele Cavo, Emilia Scalzulli, Francesca Palandri, Mario Tiribelli, Giovanni Caocci, Roberto Latagliata, Bruno Martino, Vincenzo Martinelli, Luigiana Luciano, Giulia Benevolo, Elena Rossi, Massimo Breccia, Valerio De Stefano, Robin Foà, Massimiliano Bonifacio, Novella Pugliese, Fabrizio Pane, Gianni Binotto, Breccia, Massimo, Luciano, Luigiana, Pugliese, Novella, Rossi, Elena, Tiribelli, Mario, Scalzulli, Emilia, Bonifacio, Massimiliano, Martino, Bruno, Latagliata, Roberto, Benevolo, Giulia, Caocci, Giovanni, Binotto, Gianni, Martinelli, Vincenzo, Cavo, Michele, Pane, Fabrizio, De Stefano, Valerio, Foà, Robin, Palandri, Francesca, Breccia, M., Luciano, L., Pugliese, N., Rossi, E., Tiribelli, M., Scalzulli, E., Bonifacio, M., Martino, B., Latagliata, R., Benevolo, G., Caocci, G., Binotto, G., Martinelli, V., Cavo, M., Pane, F., De Stefano, V., Foa, R., and Palandri, F.
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Male ,Ruxolitinib ,Myelofibrosis ,Cell Count ,Gastroenterology ,Primary Myelofibrosi ,0302 clinical medicine ,Retrospective Studie ,80 and over ,Leukocytes ,Hydroxyurea ,Leukocytosis ,Aged, 80 and over ,Hematology ,Myelofibrosi ,General Medicine ,Middle Aged ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Combination ,Drug Therapy, Combination ,Female ,Survival Analysi ,Patient Safety ,medicine.symptom ,Human ,medicine.drug ,Blood Platelets ,medicine.medical_specialty ,Efficacy ,Aged ,Cell Proliferation ,Drug Administration Schedule ,Humans ,Primary Myelofibrosis ,Pyrazoles ,Retrospective Studies ,Splenomegaly ,Survival Analysis ,Spleen ,03 medical and health sciences ,Drug Therapy ,Internal medicine ,Nitriles ,Myeloproliferation ,medicine ,Thrombocytosis ,business.industry ,Leukocyte ,medicine.disease ,Clinical trial ,Settore MED/15 - MALATTIE DEL SANGUE ,Pyrimidines ,Pyrazole ,Blood Platelet ,business ,030215 immunology - Abstract
Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48weeks, a significant reduction in leucocyte and platelet counts was observed (p= 0.02 and p= 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10cm below the left costal margin (range, 0-10) to 6cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.
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- 2019
46. A Comparison of Droplet Digital PCR and RT-qPCR for BCR-ABL1 Monitoring in Chronic Myeloid Leukemia
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Claudia Venturi, Maria Teresa Bochicchio, Emanuela Ottaviani, Fabrizio Pane, Filomena Daraio, Giovanni Martinelli, Emilia Giugliano, Enrico Gottardi, Jessica Petiti, Barbara Izzo, Carmen Fava, Daniele Calistri, Giuseppe Saglio, Daniela Cilloni, Giovanna Rege Cambrin, Santa Errichiello, Luigiana Luciano, Paola Berchialla, and Alessandro Martino
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business.industry ,Immunology ,Myeloid leukemia ,RNA ,Cell Biology ,Hematology ,Biochemistry ,Molecular biology ,law.invention ,Bcr abl1 ,law ,Medicine ,Digital polymerase chain reaction ,Bland–Altman plot ,Tyrosine ,Bcr-Abl Tyrosine Kinase ,business ,Polymerase chain reaction - Abstract
Background: Monitoring of BCR-ABL1 molecular levels is essential for the management of Chronic Myeloid Leukemia (CML) patients treated with Tyrosine Kinases Inhibitors (TKIs). Real Time Quantitative PCR (RT-qPCR) is currently the standard method for assessing molecular remission (MR) in patients with CML. Recently, droplet digital PCR (ddPCR) has emerged to provide a more accurate detection of minimal residual disease (MRD). In order to hypothesize the use of this new technology in the clinical practice, in the era of TKI discontinuation, we designed a multi-centric study to evaluate the potential value of ddPCR in diagnostic routine. Aims of the study were:1) the evaluation of the agreement between the measures obtained by ddPCR and RT-qPCR and 2) the assessment of the repeatability of the two methods. Methods: Total RNA was extracted from 37 CML patients using Maxwell 16 LEV simplyRNA Blood kit (Promega), following the manufacturer's instructions. Samples were divided in 5 groups based on molecular response (MR) as follow: group 1, MR Statistical analysis: Bland-Altman analysis was performed. For the measurement of the agreement we reported the bias, which is the mean of the difference between the methods, the 95% limits of agreement and the coefficient of variation. Residual variance and coefficients of repeatability (i.e. the upper limits of a prediction interval for the absolute difference between two measurements by the same method on the same item) were computed to achieve the second endpoint. An analysis of sensitivity on the labs was also carried out. All analyses were stratified by the level of disease. Results: A total of 370 measures were included in the analysis, 185 for ddPCR and 185 for RT-qPCR divided as follow: 50 for group 1 and for group 2, 90 for group 3, 4 and 5. In Table 1 we reported the median and interquartile range (IQR) for all levels of disease. Results of the Bland-Altman analysis are shown in Table 2. The coefficients of variation, which expresses the standard deviation as a percentage of the mean, were 2.35, 2.31, 1.10, 1.34, 39.12 in group 1, 2, 3, 4 and 5 respectively. The repeatability coefficients of ddPCR were smaller than qRT-PCR across all the levels of disease, showing a slightly better precision of ddPCR (Table 2). Conclusions: Higher coefficients of variation in group 1 and 2 were probably due to a greater heterogeneity of the patients. In fact, BCR-ABL1/ABL1 levels by RT-qPCR ranged between 1.43 and 6.94 and between 0.10 and 0.25 in group 1 and in group 2 respectively (Table 1). Sensitivity analysis showed that the high coefficient of variation in group 5 can be explained almost all by the variability observed in Lab B. Coefficient of repeatability of ddPCR was always smaller than RT-qPCR for all level of disease showing a slightly better precision. Our results showed that ddPCR has a good agreement with RT-qPCR and it is more precise to quantify BCR-ABL1 transcript levels, particularly for MR 4 and MR 4.5. Thus, ddPCR may be valuable in diagnostic routine. Disclosures Fava: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Martino:Bio-Rad: Employment. Saglio:Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy. Martinelli:Roche: Consultancy; BMS: Consultancy; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Cilloni:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.
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- 2019
47. Identification and assessment of frailty in older patients with chronic myeloid leukemia and myelofibrosis, and indications for tyrosine kinase inhibitor treatment
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Giulia Benevolo, Giuseppe A. Palumbo, Giovanni Caocci, Massimo Breccia, Massimiliano Bonifacio, Francesca Palandri, Fausto Castagnetti, Alessandra Iurlo, Luigiana Luciano, Francesco Landi, Breccia, Massimo, Palandri, Francesca, Luciano, Luigiana, Benevolo, Giulia, Bonifacio, Massimiliano, Caocci, Giovanni, Castagnetti, Fausto, Palumbo, Giuseppe A, Iurlo, Alessandra, and Landi, Francesco
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Oncology ,Male ,Ruxolitinib ,Myeloproliferative neoplasm ,Myelofibrosis ,Tyrosine-kinase inhibitor ,0302 clinical medicine ,Elderly ,Quality of life ,80 and over ,030212 general & internal medicine ,Chronic ,Aged, 80 and over ,Leukemia ,Frailty ,Incidence (epidemiology) ,Chronic myeloid leukemia ,Myelofibrosi ,General Medicine ,Hematology ,Protein-Tyrosine Kinases ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,medicine.medical_specialty ,medicine.drug_class ,Frail Elderly ,Context (language use) ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Nitriles ,medicine ,Toxicity ,Humans ,Aged ,Primary Myelofibrosis ,Protein Kinase Inhibitors ,Pyrazoles ,Contraindication ,business.industry ,Settore MED/09 - MEDICINA INTERNA ,medicine.disease ,Comorbidity ,Pyrimidines ,BCR-ABL Positive ,business ,Myelogenous - Abstract
The incidence of cancer, including myeloproliferative neoplasms (MPNs), is projected to increase significantly due to the growing proportion of people aged > 65 years. These older individuals are a heterogeneous population in terms of fitness, comorbidity, and psychological reserve. Therefore, age per se does not always provide an accurate indication of condition in patients with cancer. Frailty has been proposed as an alternative measure of vulnerability that might better indicate which patients can tolerate standard cancer treatment and those who may benefit from treatment adjustment. A number of methods can be used to assess frailty in older patients with hematological malignancies, including the Cardiovascular Health Study Frailty Screening Measure, the FRAIL (Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight) questionnaire, the Clinical Frailty Scale (CFS), and the Gérontopôle Frailty Screening Tool. In addition to physical frailty, comorbidity and quality of life should also be included in the assessment. Prior to the introduction of tyrosine kinase inhibitors (TKIs), age was considered a marker of poor prognosis in patients with MPNs. In contrast, data show that age is not necessarily a contraindication for TKI use. In CML, the efficacy of TKIs has been shown to be independent of age. The JAK1/2 inhibitor ruxolitinib also seems to be effective across a range of patient ages. Available data suggest that chronological age itself should not necessarily be a contraindication for many new therapies in patients with MPNs, and that frailty does provide a better measure of vulnerability. There is a need for specific methods to assess frailty in patients with MPNs, particularly the context of effective new treatment options, such as TKIs and ruxolitinib.
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- 2018
48. Ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients in real-life practice
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Anna Rita Scortechini, Alessandra Iurlo, Federica Sorà, Monica Bocchia, Massimo Breccia, Alessandro Isidori, Domenica Gangemi, Isabella Capodanno, Fausto Castagnetti, Nicola Sgherza, Michele Pizzuti, Antonella Gozzini, Patrizia Pregno, Massimiliano Bonifacio, Massimo Gentile, Alessandro Maggi, Monica Crugnola, Debora Luzi, Elisabetta Abruzzese, Luigiana Luciano, Robin Foà, Breccia, Massimo, Abruzzese, Elisabetta, Castagnetti, Fausto, Bonifacio, Massimiliano, Gangemi, Domenica, Sorà, Federica, Iurlo, Alessandra, Luciano, Luigiana, Gozzini, Antonella, Gentile, Massimo, Bocchia, Monica, Luzi, Debora, Maggi, Alessandro, Sgherza, Nicola, Isidori, Alessandro, Crugnola, Monica, Pregno, Patrizia, Scortechini, Anna Rita, Capodanno, Isabella, Pizzuti, Michele, and Foà, Robin
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Myeloid ,Male ,Drug Resistance ,Practice Patterns ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,0302 clinical medicine ,Retrospective Studie ,hemic and lymphatic diseases ,Practice Patterns, Physicians' ,Adjuvant ,Hematology ,Leukemia ,Ponatinib ,Chronic myeloid leukemia ,Imidazoles ,General Medicine ,Chronic phase chronic myeloid leukemia ,Middle Aged ,Prognosis ,Dasatinib ,Pyridazines ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Female ,Second line ,Drug ,Pyridazine ,Human ,medicine.drug ,Adult ,medicine.medical_specialty ,Prognosi ,medicine.drug_class ,Dose-Response Relationship ,03 medical and health sciences ,Internal medicine ,medicine ,Chemotherapy ,Humans ,Imidazole ,Aged ,Retrospective Studies ,Physicians' ,Dose-Response Relationship, Drug ,business.industry ,Retrospective cohort study ,Imatinib ,Settore MED/15 - MALATTIE DEL SANGUE ,chemistry ,Nilotinib ,Drug Resistance, Neoplasm ,Neoplasm ,Chronic-Phase ,business ,030215 immunology - Abstract
Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32–72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.
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- 2018
49. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib
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Elisabetta Abruzzese, Mario Tiribelli, Alessandra Iurlo, Massimo Breccia, Gianantonio Rosti, Giorgio Minotti, Antonella Gozzini, Fabio Efficace, Luigiana Luciano, and Patrizia Pregno
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safety ,QoL ,Time Factors ,medicine.drug_class ,Treatment outcome ,Antineoplastic Agents ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,tyrosine kinase inhibitors ,medicine ,Humans ,Pharmacology (medical) ,neoplasms ,Protein Kinase Inhibitors ,business.industry ,Ponatinib ,Chronic myeloid leukemia ,Imidazoles ,Myeloid leukemia ,Imatinib ,General Medicine ,respiratory tract diseases ,Pyridazines ,Treatment Outcome ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,intolerance ,Cancer research ,Quality of Life ,business ,Tyrosine kinase ,030215 immunology ,medicine.drug - Abstract
In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment.Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported. Limited attention to long-term events or more in general, to the impact of AEs on patient quality of life (QoL), remains a problem. Ponatinib is active against all BCR-ABL1 mutants, including T315I, and is widely used to treat patients who developed resistance to other TKIs in any CML phase; however, only limited data is available on the possible role of ponatinib for intolerant patients.We review the different definitions of intolerance used in sponsored trials and in clinical practice, and we discuss how such definitions impact on the management of AEs. We summarize how to evaluate QoL during treatment with TKIs and how to include ponatinib among possible option for intolerant patients.
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- 2018
50. One Size Does Not Fit to All: Intolerant or Resistant CML Patients Could Benefit from Different Ponatinib Starting Dose Strategies. Multicenter Italian Experience
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Carmen Fava, Fabrizio Pane, Sara Galimberti, Gianni Binotto, Fabio Stagno, Massimo Breccia, Alessandro Isidori, Patrizia Pregno, Monika Trawinska Malgorzata, Isabella Capodanno, Antonella Gozzini, Mario Tiribelli, Luca Frison, Mario Annunziata, Monica Bocchia, Massimiliano Bonifacio, Gianpietro Semenzato, Luciano Levato, Luigiana Luciano, Gianantonio Rosti, Giuseppe Saglio, Francesca Lunghi, Fausto Castagnetti, Gaetano La Barba, Michele Baccarani, Gabriele Gugliotta, Alessandra Iurlo, and Elisabetta Abruzzese
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medicine.medical_specialty ,Acute coronary syndrome ,business.industry ,Immunology ,Ponatinib ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Debulking ,030226 pharmacology & pharmacy ,Biochemistry ,Discontinuation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Internal medicine ,Relative risk ,Cohort ,medicine ,030212 general & internal medicine ,business ,Adverse effect ,medicine.drug - Abstract
Background: Ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Based on the concern for an unfavourable cardiovascular toxicity profile, a dose reduction to 15 mg daily is currently recommended in CP patients after the achievement of treatment milestones. As more flexible approaches with TKIs dosage are increasingly adopted in clinical practice, identifying specific profiles of patients eligible for different treatment strategies, in order to improve the benefit/risk ratio, would be of particular interest. Aims: To update previous observations in an extended cohort of CML patients, resistant or intolerant to prior TKIs, describing the efficacy and toxicity of two different ponatinib schedules (de-escalated vs 15 mg starting dose). Secondly, to investigate whether specific subsets of CML patients were managed more successfully with one strategy. Methods: A retrospective analysis of CML-CP patients treated with ponatinib 15 mg, as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib, to reduce or to start therapy with a lower dose were indicated. Cytogenetic and molecular responses were evaluated according to the ELN2013 recommendations. Toxicities under ponatinib treatment leading to transient or definitive discontinuation were recorded. Results: 68 patients were included in this analysis. Median age at ponatinib start was 57 years (range: 28-87). The median time from CML diagnosis to ponatinib treatment was 4.6 years (range: 0.4-19). Most patients (70.6%) were treated with imatinib as frontline treatment. 30/68 patients (44%) received ponatinib as 4th or subsequent line of therapy. ABL1 mutations were detected in 18 (26.5%) patients (being 44% of them positive for the T315I mutation). 50/68 (73.5%) of cases had less than MR2 at the time of ponatinib initiation, with one third exhibiting primary refractoriness to all prior treatments. Resistance to prior TKIs was the reason for switch in 85% of patients treated with higher doses of ponatinib, while 13/26 patients starting with 15 mg were purely intolerant or intolerant and resistant (p= 0.001). No other significant differences between the two groups were identified. MR2, MR3 and MR4/MR4.5 rates were 78.6%, 59.6% and 28.6% in 42 patients treated with the "de-escalated" approach, respectively. First step of dose reduction was decided after a median time of 3.1 months, with a subsequent decrease to 15 mg after a median of 10 months. Dose modifications were guided mostly by adverse events (73%) and, less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 27 months (range: 2-81), with 5/42 patients discontinuing ponatinib (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). 4 deaths were registered, three after blast crisis and one for a fatal cardiovascular event. 26 patients started ponatinib 15 mg daily, with a median duration of treatment was 15 months (range: 2-58). MR2 was obtained in 77%, MR3 in 69.3% and MR4 in 46.2% of cases, respectively. MR3 or deeper responses were maintained in 80% of patients; 7/26 lost their best acquired response, with subsequent dose escalation to higher than 15 mg in 5/26 patients. Treatment discontinuation was necessary in 3 cases (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). Of note, patients with ABL mutations gained benefit only from the "de-escalated" approach, with response improvements in 10/14 of cases vs 0/4 in the "low dose" group. Similarly, a higher rate of at least a MR2 was obtained in primary refractory patients treated ab initio with higher doses of ponatinib (57.1 % vs 14.3 %). However, focusing only on pure intolerant patients, 15 mg starting dose was very effective, with all patients achieving at least a MR3 or deeper response. Summary/Conclusion: With the limits of the retrospective nature and small sample size, these data suggest that different dose strategies could be applied to specific subsets of CP-CML patients. While mutations or refractoriness to previous treatments should address towards a "debulking approach" with 45 or 30 mg ponatinib dose, intolerant or "low level resistance" cases could benefit from lower starting dose. Further investigation in larger prospective trials is warranted. Disclosures Castagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Pane:AMGEN: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.
- Published
- 2018
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