42 results on '"Avvisati G"'
Search Results
2. PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.
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Cicconi L, Divona M, Ciardi C, Ottone T, Ferrantini A, Lavorgna S, Alfonso V, Paoloni F, Piciocchi A, Avvisati G, Ferrara F, Di Bona E, Albano F, Breccia M, Cerqui E, Sborgia M, Kropp MG, Santoro A, Levis A, Sica S, Amadori S, Voso MT, Mandelli F, and Lo-Coco F
- Subjects
- Adolescent, Adult, Aged, Arsenic Trioxide, Arsenicals therapeutic use, Disease-Free Survival, Female, Humans, Induction Chemotherapy methods, Italy, Kinetics, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute mortality, Male, Middle Aged, Mutation, Oxides therapeutic use, Prognosis, Tretinoin therapeutic use, Young Adult, Arsenicals administration & dosage, Leukemia, Promyelocytic, Acute drug therapy, Oncogene Proteins, Fusion blood, Oxides administration & dosage, Tretinoin administration & dosage, fms-Like Tyrosine Kinase 3 genetics
- Abstract
The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.
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- 2016
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3. Randomized phase III trial of retinoic acid and arsenic trioxide versus retinoic acid and chemotherapy in patients with acute promyelocytic leukemia: health-related quality-of-life outcomes.
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Efficace F, Mandelli F, Avvisati G, Cottone F, Ferrara F, Di Bona E, Specchia G, Breccia M, Levis A, Sica S, Finizio O, Kropp MG, Fioritoni G, Cerqui E, Vignetti M, Amadori S, Schlenk RF, Platzbecker U, and Lo-Coco F
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- Arsenic Trioxide, Humans, Leukemia, Promyelocytic, Acute psychology, Prospective Studies, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenicals therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Oxides therapeutic use, Quality of Life, Tretinoin therapeutic use
- Abstract
Purpose: A randomized clinical trial compared efficacy and toxicity of standard all-trans-retinoic acid (ATRA) plus chemotherapy versus ATRA plus arsenic trioxide in patients with newly diagnosed, low- or intermediate-risk acute promyelocytic leukemia (APL). Here, we report health-related quality-of-life (HRQOL) results., Patients and Methods: HRQOL was a secondary end point of this trial. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 was used to assess HRQOL at end of induction and after consolidation therapy. All analyses were based on 156 patients who received at least one dose of treatment, with groups defined according to randomly assigned treatment. Primary analysis was performed, estimating mean HRQOL score over time and differences between treatment arms using a linear mixed model., Results: Overall, 162 patients age 18 to 70 years were enrolled. Of these, 150 and 142 patients were evaluable for HRQOL after induction therapy and third consolidation course, respectively. Overall compliance with HRQOL forms was 80.1%. The largest difference, favoring patients treated with ATRA plus arsenic trioxide, was found for fatigue severity (mean score difference, -9.3; 95% CI, -17.8 to -0.7; P = .034) at end of induction therapy. This difference was also clinically relevant. HRQOL differences between treatment arms at end of consolidation showed that for several scales, differences between treatment arms were marginal., Conclusion: Overall, current HRQOL findings further support the use of ATRA plus arsenic trioxide as preferred first-line treatment in patients with low- or intermediate-risk APL., (© 2014 by American Society of Clinical Oncology.)
- Published
- 2014
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4. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.
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Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, and Platzbecker U
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- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Arsenic Trioxide, Arsenicals adverse effects, Consolidation Chemotherapy, Disease-Free Survival, Female, Humans, Induction Chemotherapy, Leukemia, Promyelocytic, Acute genetics, Maintenance Chemotherapy, Male, Middle Aged, Neutropenia chemically induced, Oxides adverse effects, Thrombocytopenia chemically induced, Tretinoin adverse effects, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenicals therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Oxides therapeutic use, Tretinoin therapeutic use
- Abstract
Background: All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity., Methods: We conducted a phase 3, multicenter trial comparing ATRA plus chemotherapy with ATRA plus arsenic trioxide in patients with APL classified as low-to-intermediate risk (white-cell count, ≤10×10(9) per liter). Patients were randomly assigned to receive either ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA-idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA. The study was designed as a noninferiority trial to show that the difference between the rates of event-free survival at 2 years in the two groups was not greater than 5%., Results: Complete remission was achieved in all 77 patients in the ATRA-arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA-chemotherapy group (95%) (P=0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA-arsenic trioxide group and 86% in the ATRA-chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P<0.001 for noninferiority and P=0.02 for superiority of ATRA-arsenic trioxide). Overall survival was also better with ATRA-arsenic trioxide (P=0.02). As compared with ATRA-chemotherapy, ATRA-arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity., Conclusions: ATRA plus arsenic trioxide is at least not inferior and may be superior to ATRA plus chemotherapy in the treatment of patients with low-to-intermediate-risk APL. (Funded by Associazione Italiana contro le Leucemie and others; ClinicalTrials.gov number, NCT00482833.).
- Published
- 2013
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5. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols.
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Breccia M, Mazzarella L, Bagnardi V, Disalvatore D, Loglisci G, Cimino G, Testi AM, Avvisati G, Petti MC, Minotti C, Latagliata R, Foà R, Pelicci PG, and Lo-Coco F
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Idarubicin adverse effects, Infant, Infant, Newborn, Leukemia, Promyelocytic, Acute mortality, Male, Middle Aged, Neoplasm Recurrence, Local diagnosis, Prognosis, Risk Factors, Survival Rate, Syndrome, Tretinoin adverse effects, Young Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Body Mass Index, Leukemia, Promyelocytic, Acute drug therapy, Neoplasm Recurrence, Local etiology, Obesity complications, Overweight complications, Tretinoin metabolism
- Abstract
We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.
- Published
- 2012
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6. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group.
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Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A, Paoloni F, Fioritoni G, Ferrara F, Specchia G, Cimino G, Diverio D, Borlenghi E, Martinelli G, Di Raimondo F, Di Bona E, Fazi P, Peta A, Bosi A, Carella AM, Fabbiano F, Pogliani EM, Petti MC, Amadori S, and Mandelli F
- Subjects
- Adolescent, Adult, Anthracyclines administration & dosage, Anthracyclines therapeutic use, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cytarabine administration & dosage, Cytarabine therapeutic use, Humans, Idarubicin administration & dosage, Leukemia, Promyelocytic, Acute diagnosis, Middle Aged, Remission Induction, Tretinoin administration & dosage, Young Adult, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Idarubicin therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
After the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)-like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non-risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group.
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- 2010
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7. Clinical and biological features of acute promyelocytic leukemia patients developing retinoic acid syndrome during induction treatment with all-trans retinoic acid and idarubicin.
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Breccia M, Latagliata R, Carmosino I, Cannella L, Diverio D, Guarini A, De Propris MS, Petti MC, Avvisati G, Cimino G, Mandelli F, and Lo-Coco F
- Subjects
- Humans, Syndrome, Treatment Outcome, Tretinoin therapeutic use, Idarubicin therapeutic use, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin adverse effects
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- 2008
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8. Prolonged molecular remission in a newly diagnosed acute promyelocytic leukaemia with a severe cardiomyopathy using low-dose gemtuzumab ozogamicin and all-trans retinoic acid.
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Martini V, Minotti C, Breccia M, De Angelis G, Buffolino S, Mariella M, Lo-Coco F, Avvisati G, and Cimino G
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- Antibodies, Monoclonal, Humanized, Antineoplastic Agents therapeutic use, Arsenic Trioxide, Arsenicals therapeutic use, Cardiomyopathies pathology, Cardiomyopathies physiopathology, Drug Therapy, Combination, Echocardiography, Gemtuzumab, Humans, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute genetics, Male, Middle Aged, Oncogene Proteins, Fusion genetics, Oxides therapeutic use, Remission Induction, Reverse Transcriptase Polymerase Chain Reaction, Treatment Outcome, Aminoglycosides therapeutic use, Antibodies, Monoclonal therapeutic use, Cardiomyopathies complications, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
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- 2007
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9. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features.
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Breccia M, Avvisati G, Latagliata R, Carmosino I, Guarini A, De Propris MS, Gentilini F, Petti MC, Cimino G, Mandelli F, and Lo-Coco F
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- Adult, Aged, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic adverse effects, Antineoplastic Agents administration & dosage, CD2 Antigens, Female, Humans, Idarubicin administration & dosage, Idarubicin adverse effects, Leukemia, Promyelocytic, Acute blood, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute immunology, Leukocyte Count, Lewis X Antigen, Male, Middle Aged, Mutation, Predictive Value of Tests, Risk Factors, Tandem Repeat Sequences genetics, Thrombosis genetics, Thrombosis immunology, Tretinoin administration & dosage, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents adverse effects, Leukemia, Promyelocytic, Acute drug therapy, Thrombosis chemically induced, Tretinoin adverse effects
- Abstract
Although the occurrence of thrombosis in acute promyelocytic leukemia (APL) has been reported during retinoic acid treatment, no studies carried out in large clinical cohorts have specifically addressed this issue. We analyzed 124 APL patients treated with the all-trans retinoic acid and idarubicin protocol and compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 patients who had no thrombosis. In seven patients, the events were recorded during induction, whereas in four patients deep vein thrombosis occurred in the post-induction phase. Comparison of clinico-biological characteristics of patients with and without thrombosis revealed in the former group higher median white blood cell (WBC) count (17 x 10(9)/l, range 1.2-56, P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3-ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correlation was found with sex, age, French-American-British subtype, all-trans-retinoic acid syndrome or with thrombophilic state that was investigated in 5/11 patients. Our findings suggest that, in APL patients consistent biologic features of leukemia cells may predict increased risk of developing thrombosis.
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- 2007
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10. All-trans retinoic acid in acute promyelocytic leukaemia.
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Avvisati G and Tallman MS
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- Drug Resistance, Neoplasm, Humans, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute diagnosis, Prognosis, Remission Induction methods, Treatment Outcome, Tretinoin adverse effects, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed.
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- 2003
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11. Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols.
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Mandelli F, Latagliata R, Avvisati G, Fazi P, Rodeghiero F, Leoni F, Gobbi M, Nobile F, Gallo E, Fanin R, Amadori S, Vignetti M, Fioritoni G, Ferrara F, Peta A, Giustolisi R, Broccia G, Petti MC, and Lo-Coco F
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- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Humans, Idarubicin adverse effects, Leukemia, Promyelocytic, Acute genetics, Male, Middle Aged, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, RNA, Messenger metabolism, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Remission Induction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Treatment Outcome, Tretinoin adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Idarubicin therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.
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- 2003
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12. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.
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Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De Santis S, Avvisati G, Pinazzi MB, Petti MC, Mandelli F, and Lo Coco F
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- Acute Disease, Adult, Aged, DNA Primers chemistry, DNA, Neoplasm metabolism, Female, Hemoglobins analysis, Humans, Leukemia, Promyelocytic, Acute diagnosis, Leukemia, Promyelocytic, Acute drug therapy, Leukocyte Count, Male, Middle Aged, Mutation, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Platelet Count, RNA, Messenger metabolism, RNA, Neoplasm metabolism, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Tandem Repeat Sequences, Treatment Outcome, fms-Like Tyrosine Kinase 3, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Idarubicin therapeutic use, Leukemia, Promyelocytic, Acute genetics, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Tretinoin therapeutic use
- Abstract
Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.
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- 2002
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13. Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell'Adulto.
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Specchia G, Lo Coco F, Vignetti M, Avvisati G, Fazi P, Albano F, Di Raimondo F, Martino B, Ferrara F, Selleri C, Liso V, and Mandelli F
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- Adult, Female, Hematopoiesis, Extramedullary, Humans, Leukemia, Promyelocytic, Acute cerebrospinal fluid, Leukemia, Promyelocytic, Acute pathology, Male, Middle Aged, RNA analysis, Receptors, Retinoic Acid analysis, Receptors, Retinoic Acid genetics, Recurrence, Retinoic Acid Receptor alpha, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors, Tretinoin administration & dosage, Tretinoin adverse effects, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
Purpose: Recent reports of extramedullary disease (EMD) at recurrence in acute promyelocytic leukemia (APL) have raised increasing concern about a possible role of retinoic acid (RA) therapy., Patients and Methods: We analyzed the risk of developing EMD localization at relapse in APL patients enrolled onto two consecutive studies of the Gruppo Italiano Malattie Ematologiche dell'Adulto. The studies investigated chemotherapy alone (LAP0389) versus RA plus chemotherapy (AIDA)., Results: When all relapse types were taken into account, 94 (51%) of 184 patients and 131 (18%) of 740 patients who attained hematologic remission underwent relapse in the LAP0389 and AIDA studies, respectively (P < .0001). EMD localization was documented in five (5%) of 94 and 16 (12%) of 131 patients (P = .08). Hematologic and/or molecular relapse was diagnosed concomitantly in all but two patients with EMD in the AIDA study. For patients in the LAP0389 and AIDA series, the probability of EMD localization of any type at relapse was 3% and 4.5%, respectively (P = .79), while the probability of CNS involvement was 0.6% and 2% (P = .28). No significant differences were found with regard to mean WBC count and promyelocytic leukemia/retinoic acid receptor-alpha junction type in comparisons of patients with EMD and hematologic relapse., Conclusion: APL patients receiving all-trans retinoic acid in addition to chemotherapy have no increased risk of developing EMD at relapse as compared with those treated with chemotherapy alone.
- Published
- 2001
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14. Intraventricular thrombosis during all-trans retinoic acid treatment in acute promyelocytic leukemia.
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Torromeo C, Latagliata R, Avvisati G, Petti MC, and Mandelli F
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- Adult, Female, Heart Ventricles pathology, Humans, Male, Middle Aged, Thrombosis pathology, Tretinoin therapeutic use, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute drug therapy, Thrombosis etiology, Tretinoin adverse effects
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- 2001
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15. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia.
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Di Bona E, Avvisati G, Castaman G, Luce Vegna M, De Sanctis V, Rodeghiero F, and Mandelli F
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- Adolescent, Adult, Aged, Child, Child, Preschool, Drug Therapy, Combination, Evaluation Studies as Topic, Female, Fibrinogen analysis, Hemorrhage prevention & control, Humans, Incidence, Infant, Italy, Leukemia, Promyelocytic, Acute complications, Leukemia, Promyelocytic, Acute mortality, Male, Middle Aged, Morbidity, Multivariate Analysis, Platelet Count, Prospective Studies, Remission Induction, Time Factors, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Agents therapeutic use, Hemorrhage etiology, Hemorrhage mortality, Idarubicin therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
A total of 622 consecutive patients with acute promyelocytic leukaemia (APL) treated within the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group during 1989-97 have been reviewed to assess the clinical effectiveness of all-trans retinoic acid (ATRA) on the incidence of early haemorrhagic deaths and on APL-associated coagulopathy. Of them, 499 were treated with idarubicin plus ATRA (study A) and 123 with Idarubicin alone (study B). In both studies, similar guidelines for supportive treatment were used. Haemorrhagic symptoms were evaluated according to a reproducible score system. Deaths occurring within 10 d of starting treatment were 19 (3.8%) in study A and nine (7.3%) in study B (P = 0.09), with 15 (3%) and five (4.1%) (P not significant) due to haemorrhage. Overall, induction mortality was 7.6% and 16.2% respectively (P < 0.003). In study A, days with platelet counts = 20 x 109/l or with fibrinogen = 1 g/L were reduced by about 30%, the haemorrhagic score by 50% and the consumption of blood products by about 40%, and fewer patients were treated with antihaemorrhagic drugs (39% vs. 61%; P < 0.001). On multivariate analysis, early deaths were influenced by blast count at diagnosis > 30 x 109/l (P < 0.001) in both studies, and by a haemorrhagic score of 3 in study A (P < 0.001). Although the reduction of early fatal haemorrhages was not significant, a substantial clinical improvement was evident in terms of reduction of the severity of bleeding symptoms, blood product consumption and overall induction mortality when ATRA was combined with idarubicin.
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- 2000
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16. Coronaric thrombotic events in acute promyelocytic leukemia during all-trans retinoic acid treatment: a role for adhesion molecules overexpression?
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Torromeo C, Latagliata R, Avvisati G, Petti MC, and Mandelli F
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- Aged, Humans, Leukemia, Promyelocytic, Acute complications, Middle Aged, Cell Adhesion Molecules biosynthesis, Coronary Thrombosis chemically induced, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin adverse effects
- Published
- 1999
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17. Acute promyelocytic leukemia: a curable disease.
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Lo Coco F, Nervi C, Avvisati G, and Mandelli F
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- Aged, Arsenic Trioxide, Arsenicals therapeutic use, Child, Drug Resistance, Hematopoietic Stem Cell Transplantation, Humans, Immunophenotyping, Karyotyping, Leukemia, Promyelocytic, Acute diagnosis, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute metabolism, Neoplasm Proteins metabolism, Neoplasm, Residual, Oxides therapeutic use, Promyelocytic Leukemia Protein, Recurrence, Research, Rome, Transcription Factors metabolism, Tumor Suppressor Proteins, Antineoplastic Agents therapeutic use, Leukemia, Promyelocytic, Acute therapy, Nuclear Proteins, Tretinoin therapeutic use
- Abstract
The Second International Symposium on Acute Promyelocytic Leukemia (APL) was held in Rome in 12-14 November 1997. Clinical and basic investigators had the opportunity to discuss in this meeting the important advances in the biology and treatment of this disease achieved in the last 4 years, since the First Roman Symposium was held in 1993. The first part of the meeting was dedicated to relevant aspects of laboratory research, and included the following topics: molecular mechanisms of leukemogenesis and of response/resistance to retinoids, biologic and therapeutic effects of new agents such as arsenicals and novel synthetic retinoids; characterization of APL heterogeneity at the morphological, cytogenetic and immunophenotypic level. The updated results of large cooperative clinical trials using variable combinations of all-trans retinoic acid (ATRA) and chemotherapy were presented by the respective group chairmen, and formed the 'core' part of the meeting. These studies, which in most cases integrated the molecular assessment of response to treatment, provided a stimulating framework for an intense debate on the most appropriate frontline treatment options to be adopted in the future. The last day was dedicated to special entities such as APL in the elderly and in the child, as well as the role of bone marrow transplantation. The prognostic value of molecular monitoring studies was also discussed in the final session of the meeting. In this article, we review the major advances and controversial issues in APL biology and treatment discussed in this symposium and emerging from very recent publications. We would like to credit the successful outcome of this meeting to the active and generous input of all invited speakers and to participants from all over the world who provided constructive and fruitful discussions.
- Published
- 1998
- Full Text
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18. All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia in the chronic phase.
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Russo D, Regazzi M, Sacchi S, Visani G, Lazzarino M, Avvisati G, Pelicci PG, Dastoli G, Grandi C, Iacona I, Candoni A, Grattoni R, Galieni P, Rupoli S, Liberati AM, and Maiolo AT
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Drug Administration Schedule, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Leukemia, Myeloid, Chronic-Phase blood, Leukemia, Myeloid, Chronic-Phase metabolism, Leukocyte Count drug effects, Male, Middle Aged, Tretinoin adverse effects, Tretinoin pharmacokinetics, Antineoplastic Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid, Chronic-Phase drug therapy, Tretinoin therapeutic use
- Abstract
Since in vitro observations indicated that all-trans retinoic acid (ATRA), especially in combination with IFNalpha, can exert significant suppressive effects on Ph+ cells, we investigated the effects and the pharmacokinetic profile of ATRA in a selected cohort of patients with Ph+ chronic myeloid leukemia (CML) in chronic phase. Eighteen patients were treated with ATRA at a dose of 80 mg/m2/day (p.o.), divided into two equal doses after meals, for 7 consecutive days every other week for a maximum of 12 courses (1 course = 1 week on and 1 week off). Pharmacokinetic profiles of ATRA were evaluated during intermittent therapy on days 1 and 7 of course 1; on day 1 of course 2; on day 1 of course 6. Out of the 18 patients treated with ATRA, 11 (61%) went off study before the sixth course of treatment because of progressive hyperleukocytosis (seven cases), or thrombocytosis (one case), or refusal (three cases). Seven (39%) patients completed the first six courses (12 weeks) of treatment with ATRA and two of them (11%) maintained a white blood cell (WBC) <10 x 10[9]/l which was induced by the pretreatment with hydroxyurea. One patient completed the 12th course of ATRA maintaining WBC <10 x 10(9)/l, platelets <500 x 10(9)/l and spleen not palpable. The treatment with ATRA was well tolerated and only one patient discontinued the therapy because of non-hematological side-effects. The area under the concentration-time curve (AUC) decreased significantly (P< 0.001) during the first week of therapy. By adopting an intermittent dosing regimen, 1 week on/ 1 week off (1 course), at the start of courses 2 and 6, we obtained the ATRA AUCs equivalent to the ones achieved on day 1 of course 1. In conclusion, our results showed that ATRA alone appeared to be unable to control the WBC expansion in the CML patients in chronic phase. Moreover, it did not induce any remarkable cytoreductive effects on the platelet count and on the hemoglobin level. The major interest of ATRA would be in combination with other therapies. If ATRA was given in combination with IFNalpha or other agents, dose reduction of these would not be planned. On the basis of the pharmacokinetic profile, ATRA should be administered intermittently rather than continuously.
- Published
- 1998
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19. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells.
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Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K, Lamph WW, Waxman S, Pelicci PG, Lo Coco F, Avvisati G, Testa U, Peschle C, Gambacorti-Passerini C, Nervi C, and Miller WH Jr
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenic Trioxide, Arsenicals therapeutic use, Blotting, Northern, Blotting, Western, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Flow Cytometry, Humans, Oxides therapeutic use, Retinoic Acid Receptor alpha, Transglutaminases metabolism, Tretinoin therapeutic use, Tumor Cells, Cultured, Antineoplastic Combined Chemotherapy Protocols pharmacology, Apoptosis drug effects, Arsenicals pharmacology, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute physiopathology, Oxides pharmacology, Receptors, Retinoic Acid drug effects, Tretinoin pharmacology
- Abstract
Background: Retinoids, which are derivatives of vitamin A, induce differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients. However, APL cells develop resistance to retinoic acid treatment. Arsenic trioxide (As2O3) can induce clinical remission in patients with APL, including those who have relapsed after retinoic acid treatment, by inducing apoptosis (programmed cell death) of the leukemia cells. In this study, we investigated the molecular mechanisms by which As2O3 induces apoptosis in retinoic acid-sensitive NB4 APL cells, in retinoic acid-resistant derivatives of these cells, and in fresh leukemia cells from patients., Methods: Apoptosis was assessed by means of DNA fragmentation analyses, TUNEL assays (i.e., deoxyuridine triphosphate labeling of DNA nicks with terminal deoxynucleotidyl transferase), and flow cytometry. Expression of the PML/RAR alpha fusion protein in leukemia cells was assessed by means of western blotting, ligand binding, and immunohistochemistry. Northern blotting and ribonuclease protection assays were used to evaluate changes in gene expression in response to retinoic acid and As2O3 treatment., Results and Conclusions: As2O3 induces apoptosis without differentiation in retinoic acid-sensitive and retinoic acid-resistant APL cells at concentrations that are achievable in patients. As2O3 induces loss of the PML/RAR alpha fusion protein in NB4 cells, in retinoic-acid resistant cells derived from them, in fresh APL cells from patients, and in non-APL cells transfected to express this protein. As2O3 and retinoic acid induce different patterns of gene regulation, and they inhibit the phenotypes induced by each other. Understanding the molecular basis of these differences in the effects of As2O3 and retinoic acid may guide the clinical use of arsenic compounds and provide insights into the management of leukemias that do not respond to retinoic acid.
- Published
- 1998
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20. The role of all-trans-retinoic acid (ATRA) treatment in newly-diagnosed acute promyelocytic leukemia patients aged > 60 years.
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Latagliata R, Avvisati G, Lo Coco F, Petti MC, Diverio D, Spadea A, Fazi P, Torromeo C, Breccia M, Malagnino F, and Mandelli F
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Female, Humans, Male, Middle Aged, Remission Induction, Retrospective Studies, Treatment Outcome, Tretinoin adverse effects, Antineoplastic Agents therapeutic use, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
Background: To evaluate the role and toxicity of ATRA therapy in newly-diagnosed APL patients aged > 60 yrs, the outcome of 16 consecutive elderly APL patients observed between January 1990 and June 1996 were analyzed., Patients and Methods: Their median age was 65.5 yrs (range 60-81 years), the male/female ratio was 7:9, and molecular biology analysis showed a PML/RARa rearrangement in all patients. Seven patients had a concomitant cardiovascular disease. ATRA 45 mg/sqm/day was given to all patients, and in 11 was associated with idarubicin (AIDA protocol); in two patients ATRA was associated with mitoxantrone + ara-C, while the remaining three patients received ATRA alone., Results: Fourteen patients (87.5%) achieved CR, and two patients (12.5%) died during induction. Despite the high CR rate, eight episodes of severe cardiovascular complication were observed in seven patients, three of whom had previously had cardiovascular disease; in addition, three patients had sepsis (two bacterial and one fungal). As of 31 March 1997, 9 of 14 patients were still in first CR after a 19-month (range 7-64 months) median follow-up since attainment of the CR. One patient died in CR of a fungal complication and four patients relapsed after 8, 9, 23 and 35 months following CR: two of them achieved a second CR lasting seven and +15 months with ATRA alone. Of the nine patients still in first CR, only three have received the planned consolidation therapy and five have been in CR for more than 24 months (+25, +33, +34, +38, +63)., Conclusions: Despite the fact that most of these patients received shorter consolidation treatments than do younger patients, the good results achieved in them might be considered an indication for modifying treatment schedules in order to reduce severe toxicity and improve protocol compliance.
- Published
- 1997
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21. Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells.
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Benedetti L, Levin AA, Scicchitano BM, Grignani F, Allenby G, Diverio D, Lo Coco F, Avvisati G, Ruthardt M, Adamo S, Pelicci PG, and Nervi C
- Subjects
- Alitretinoin, Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Binding, Competitive, COS Cells, Chromosomes, Human, Pair 15 genetics, Chromosomes, Human, Pair 15 ultrastructure, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 ultrastructure, DNA-Binding Proteins metabolism, Gene Expression Regulation, Leukemic drug effects, Humans, Kruppel-Like Transcription Factors, Leukemia, Promyelocytic, Acute drug therapy, Neoplasm Proteins classification, Oncogene Proteins, Fusion classification, Prognosis, Promyelocytic Leukemia Zinc Finger Protein, Protein Binding, Recombinant Fusion Proteins metabolism, Remission Induction, Structure-Activity Relationship, Transcription Factors metabolism, Transcription, Genetic, Transfection, Translocation, Genetic, Tretinoin pharmacology, Tretinoin therapeutic use, Leukemia, Promyelocytic, Acute metabolism, Neoplasm Proteins metabolism, Oncogene Proteins, Fusion metabolism, Tretinoin metabolism
- Abstract
The bcr1- and bcr3- promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) are the two major fusion proteins expressed in acute promyelocytic leukemia (APL) patients. These proteins, which are present in different lengths of PML (amino acids 1-552 and 1-394, respectively), contain most of the functional domains of PML and RAR alpha, bind all-trans-retinoic acid (t-RA), and act as t-RA-dependent transcription factors. T-RA is an effective inducer of clinical remission only in patients carrying the t(15;17) and expressing the PML/RAR alpha products. However, in APL patients achieving complete remission with t-RA therapy the bcr3-PML/RAR alpha product has been found associated with a poorer prognosis than bcr1-PML/RAR alpha. In the present study we have investigated the structural and functional properties of the bcr3-PML/RAR alpha in comparison to the previously characterized bcr1-PML/RAR alpha. In particular, we have measured the binding properties of the two endogenous ligands t-RA and 9-cis-RA to both of these isoforms. T-RA binding analysis of nuclear and cytosolic extracts prepared from bcr3-PML/RAR alpha APL patients and from bcr3-PML/RAR alpha COS-1 transfected cells indicates that this protein is present only as high-molecular-weight nuclear complexes. Using saturation binding assays and Scatchard analyses we found that t-RA binds with slightly less affinity to the bcr3-PML/RAR alpha receptor than to bcr1-PML/RAR alpha or RAR alpha (Kd = 0.4 nmol/L, 0.13 nmol/L or 0.09 nmol/L, respectively). Moreover, two different high-affinity 9-cis-RA binding sites (Kd = 0.45 and 0.075 nmol/L) were detectable in the bcr3-PML/RAR alpha product but not in the bcr1-PML/RAR alpha product (Kd = 0.77 nmol/L). By competition binding experiments we showed that 9-cis-RA binds with higher specificity to the bcr3-PML/RAR alpha isoform than to the bcr1-PML/RAR alpha or RAR alpha. Consistent with these data, the binding of 9-cis-RA to the bcr3-PML/RAR alpha product resulted in increased transcriptional activation of the RA-responsive element (RARE) TRE, but not of the betaRARE, in transiently transfected COS-1 cells. These results provide evidence indicating that preferential retinoid binding to the different PML/RAR alpha products can be measured.
- Published
- 1997
22. All-trans retinoic acid in hematological malignancies, an update. GER (Gruppo Ematologico Retinoidi).
- Author
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Sacchi S, Russo D, Avvisati G, Dastoli G, Lazzarino M, Pelicci PG, Bonora MR, Visani G, Grassi C, Iacona I, Luzzi L, and Vanzanelli P
- Subjects
- Adult, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Biotransformation, Cell Differentiation drug effects, Child, Clinical Trials as Topic, Drug Resistance, Neoplasm, Gene Expression Regulation drug effects, Hematologic Neoplasms mortality, Humans, Models, Genetic, Neoplastic Stem Cells drug effects, Pseudotumor Cerebri chemically induced, Receptors, Retinoic Acid drug effects, Remission Induction, Respiration Disorders chemically induced, Signal Transduction, Transcription, Genetic drug effects, Tretinoin adverse effects, Tretinoin pharmacokinetics, Tretinoin pharmacology, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Tretinoin therapeutic use
- Abstract
Background and Objective: During the past ten years, the study of retinoids has undergone a total transformation. The Italian Society of Experimental Hematology decided to discuss these advances at a meeting in Florence on April 18, 1996., Information Sources: The material examined in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. In addition, all the authors of the present article have been actively working in the field of retinoids and have contributed several papers. Summaries of their oral presentations at the Florence meeting are reported in the Appendix to this review article., State of Art and Perspectives: One of the most important advances has been the elucidation of new molecular mechanisms of control of gene expression by retinoids. A number of new retinoids have been synthesized by chemists, some of which are being screened for potential clinical use, and a few have already had a tremendous impact on clinical practice. The most important achievements have been obtained in acute promyelocytic leukemia. In 1988 a Chinese group working in Shanghai showed that using all-trans retinoic acid (ATRA) alone 94% of acute promyelocytic leukemic patients obtained complete remission through differentiation of the leukemic clone. This result transformed a dream into reality and allowed researchers to move from laboratory experience to clinical applications of this differentiating therapy. Expanding the spectrum of hematological malignancies that may respond to ATRA remains a challenge; however, several results show some activity of retinoids alone or in combination with other drugs in juvenile chronic myeloid leukemia (CML), myelodysplastic syndrome, cutaneous T-cell lymphoma and CML. Particularly interesting are the studies that explored the potential clinical synergism of ATRA-based combination therapies with growth factors, other differentiating agents such as vitamin D3, immunomodulators like interferons, or chemotherapeutic agents, in particular Ara-C, all of which show promising in vitro effects when used in combination with retinoids.
- Published
- 1997
23. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study.
- Author
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Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, and Mandelli F
- Subjects
- Adult, Aged, Child, DNA, Neoplasm genetics, Female, Humans, Male, Middle Aged, Neoplasm Proteins genetics, Oncogene Proteins, Fusion genetics, Oncogenes, Pilot Projects, RNA, Neoplasm genetics, Survival Analysis, Translocation, Genetic, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Idarubicin administration & dosage, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin administration & dosage
- Abstract
From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared at successive testing performed 2 months later. As of September 30, 1995, after a median follow-up period from diagnosis of 27 months (range, 24 to 31 months), the overall survival and event-free survival durations are 85% and 69%, respectively; moreover, 14 of 18 (78%) patients who achieved CR are still alive and in first molecular and hematologic CR. Of the 4 relapsed patients, 3 achieved a second CR with ATRA and, after further treatment, are now in molecular and hematologic CR after 4+, 16+, and 17+ months from the second CR. These results indicate that (1) the AIDA protocol is highly effective in treating APL; (2) after 3 consolidation courses, the majority of patients who achieved CR are RT-PCR- for the hybrid gene PML-RAR alpha; (3) the persistence of an RT-PCR positivity for the PML-RAR alpha hybrid gene after 3 consolidation courses is indicative of early relapse, thus these patients still require additional treatment. These results have prompted the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) to initiate, in cooperation with the Associazione Italiana di Ematologia ed Oncologia Pediatrica and some European Organization for Research and Treatment of Cancer (EORTC) centers, a new multicentric clinical trial named AIDA LAP 0493 for the treatment of adult and pediatric APL patients. All patients are considered eligible if APL diagnosis is confirmed with molecular or cytogenetic studies for PML-RAR alpha hybrid gene or t(15;17) and are enrolled to receive the same induction and consolidation therapy of this pilot study. After consolidation, patients who are RT-PCR- for PML-RAR alpha hybrid gene are randomized to four arms, whereas patients who are RT-PCR+ after consolidation undergo, if eligible, an allogenic transplantation procedure.
- Published
- 1996
24. Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase.
- Author
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Benedetti L, Grignani F, Scicchitano BM, Jetten AM, Diverio D, Lo Coco F, Avvisati G, Gambacorti-Passerini C, Adamo S, Levin AA, Pelicci PG, and Nervi C
- Subjects
- Apoptosis drug effects, Benzoates pharmacology, CD18 Antigens biosynthesis, CD18 Antigens genetics, Cell Differentiation drug effects, Chromosomes, Human, Pair 15 genetics, Chromosomes, Human, Pair 15 ultrastructure, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 17 ultrastructure, Cytosol enzymology, Drug Resistance, Neoplasm, Enzyme Induction drug effects, Fenretinide pharmacology, Gene Expression Regulation, Leukemic drug effects, Humans, Isoenzymes genetics, Leukemia, Promyelocytic, Acute genetics, Neoplasm Proteins chemistry, Neoplasm Proteins drug effects, Neoplasm Proteins genetics, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Oncogene Proteins, Fusion chemistry, Oncogene Proteins, Fusion drug effects, Protein Multimerization, Receptors, Retinoic Acid drug effects, Receptors, Retinoic Acid physiology, Retinoids pharmacology, Signal Transduction drug effects, Tetrahydronaphthalenes pharmacology, Transglutaminases genetics, Translocation, Genetic, Tumor Cells, Cultured drug effects, Isoenzymes biosynthesis, Leukemia, Promyelocytic, Acute pathology, Neoplasm Proteins physiology, Neoplastic Stem Cells drug effects, Oncogene Proteins, Fusion physiology, Transglutaminases biosynthesis, Tretinoin pharmacology
- Abstract
All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to induce type II TGase in response to t-RA. On the basis of these results we hypothesize a specific involvement of a signaling pathway involving PML-RAR alpha for the induction of growth arrest, granulocytic differentiation, and type II TGase by retinoids in APL cells.
- Published
- 1996
25. On the differentiative mode of action of All-trans retinoic acid in acute promyelocytic leukemia.
- Author
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Lo Coco F, Diverio D, Avvisati G, Mandelli F, Biondi A, and Pelicci PG
- Subjects
- Biomarkers, Tumor, Cell Differentiation drug effects, Gene Rearrangement, Humans, Immunologic Factors therapeutic use, Leukemia, Promyelocytic, Acute pathology, Neoplasm Proteins drug effects, Neoplasm Proteins genetics, Neoplastic Stem Cells pathology, Receptors, Retinoic Acid drug effects, Receptors, Retinoic Acid genetics, Retinoic Acid Receptor alpha, Tretinoin therapeutic use, Immunologic Factors pharmacology, Leukemia, Promyelocytic, Acute therapy, Neoplastic Stem Cells drug effects, Tretinoin pharmacology
- Published
- 1995
26. Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia.
- Author
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Lo Coco F, Avvisati G, Diverio D, Petti MC, Alcalay M, Pandolfi PP, Zangrilli D, Biondi A, Rambaldi A, and Moleti ML
- Subjects
- Adult, Aged, Blotting, Southern, Carrier Proteins drug effects, DNA, Neoplasm drug effects, DNA, Neoplasm genetics, Female, Gene Rearrangement, Humans, Leukemia, Promyelocytic, Acute genetics, Male, Middle Aged, Receptors, Retinoic Acid, Restriction Mapping, Antineoplastic Agents, Carrier Proteins genetics, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin therapeutic use
- Abstract
The advent of retinoic acid (RA) in the treatment of acute promyelocytic leukemia (APL) has led to a high frequency of short-lasting complete remissions (CR). We studied the response to RA by molecularly analyzing the RA receptor alpha (RAR alpha) locus, which has recently been shown to be rearranged in all APLs. Southern blot analysis demonstrated that the RAR alpha rearrangements persisted in the APL samples containing maturing myeloid cells 2 to 3 weeks after the start of RA treatment, but disappeared after 5 to 8 weeks, when the patients achieved CR. Our investigations provide clear evidence that CR occurs at molecular level and that there is reconstitution of an apparently normal, nonclonal hematopoiesis. Further, it shows that RA acts by triggering differentiation rather than by exerting a cytotoxic effect on the leukemic clone.
- Published
- 1991
27. Acute promyelocytic leukemia: Clinical and morphologic features and prognostic factors
- Author
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Avvisati, G, LO COCO, F, and Mandelli, F
- Subjects
Promyelocytic ,Leukemia ,Leukemia, Promyelocytic, Acute ,Humans ,Antineoplastic Agents ,Prognosis ,Tretinoin ,Hematology ,Acute ,Settore MED/15 - Malattie del Sangue - Abstract
The most impressive clinical feature of acute promyelocytic leukemia (APL) at diagnosis is the presence in 80% to 90% of patients of a severe hemorrhagic syndrome. Recent data favor a fibrinolytic/proteolytic process rather than a disseminated intravascular coagulation as the mechanism mainly responsible for the hemorrhagic diathesis in APL. Morphologically, two main cytologic variants have been Identified: the classical hypergranular APL (M3), which represents the great majority of all APL, and the microgranular variant (M3v), which accounts for about 15% to 20% of all APL. A rare basophilic variant has also been described. With regard to prognosis, it has markedly changed from that of a rapidly fatal acute leukemia to that of a highly curable disease. This revolutionary progress was mainly due to the introduction during the 1990s of all-trans retinoic acid (ATRA) for the treatment of this disease. After the introduction of ATRA, in addition to clinical features such as hyperleukocytosis (white blood cell count10 x 10(9)/L) or thrombocytopenia (platelet count10 x 10(3)/L) at presentation, immunophenotype markers and polymerase chain reaction status for promyelocytic leukemia/retinoic acid receptor-alpha during follow-up also had an impact on prognosis.
- Published
- 2001
28. Prolonged molecular remission in a newly diagnosed acute promyelocytic leukaemia with a severe cardiomyopathy using low-dose gemtuzumab ozogamicin and all-trans retinoic acid [2]
- Author
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Martini, V, Minotti, C, Breccia, M, Angelis, G, Buffolino, S, Mariella, M, LO COCO, F, Avvisati, G, and Cimino, G
- Subjects
Promyelocytic ,Male ,Oncogene Proteins ,Leukemia ,Reverse Transcriptase Polymerase Chain Reaction ,Remission Induction ,Antineoplastic Agents ,Oxides ,Tretinoin ,Acute ,Middle Aged ,Antibodies ,Arsenicals ,Aminoglycosides ,Treatment Outcome ,Drug Therapy ,Echocardiography ,Antibodies, Monoclonal ,Antibodies, Monoclonal, Humanized ,Cardiomyopathies ,Drug Therapy, Combination ,Humans ,Leukemia, Promyelocytic, Acute ,Oncogene Proteins, Fusion ,Monoclonal ,Combination ,Fusion ,Humanized ,Settore MED/15 - Malattie del Sangue - Published
- 2007
29. Treatment of elderly patients (> or =60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols
- Author
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Mandelli, F, Latagliata, R, Avvisati, G, Fazi, P, Rodeghiero, F, Leoni, F, Gobbi, M, Nobile, F, Gallo, E, Fanin, Renato, Amadori, S, Vignetti, M, Fioritoni, G, Ferrara, F, Peta, A, Giustolisi, R, Broccia, G, Petti, Mc, Lo Coco, F, and Italian GIMEMA Cooperative Group
- Subjects
Male ,Acute promyelocytic leukemia ,Cancer Research ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,medicine.medical_treatment ,Tretinoin ,Leukemia, Promyelocytic, Acute ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Idarubicin ,RNA, Messenger ,RNA, Neoplasm ,ATRA ,AML of the elderly ,Survival rate ,Aged ,Chemotherapy ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Remission Induction ,Hematology ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,Surgery ,Survival Rate ,Clinical trial ,Leukemia ,Treatment Outcome ,Oncology ,Toxicity ,Female ,business ,Complication ,Settore MED/15 - Malattie del Sangue ,medicine.drug - Abstract
In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.
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- 2003
30. Arsenic trioxide as an inducer of apoptosis and loss of PML/RAR alpha protein in acute promyelocytic leukemia cells
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Shao, W, Fanelli, M, Ferrara, F, Riccioni, R, Rosenauer, A, Davison, K, Lamph, W, Waxman, S, Pelicci, P, LO COCO, F, Avvisati, G, Testa, U, Peschle, C, Gambacorti Passerini, C, Nervi, C, and Miller, W
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Electrophoresis ,Promyelocytic ,Antineoplastic Combined Chemotherapy Protocols ,Apoptosis ,Arsenicals ,Blotting, Northern ,Blotting, Western ,Down-Regulation ,Electrophoresis, Polyacrylamide Gel ,Flow Cytometry ,Humans ,Leukemia, Promyelocytic, Acute ,Oxides ,Receptors, Retinoic Acid ,Transglutaminases ,Tretinoin ,Tumor Cells, Cultured ,Polyacrylamide Gel ,Leukemia ,Cultured ,Blotting ,Retinoic Acid ,Acute ,Tumor Cells ,Receptors ,Northern ,Western ,Settore MED/15 - Malattie del Sangue - Published
- 1998
31. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene
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Meloni, Giovanna, Diverio, D., Vignetti, Marco, Avvisati, G., Capria, S., Petti, Maria Concetta, Mandelli, Franco, and LO COCO, F.
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Adult ,Male ,Neoplasm, Residual ,Adolescent ,Oncogene Proteins, Fusion ,Antibiotics, Antineoplastic ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Child ,Combined Modality Therapy ,Cytarabine ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Idarubicin ,Leukemia, Promyelocytic, Acute ,Middle Aged ,Mitoxantrone ,Neoplasm Proteins ,Polymerase Chain Reaction ,Prognosis ,Prospective Studies ,Remission Induction ,Salvage Therapy ,Transplantation, Autologous ,Treatment Outcome ,Tretinoin ,Bone Marrow Transplantation ,Acute ,Antibiotics ,Fusion ,Promyelocytic ,Oncogene Proteins ,Transplantation ,Tumor ,Leukemia ,Antineoplastic ,Residual ,Neoplasm ,Autologous ,Settore MED/15 - Malattie del Sangue ,Biomarkers - Abstract
Reverse-transcription polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene may predict relapse in acute promyelocytic leukemia (APL) patients in hematologic complete remission (CR). We have prospectively studied by RT-PCR 15 PML/RAR alpha+ APL patients undergoing autologous bone marrow transplantation (ABMT) in second CR. The median time of first CR duration was 12 months (range, 6 to 40). All patients were reinduced with all-trans retinoic acid (ATRA), followed in 12 of 15 cases by mitoxantrone and Ara-C as consolidation. Fourteen patients received the BAVC (BCNU, Ara-C, m-AMSA, and VP-16) schedule as conditioning regimen. Unpurged marrows were collected immediately before conditioning treatment, analyzed by RT-PCR, and reinfused at median of 2 months (range, 2 to 7) from the achievement of second CR. Seven patients were PCR+ and eight PCR for PML/RAR alpha in their pretransplant marrows. All seven patients of the former group remained PCR+ during the follow-up and relapsed at a median time of 5 months (range, 2 to 9) from ABMT and 9 months (range, 4 to 14) from second CR. Of the eight PCR- patients, all remained PCR- during the follow-up controls. One patient relapsed at 10 months from ABMT, one died of a secondary (PML/RAR alpha-) leukemia, and six are in hematologic and molecular remission at a median time of 28 months (range, 15 to 60) after ABMT and 32 months (range, 17 to 62) from second CR. Our results indicate that, in APL patients in second CR, ABMT with PML/RAR alpha- marrow cells is likely to result in prolonged clinical and molecular remissions. Conversely, patients who test PCR+ after reinduction necessitate the use of alternative aggressive approaches, including unrelated allogeneic transplant.
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- 1997
32. Acute promyelocytic leukemia: a curable disease.
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Coco, F Lo, Nervi, C, Avvisati, G, and Mandelli, F
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LEUKEMIA ,TRETINOIN - Abstract
The Second International Symposium on Acute Promyelocytic Leukemia (APL) was held in Rome in 12-14 November 1997. Clinical and basic investigators had the opportunity to discuss in this meeting the important advances in the biology and treatment of this disease achieved in the last 4 years, since the First Roman Symposium was held in 1993. The first part of the meeting was dedicated to relevant aspects of laboratory research, and included the following topics: molecular mechanisms of leukemogenesis and of response/resistance to retinoids, biologic and therapeutic effects of new agents such as arsenicals and novel synthetic retinoids; characterization of APL heterogeneity at the morphological, cytogenetic and immunophenotypic level. The updated results of large cooperative clinical trials using variable combinations of all-trans retinoic acid (ATRA) and chemotherapy were presented by the respective group chairmen, and formed the 'core' part of the meeting. These studies, which in most cases integrated the molecular assessment of response to treatment, provided a stimulating framework for an intense debate on the most appropriate front-line treatment options to be adopted in the future. The last day was dedicated to special entities such as APL in the elderly and in the child, as well as the role of bone marrow transplantation. The prognostic value of molecular monitoring studies was also discussed in the final session of the meeting. In this article, we review the major advances and controversial issues in APL biology and treatment discussed in this symposium and emerging from very recent publications. We would like to credit the successful outcome of this meeting to the active and generous input of all invited speakers and to participants from all over the world who provided constructive and fruitful discussions. [ABSTRACT FROM AUTHOR]
- Published
- 1998
- Full Text
- View/download PDF
33. Time-Dependent Kinetics of Tretinoin in Chronic Myelogenous Leukaemia during Intermittent Dose Scheduling: 1 Week On/1 Week Off.
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Grandi, C., Regazzi, M.B., Spreafico, S., Russo, D., Grattoni, R., Iacona, I., Galieni, P., Sacchi, S., Rupoli, S., Visani, G., Maiolo, A.M., Lazzarino, M., Guerra, E., Avvisati, G., Liberati, A.M., Pelicci, P.G., and Dastoli, G.
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TRETINOIN ,LEUKEMIA treatment ,MYELOID leukemia ,PHARMACOKINETICS - Abstract
Objective: This study investigated the pharmacokinetics of tretinoin during alternating cycles of 1 week of tretinoin treatment and 1 week drug-free in patients with Ph1+ chronic myelogenous leukaemia (CML) in the chronic phase. Patients: Eighteen patients with CML were treated with tretinoin 80 mg/m/day (in two divided doses) for 7 consecutive days every other week (one cycle = 1 week on/1 week off). Results: Body systemic exposure to tretinoin as determined by the area under the plasma concentration-time curve (AUC) decreased significantly during the first week of drug administration, from (mean ± SD) 678.3 ± 498.1 to 258.7 ± 272.4 µg/L·h. In about 40% of the patients the decline in plasma concentrations was ≥80%, while 17% of the population did not experience any decline. On day 7 of cycle 1, the mean apparent oral clearance (CL/F) was 2.6 times the corresponding value on day 1. After 1 week without tretinoin, the mean AUC on day 1 of cycle 2 was lower (down 15%) but not statistically different from the corresponding value observed on day 1 of cycle 1; 62% of patients showed an increase in the AUC, which was 40% higher than the corresponding value on day 7 of cycle 1. On day 1 of cycle 6, the AUC and CL/F of tretinoin during a dosage interval were not statistically different from those observed on day 1 of cycle 1 and cycle 2. On all occasions the peak plasma concentration (C) was strongly correlated to the corresponding AUC. No significant change in the time to observed C (t) and in the elimination half-life (t) was observed during the whole study. These results confirmed that the metabolism of tretinoin is rapidly up-regulated in CML patients, with significant declines in plasma drug exposure during the first week of drug administration. After tretinoin was discontinued, a return to the noninduced state followed a mean time-cycle similar to the induction. The strong decrease in the apparent oral drug clearance and the absence of significant variations in the drug half-life demonstrated that the presystemic extraction of tretinoin is the main cause of the marked decline in plasma drug exposure. Conclusion: The favourable pharmacokinetic profile of tretinoin obtained by an intermittent regimen, 1 week on/1 week off therapy (vs continuous administration), suggests that such a therapeutic schedule is the most appropriate for the assessment of clinical efficacy in those pathologies in which its use is suitable. [ABSTRACT FROM AUTHOR]
- Published
- 1998
34. Definition of relapse risk and role of nonanthracycline drags for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups
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Sanz, M. A., Lo Coco, F., Martin, G., Avvisati, G., Rayon, C., Barbui, T., Diaz-Mediavilla, J., Fioritoni, G., Gonzalez, J. D., Liso, V., Esteve, J., Ferrara, F., Bolufer, P., Bernasconi, C., Gonzalez, M., Rodeghiero, F., DOLORS COLOMER, Petti, M. C., Ribera, J. M., and Mandelli, F.
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Adult ,Promyelocytic ,Male ,Risk ,Leukemia ,Adolescent ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Cohort Studies ,Cytarabine ,Etoposide ,Female ,Humans ,Idarubicin ,Leukemia, Promyelocytic, Acute ,Middle Aged ,Mitoxantrone ,Multivariate Analysis ,Predictive Value of Tests ,Recurrence ,Thioguanine ,Tretinoin ,Acute ,Settore MED/15 - Malattie del Sangue - Abstract
Preliminary independent reports of the Italian GIMEMA and the Spanish PETHEMA trials for newly diagnosed acute promyelocytic leukemia (APL) indicated a similarly high antileukemic efficacy in terms of complete remission and disease-free survival rates. To better investigate these studies and the prognostic factors influencing relapse risk, this study analyzed the updated results of 217 patients with PML/RAR alpha-positive APL enrolled in GIMEMA (n = 108) and PETHEMA (n = 109). All patients received identical induction (AIDA schedule) and maintenance. For consolidation, GIMEMA patients received 3 courses including idarubicin/cytarabine, mitoxantrone/etoposide, and idarubicin/cytarabine/thioguanine, whereas PETHEMA patients received the same drugs and dose schedule of idarubicin and mitoxantrone with the omission of nonintercalating agents. Depending on whether molecular relapses were classified as censored or uncensored events, the 3-year Kaplan-Meier estimates of relapse-free survival (RFS) for the combined series were 90 +/- 2% and 86 +/- 2%, respectively. Minor differences observed between the 2 patient cohorts were negligible. Multivariate regression analysis of RFS showed that initial leukocyte (WBC) and platelet counts were the only variables with independent prognostic value. The resulting predictive model for RFS demonstrated its capability of segregating patients into low-risk (WBC count/= 10 x 10(9)/L, platelet count40 x 10(9)/L), intermediate-risk (WBC count/= 10 x 10(9)/L, platelets/= 40 x 10(9)/L), and high-risk (WBC count10 x 10(9)/L) groups, with distinctive RFS curves (P.0001). The conclusions are that omission of nonanthracycline drugs from the AIDA regimen is not associated with reduced antileukemic efficacy and a simple predictive model may be used for risk-adapted therapy in this disease. (Blood. 2000;96:1247-1253)
35. Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells
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Benedetti, L., Levin, A. A., Scicchitano, B. M., Grignani, F., Nervi, Clara, Allenby, G., Diverio, D., Lo Coco, F., Avvisati, G., Ruthardt, M., Adamo, Sergio, Pelicci, P. G., and Nervi, C.
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Oncogene Proteins, Fusion ,Transcription, Genetic ,viruses ,Retinoic Acid ,Leukemia ,PML/RAR ,Protein Complexes ,Retinoic acid ,Biochemistry ,Translocation, Genetic ,chemistry.chemical_compound ,Competitive ,Leukemia, Promyelocytic, Acute ,Promyelocytic Leukemia Zinc Finger Protein ,Alitretinoin ,Leukemic ,Promyelocytic ,Oncogene Proteins ,Gene Expression Regulation, Leukemic ,Remission Induction ,Hematology ,Prognosis ,Animals ,Antineoplastic Agents ,Binding, Competitive ,COS Cells ,Chromosomes, Human, Pair 15 ,Chromosomes, Human, Pair 17 ,DNA-Binding Proteins ,Humans ,Kruppel-Like Transcription Factors ,Neoplasm Proteins ,Protein Binding ,Recombinant Fusion Proteins ,Structure-Activity Relationship ,Transcription Factors ,Transfection ,Tretinoin ,embryonic structures ,Transcription ,medicine.drug ,Human ,Acute promyelocytic leukemia ,Retinoid binding ,Immunology ,Alpha (ethology) ,Translocation ,Biology ,Acute ,Chromosomes ,Genetic ,medicine ,Binding site ,Fusion ,neoplasms ,organic chemicals ,Pair 17 ,Pair 15 ,Cell Biology ,Binding ,medicine.disease ,Fusion protein ,body regions ,chemistry ,Gene Expression Regulation ,Retinoic acid receptor alpha ,Settore MED/15 - Malattie del Sangue - Abstract
The bcr1- and bcr3- promyelocytic leukemia/retinoic acid receptor alpha (PML/RAR alpha) are the two major fusion proteins expressed in acute promyelocytic leukemia (APL) patients. These proteins, which are present in different lengths of PML (amino acids 1-552 and 1-394, respectively), contain most of the functional domains of PML and RAR alpha, bind all-trans-retinoic acid (t-RA), and act as t-RA-dependent transcription factors. T-RA is an effective inducer of clinical remission only in patients carrying the t(15;17) and expressing the PML/RAR alpha products. However, in APL patients achieving complete remission with t-RA therapy the bcr3-PML/RAR alpha product has been found associated with a poorer prognosis than bcr1-PML/RAR alpha. In the present study we have investigated the structural and functional properties of the bcr3-PML/RAR alpha in comparison to the previously characterized bcr1-PML/RAR alpha. In particular, we have measured the binding properties of the two endogenous ligands t-RA and 9-cis-RA to both of these isoforms. T-RA binding analysis of nuclear and cytosolic extracts prepared from bcr3-PML/RAR alpha APL patients and from bcr3-PML/RAR alpha COS-1 transfected cells indicates that this protein is present only as high-molecular-weight nuclear complexes. Using saturation binding assays and Scatchard analyses we found that t-RA binds with slightly less affinity to the bcr3-PML/RAR alpha receptor than to bcr1-PML/RAR alpha or RAR alpha (Kd = 0.4 nmol/L, 0.13 nmol/L or 0.09 nmol/L, respectively). Moreover, two different high-affinity 9-cis-RA binding sites (Kd = 0.45 and 0.075 nmol/L) were detectable in the bcr3-PML/RAR alpha product but not in the bcr1-PML/RAR alpha product (Kd = 0.77 nmol/L). By competition binding experiments we showed that 9-cis-RA binds with higher specificity to the bcr3-PML/RAR alpha isoform than to the bcr1-PML/RAR alpha or RAR alpha. Consistent with these data, the binding of 9-cis-RA to the bcr3-PML/RAR alpha product resulted in increased transcriptional activation of the RA-responsive element (RARE) TRE, but not of the betaRARE, in transiently transfected COS-1 cells. These results provide evidence indicating that preferential retinoid binding to the different PML/RAR alpha products can be measured.
36. Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15;17) translocation
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Clara NERVI, Ec, Poindexter, Grignani F, Pp, Pandolfi, Lo Coco F, Avvisati G, Pg, Pelicci, and Am, Jetten
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Receptors, Retinoic Acid ,Recombinant Fusion Proteins ,Immunoblotting ,Retinoic Acid ,Translocation ,Tretinoin ,Acute ,Translocation, Genetic ,Chromosomes ,Leukemia, Promyelocytic, Acute ,Genetic ,Receptors ,Humans ,Chromatography, High Pressure Liquid ,Promyelocytic ,Chromosomes, Human, Pair 15 ,Chromatography ,Leukemia ,Pair 17 ,Pair 15 ,Carrier Proteins ,Transcription Factors ,Chromosomes, Human, Pair 17 ,High Pressure Liquid ,Settore MED/15 - Malattie del Sangue ,Human - Abstract
The acute promyelocytic leukemia 15;17 chromosomal translocation fuses the PML gene to the RAR alpha locus. The resulting chimeric gene encodes for a putative PML-RAR alpha fusion protein. PML is a putative transcriptional factor and RAR alpha is one of the nuclear retinoic acid receptors through which retinoic acid regulates gene expression. In this study, we investigated the retinoid binding and biochemical properties of the PML-RAR alpha protein by size exclusion high-performance liquid chromatography and immunoblot analysis and compared them with those of normal RAR alpha. The introduction of the expression vector PSG5/PML-RAR alpha into COS-1 cells led to high levels of expression of the PML-RAR alpha fusion protein. This protein was primarily localized in the nucleus and bound retinoids with the same affinity and specificity as the wild type RAR alpha receptor. The PML-RAR alpha fusion protein, but not the RAR alpha, was found in high molecular weight complexes with either itself or other nuclear factors. In the acute promyelocytic leukemia-derived cell line NB4, which contains the t(15;17) chromosomal marker, the PML-RAR alpha product was also found as a high molecular complex. The interaction of the PML-RAR alpha with itself or with other nuclear proteins may be important in understanding the role of the PML-RAR alpha fusion protein in promyelocytic leukemogenesis.
37. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group
- Author
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Francesca Paoloni, Giuseppe Cimino, Antonio Peta, Daniela Diverio, Enrico Pogliani, Francesco Lo-Coco, Franco Mandelli, Marco Vignetti, Angelo Michele Carella, Francesco Fabbiano, Francesco Di Raimondo, Giuseppe Fioritoni, Giorgina Specchia, Alberto Bosi, Paola Fazi, Maria Concetta Petti, Eugenio Gallo, Eros Di Bona, Massimo Breccia, Erika Borlenghi, Giuseppe Avvisati, Felicetto Ferrara, Giovanni Martinelli, Alessandro Rambaldi, Sergio Amadori, Lo-Coco F., Avvisati G., Vignetti M., Breccia M., Gallo E., Rambaldi A., Paoloni F., Fioritoni G., Ferrara F., Specchia G., Cimino G., Diverio D., Borlenghi E., Martinelli G., Di Raimondo F., Di Bona E., Fazi P., Peta A., Bosi A., Carella A.M., Fabbiano F., Pogliani E.M., Petti M.C., Amadori S., Mandelli F., Lo Coco, F, Avvisati, G, Vignetti, M, Breccia, M, Gallo, E, Rambaldi, A, Paoloni, F, Fioritoni, G, Ferrara, F, Specchia, G, Cimino, G, Diverio, D, Borlenghi, E, Martinelli, G, Di Raimondo, F, Di Bona, E, Fazi, P, Peta, A, Bosi, A, Carella, A, Fabbiano, F, Pogliani, E, Petti, M, Amadori, S, and Mandelli, F
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Adult ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Adolescent ,Anthracycline ,Immunology ,Antineoplastic Agents ,Tretinoin ,Biochemistry ,Antineoplastic Agent ,Young Adult ,Leukemia, Promyelocytic, Acute ,MED/15 - MALATTIE DEL SANGUE ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Idarubicin ,Anthracyclines ,Cumulative incidence ,Antibiotics, Antineoplastic ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Remission Induction ,Cytarabine ,ACUTE PROMYELOCYTIC LEUKEMIA (APL) ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Surgery ,Clinical trial ,ALL-TRANS RETINOIC AND IDARUBICIN (AIDA) ,Leukemia ,business ,Settore MED/15 - Malattie del Sangue ,Human ,GIMEMA ,medicine.drug - Abstract
After the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)–like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non–risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group. This trial was registered at www.clinicaltrials.gov as #NCT 001064570.
- Published
- 2010
38. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non–High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial
- Author
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Erika Borlenghi, Arnold Ganser, Christian Thiede, Hartmut Döhner, Roberto Cairoli, Mohammed Wattad, Norbert Schmitz, Agostino Cortelezzi, Alfonso Maria D'Arco, Massimo Breccia, Franco Mandelli, Richard F. Schlenk, Mariadomenica Divona, Marco Sborgia, Francesco Albano, Laura Cicconi, Enrico Maria Pogliani, Konstanze Döhner, Claudio Fozza, Giuseppe Avvisati, Francesco Lo-Coco, Michael Lübbert, Felicetto Ferrara, Sergio Amadori, Walter Fiedler, Francesco Fabbiano, Bernd Hertenstein, Helmut R. Salih, Lorella Melillo, Uwe Platzbecker, Alessandro Rambaldi, Giorgio La Nasa, Christian Brandts, Nicola Di Renzo, Christoph Röllig, Hartmut Link, Marco Vignetti, Francesca Paoloni, Eros Di Bona, Fabio Efficace, Peter Brossart, Chiara Frairia, Paola Fazi, Gerhard Ehninger, Mathias Hänel, Platzbecker, U, Avvisati, G, Cicconi, L, Thiede, C, Paoloni, F, Vignetti, M, Ferrara, F, Divona, M, Albano, F, Efficace, F, Fazi, P, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Wattad, M, Lübbert, M, Brandts, C, Hänel, M, Röllig, C, Schmitz, N, Link, H, Frairia, C, Pogliani, E, Fozza, C, D'Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Döhner, K, Ganser, A, Döhner, H, Amadori, S, Mandelli, F, Ehninger, G, Schlenk, R, and Lo-Coco, F
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Phases of clinical research ,Gastroenterology ,Arsenicals ,law.invention ,0302 clinical medicine ,Arsenic Trioxide ,Leukemia, Promyelocytic, Acute ,Randomized controlled trial ,Maintenance therapy ,Risk Factors ,law ,Antineoplastic Combined Chemotherapy Protocols ,Arsenical ,Cumulative incidence ,Prospective Studies ,Oxides ,Middle Aged ,Leukemia ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Human ,medicine.drug ,Adult ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Adolescent ,Tretinoin ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,neoplasms ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Risk Factor ,organic chemicals ,Oxide ,Induction chemotherapy ,medicine.disease ,biological factors ,Surgery ,Prospective Studie ,030104 developmental biology ,Commentary ,business ,Settore MED/15 - Malattie del Sangue - Abstract
Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
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- 2017
39. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial
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Marco Sborgia, Marco Vignetti, Massimo Breccia, Fabio Efficace, Roberto Cairoli, Hartmut Link, Uwe Platzbecker, Norbert Schmitz, Ombretta Annibali, Agostino Cortelezzi, Francesca Paoloni, Eros Di Bona, Nicola Di Renzo, Alfonso Maria D'Arco, Lorella Melillo, Francesco Lo-Coco, Peter Brossart, Felicetto Ferrara, Chiara Frairia, Franco Mandelli, Christoph Röllig, Laura Cicconi, Claudio Fozza, Konstanze Döhner, Walter Fiedler, Bernd Hertenstein, Francesco Fabbiano, Richard F. Schlenk, Mariadomenica Divona, Francesco Albano, Mohammed Wattad, Maria Teresa Voso, Christian Thiede, Christian Brandts, Paola Fazi, Gerhard Ehninger, Mathias Hänel, Sergio Amadori, Alessandro Rambaldi, Giorgio La Nasa, Helmut R. Salih, Hartmut Döhner, Michael Lübbert, Giuseppe Avvisati, Arnold Ganser, Erika Borlenghi, Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, and Lo-Coco, F
- Subjects
Adult ,Male ,Oncology ,Acute promyelocytic leukemia ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Retinoic acid ,Tretinoin ,Follow-Up Studie ,law.invention ,Young Adult ,chemistry.chemical_compound ,Leukemia, Promyelocytic, Acute ,Randomized controlled trial ,law ,Germany ,Internal medicine ,medicine ,acute leukemia ,Arsenic trioxide ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,All trans ,Hematology ,Long term results ,Middle Aged ,APL ,arsenic trioxide ,medicine.disease ,Clinical trial ,Prospective Studie ,Leukemia ,Treatment Outcome ,Italy ,chemistry ,Female ,business ,Settore MED/15 - Malattie del Sangue ,Human - Published
- 2019
40. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols
- Author
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Giuseppe Avvisati, Massimo Breccia, Francesco Lo-Coco, Davide Disalvatore, Roberto Latagliata, Luca Mazzarella, Vincenzo Bagnardi, Maria Concetta Petti, Clara Minotti, Giuseppina Loglisci, Pier Giuseppe Pelicci, Anna Maria Testi, Robin Foà, Giuseppe Cimino, Breccia, M, Mazzarella, L, Bagnardi, V, Disalvatore, D, Loglisci, G, Cimino, G, Testi, A, Avvisati, G, Petti, M, Minotti, C, Latagliata, R, Foà, R, Pelicci, P, and Lo Coco, F
- Subjects
Male ,Overweight ,Biochemistry ,Leukemia, Promyelocytic, Acute ,Risk Factors ,Antineoplastic Combined Chemotherapy Protocols ,Cumulative incidence ,Child ,Adolescent ,Adult ,Aged ,Child, Preschool ,Female ,Follow-Up Studies ,Humans ,Idarubicin ,Infant ,Infant, Newborn ,Middle Aged ,Neoplasm Recurrence, Local ,Obesity ,Prognosis ,Survival Rate ,Syndrome ,Tretinoin ,Young Adult ,Body Mass Index ,Promyelocytic ,Leukemia ,Hazard ratio ,Hematology ,Local ,medicine.symptom ,Underweight ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Immunology ,body mass index ,Acute ,Internal medicine ,medicine ,Preschool ,business.industry ,Cell Biology ,Odds ratio ,Newborn ,medicine.disease ,Surgery ,Neoplasm Recurrence ,business ,Settore MED/15 - Malattie del Sangue ,Body mass index ,Weight gain - Abstract
We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.
- Published
- 2012
41. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors
- Author
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Roberto, Latagliata, Massimo, Breccia, Paola, Fazi, Marco, Vignetti, Francesco, Di Raimondo, Marco, Sborgia, Donatella, Vincelli, Anna, Candoni, Flavia, Salvi, Serena, Rupoli, Giovanni, Martinelli, Maria Grazia, Kropp, Anna, Tonso, Adriano, Venditti, Lorella, Melillo, Giuseppe, Cimino, Maria Concetta, Petti, Giuseppe, Avvisati, Francesco, Lo-Coco, Franco, Mandelli, Latagliata R., Breccia M., Fazi P., Vignetti M., Di Raimondo F., Sborgia M., Vincelli D., Candoni A., Salvi F., Rupoli S., Martinelli G., Kropp M.G., Tonso A., Venditti A., Melillo L., Cimino G., Petti M.C., Avvisati G., Lo-Coco F., and Mandelli F.
- Subjects
Male ,gimema ,acute promyelocytic leukaemia ,elderly acute promyelocytic leukaemia ,Hemorrhage ,Tretinoin ,Opportunistic Infections ,elderly ,all-trans retinoic acid ,consolidation therapy ,Leukemia, Promyelocytic, Acute ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Aged ,Elderly acute promyelocytic leukaemia ,All-trans retinoic acid ,Remission Induction ,Cytarabine ,ACUTE PROMYELOCYTIC LEUKEMIA (APL) ,Middle Aged ,Prognosis ,Survival Analysis ,Acute promyelocytic leukaemia ,Consolidation therapy ,Idarubicin - Abstract
To reduce toxicity in elderly patients with acute promyelocytic leukaemia, in 1997 the Gruppo Italiano Malattie Ematologiche Dell'Adulto (GIMEMA) started an amended protocol for patients aged >60years, with the same induction [all-trans retinoic acid (ATRA)+idarubicin] as in younger patients, followed by a single consolidation course (idarubicin+ cytarabine) and maintenance with intermittent ATRA. Among 60 enrolled patients, 54 (90%) achieved haematological remission and six died during induction. Four additional patients died in complete remission (CR) from haemorrhage (2) and infection (2) prior or during consolidation therapy. Eleven patients relapsed at a median time of 17·5months from CR. The 5-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) rates were 76·1%, 64·6% and 27·4%, respectively. Univariate analysis identified a performance score (PS)=2 as the only significant adverse prognostic factor for both OS (P=0·017) and DFS (P=0·0003). Male sex had an unfavourable impact on DFS (P=0·021) and on CIR (P=0·019), but not on OS (P=0·234). In multivariate analysis for DFS, only PS=2 retained prognostic significance (HR=4·5, P=0·0083). In conclusion, the amended GIMEMA protocol is effective, with similar relapse rate and inferior toxicity compared to the original AIDA 0493. However, considering the recent availability of effective new agents, a less aggressive approach should be tested in this setting.
- Published
- 2011
42. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance
- Author
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Francesco Lo-Coco, Francesca Paoloni, Giuseppe Rossi, Nicola Cantore, Filippo Marmont, Giuseppe Avvisati, Giuseppe Fioritoni, Giorgina Specchia, Paola Fazi, Franco Mandelli, Marco Vignetti, Francesco Di Raimondo, Roberto Latagliata, Michele Baccarani, Maria Concetta Petti, Eros Di Bona, Giovanni Pizzolo, A. Gabbas, Alessandro Rambaldi, Sergio Amadori, Maria Grazia Kropp, Daniela Diverio, Felicetto Ferrara, Enrico Maria Pogliani, Francesco Nobile, Avvisati, G, Lo Coco, F, Paoloni, F, Petti, M, Diverio, D, Vignetti, M, Latagliata, R, Specchia, G, Baccarani, M, Di Bona, E, Fioritoni, G, Marmont, F, Rambaldi, A, Di Raimondo, F, Kropp, M, Pizzolo, G, Pogliani, E, Rossi, G, Cantore, N, Nobile, F, Gabbas, A, Ferrara, F, Fazi, P, Amadori, S, and Mandelli, F
- Subjects
Male ,fusion ,Oncogene Proteins, Fusion ,Biochemistry ,oncogene proteins ,Clinical Protocols ,Leukemia, Promyelocytic, Acute ,Antineoplastic Combined Chemotherapy Protocols ,AIDA 0493 protocol ,genetics ,administration /&/ dosage ,Child ,promyelocytic ,acute promyelocytic leukemia ,Hematology ,acute ,adolescent ,adult ,aged ,antineoplastic combined chemotherapy protocols ,child ,clinical protocols ,diagnosis/drug therapy/genetics ,disease-free survival ,female ,humans ,idarubicin ,infant ,leukemia ,male ,middle aged ,preschool ,remission induction ,tretinoin ,young adult ,Remission Induction ,Middle Aged ,Leukemia ,Child, Preschool ,Female ,medicine.drug ,Human ,Acute promyelocytic leukemia ,Adult ,medicine.medical_specialty ,Randomization ,Adolescent ,Immunology ,Tretinoin ,Disease-Free Survival ,Young Adult ,Internal medicine ,medicine ,Idarubicin ,Humans ,Clinical Protocol ,Aged ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Cancer ,Infant ,Cell Biology ,medicine.disease ,Surgery ,Methotrexate ,business ,Settore MED/15 - Malattie del Sangue - Abstract
All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction–negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction–negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.
- Published
- 2011
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