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2. Corrigendum: 'Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience' (Leukemia Research (2022) 114, (106803), (S0145212622000297), (10.1016/j.leukres.2022.106803))

Author

De Bellis, E., Imbergamo, S., Candoni, A., Lico, A., Tanasi, I., Mauro, E., Mosna, F., Leoncin, M., Stulle, M., Griguolo, D., Pravato, S., Trentin, L., Lazzarotto, D., Di Bona, E., Sancetta, R., Lucchini, E., Poiani, M., Palmieri, C., and Zaja, F.

Published
2022

3. Corrigendum to 'Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience' [Leukemia Res. 114 (March 2022) 106803](S0145212622000297)(10.1016/j.leukres.2022.106803)

Author

De Bellis, E., Imbergamo, S., Candoni, A., Lico, A., Tanasi, I., Mauro, E., Mosna, F., Leoncin, M., Stulle, M., Griguolo, D., Pravato, S., Trentin, L., Lazzarotto, D., Di Bona, E., Sancetta, R., Lucchini, E., Poiani, M., Palmieri, C., and Zaja, F.

Published
2022

5. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

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 HR, 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 RF, Lo-Coco F., 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
Hematology
Published
2019

10. ESTABLISHING A NATIONAL NETWORK OF LABORATORIES USING NEXT GENERATION AMPLICON DEEP SEQUENCING FOR BCR-ABL1 KINASE DOMAIN MUTATION SCREENING: THE 'NEXT-IN-CML' STUDY

Author

Soverini, S., Benedittis, C., Bavaro, L., Martelli, M., Stella, S., Iurlo, A., Orofino, N., Barate, C., Galimberti, S., Sica, S., Sora, F., Rossi, A. Russo, Albano, F., Ciceri, F., Lunghi, F., Castagnetti, F., Gugliotta, G., Tenti, E., Rosti, G., CRISTINA PAPAYANNIDIS, Stagno, F., Vigneri, P., Serra, A., Saglio, G., Carnuccio, F., Pane, F., Errichiello, S., Annunziata, M., Breccia, M., Abruzzese, E., Bonifacio, M., Novella, E., Di Bona, E., Sancetta, R., Calistri, E., Spinosa, G., D Adda, M., Capodanno, I., Baccarani, M., Cavo, M., and Martinelli, G.

Published
2017

11. CLINICAL SIGNIFICANCE OF END OF INDUCTION MINIMAL RESIDUAL DISEASE IN ADULT PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA IN COMPLETE REMISSION AFTER A SINGLE CHEMOTHERAPY COURSE

Author

Bassan, R, Masciulli, A, Intermesoli, T, Spinelli, O, Tosi, M, Pavoni, C, Audisio, E, Cattaneo, C, Fumagalli, M, Cassibba, V, Mattei, D, Romani, C, Cortelezzi, A, Ciceri, F, Scattolin, Am, Vitolo, U, Borlenghi, E, Gallamini, A, Depaoli, L, Campiotti, L, Bocchia, M, Di Bona, E, Oldani, E, and Rambaldi, A

Published
2017

13. Sustained response to low-dose rituximab in idiopathic autoimmune hemolytic anemia

Author

Barcellini, W, Zaja, Francesco, Zaninoni, A, Imperiali, Fg, Di Bona, E, Fattizzo, B, Consonni, D, Cortelezzi, A, Zanella, A., Barcellini, W, Zaja, Francesco, Zaninoni, A, Imperiali, Fg, Di Bona, E, Fattizzo, B, Consonni, D, Cortelezzi, A, and Zanella, A.

Abstract

ObjectivesTo evaluate the sustained response to low-dose (LD) rituximab in autoimmune hemolytic anemia (AIHA), the ex vivo effect on anti-RBC antibody production by mitogen-stimulated direct antiglobulin test (MS-DAT), and the in vitro dose effect of the drug on the production of anti-RBC antibodies. MethodsThirty two patients, 18 warm (W) AIHA and 14 cold hemagglutinin disease (CHD), were treated with LD rituximab (100mg fixed dose x4 weekly infusions) along with a short course of oral prednisone. Complete clinical examination, blood counts, and hemolytic markers were performed at enrollment and at month 6, 12, 24, and 36. ResultsHematological parameters significantly improved at all time points compared to enrollment. The overall response was 90%, 100%, 100%, and 89% and the relapse-free survival 87%, 79%, 68%, and 68% at 6, 12, 24, and 36months, respectively. Response rates were slightly better in WAIHA than in CHD, and relapse risk was greater in cold than warm forms (HR 2.1, 95% CI 0.6-7.9). Four patients were retreated (one patient twice), all achieving a response, lasting a median of 18months (range 9-30). Treatment was well tolerated without adverse events or infections. Anti-RBC antibody production by MS-DAT significantly decreased over time. In vitro studies showed that rituximab effectively inhibited anti-RBC antibody production at 50g/mL, 1/6 of the drug concentration after therapy with standard doses. ConclusionsThese data confirm that LD rituximab treatment is effective and induces sustained responses in AIHA, and that a lower dose of the drug is enough to down-regulate autoantibody production.

Published
2013

14. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib

Author

Castagnetti, F, Gugliotta, G., Breccia, M., Stagno, F., Iurlo, A., Albano, F., Abruzzese, E., Martino, B., Levato, L., Intermesoli, T., Pregno, P., Rossi, G., Gherlinzoni, F., Leoni, P., Cavazzini, F., Venturi, C., Soverini, S., Testoni, N., Alimena, G., Cavo, M., Martinelli, G., Pane, F., Saglio, G., Rosti, G., Baccarani, M., on behalf of the GIMEMA CML Working Party (Lucarelli, G., Polimeno, G., Ladetto, M., Pini, M., Rupoli, S., Scortechini, A. R., Galieni, P., Bigazzi, C., Cantore, N., Palmieri, F., Specchia, G., Russo, Rossi., Rambaldi, A., Ferrari, M. L., Palandri, F., Luatti, S., Iacobucci, I., Bochicchio, M. T., Apolinari, M., Fogli, M., Cervello, I., Capucci, A., Giuliani, G., Malpignano, A., Girasoli, M., Angelucci, E., Usala, E., De Biasi, E., Tagariello, G., Sartori, R., Di Raimondo, F., Vigneri, P., Molica, S., Lentini, M., Lanza, F., Viganò, C., Grasso, M., Rapezzi, D., Cuneo, A., Ciccone, M., Bosi, A., Gozzini, A., Gobbi, M., Pierri, I., Chianese, R., De Blasio, A., Ciccone, F., Capochiani, E., Pelosini, M., Musolino, C., Russo, S., Cortelezzi, A., Luppi, M., Marasca, R., Pogliani, E. M., Gambacorti-Passerini, C., Luciano, L., Izzo, B., Ferrara, F., Annunziata, M., Mettivier, V., Sessa, U., Latte, G., Noli, D., Rege-Cambrin, G., Fava, C., Semenzato, G., Binotto, G., Fabbiano, F., Turri, D., Siragusa, S., Caracciolo, C., Musso, M., Porretto, F., Cazzola, M., Orlandi, E., Falini, B., Falzetti, F., Visani, G., Isidor, I., Di Bartolomeo, P., Di Lorenzo, R., Vallisa, D., Trabacch, I., Pizzuti, M., Zuffa, E., Salvucci, M., Ronco, F., Lelo, D., Merli, F., Avanzini, P., Tosi, P., Merli, A., Sica, S., Sorà, F., Latagliata, R., De Fabritiis, P., Trawiska, M., Amadori, S., Cantonetti, M., Majolino, I., Pacilli, L., Ronci, B., Cedrone, M., Mengarelli, A., Romano, A., Tafuri, A., Montefusc, O., Iuliano, F., Infusino, S., Dore, F., Fozza, C., Bocchia, M., Defina, M., Liberati, Am., Luzi, D., Boccadoro, M., Ferrero, D., Vitolo, U., Nicolosi, M., Gottardi, M., Calistri, E., Fanin, R., Tiribelli, M., Pizzolo, G., Bonifacio, M., Rodeghiero, F., Di Bona, E. )., Castagnetti, F, Gugliotta, G., Breccia, M., Stagno, F., Iurlo, A., Albano, F., Abruzzese, E., Martino, B., Levato, L., Intermesoli, T., Pregno, P., Rossi, G., Gherlinzoni, F., Leoni, P., Cavazzini, F., Venturi, C., Soverini, S., Testoni, N., Alimena, G., Cavo, M., Martinelli, G., Pane, F., Saglio, G., Rosti, G., Baccarani, M., and on behalf of the GIMEMA CML Working Party [, Palandri F.], Pane, Fabrizio, Gugliotta, G, Breccia, M, Stagno, F, Iurlo, A, Albano, F, Abruzzese, E, Martino, B, Levato, L, Intermesoli, T, Pregno, P, Rossi, G, Gherlinzoni, F, Leoni, P, Cavazzini, F, Venturi, C, Soverini, S, Testoni, N, Alimena, G, Cavo, M, Martinelli, G, Pane, F, Saglio, G, Rosti, G, Baccarani, M, and GAMBACORTI PASSERINI, C

Subjects
DIAGNOSED CHRONIC-PHASE, Oncology, Male, Cancer Research, Time Factors, bcr-abl, Fusion Proteins, bcr-abl, Antineoplastic Agent, Hematology, Anesthesiology and Pain Medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Cumulative incidence, Young adult, Chronic, Aged, 80 and over, Leukemia, PATIENTS RECEIVING IMATINIB, CHRONIC MYELOGENOUS LEUKEMIA, TYROSINE KINASE INHIBITORS, BCR-ABL1 TRANSCRIPT LEVELS, EARLY MOLECULAR RESPONSE, CML WORKING PARTY, 3-YEAR FOLLOW-UP, EUROPEAN LEUKEMIANET, 400 MG, Myeloid leukemia, Middle Aged, Prognosis, Treatment Outcome, Retreatment, Imatinib Mesylate, Female, Tyrosine kinase, Human, medicine.drug, Adult, medicine.medical_specialty, Time Factor, Adolescent, Prognosi, Protein Kinase Inhibitor, Socio-culturale, Antineoplastic Agents, Treatment results, Follow-Up Studie, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Internal medicine, medicine, Humans, Protein Kinase Inhibitors, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Fusion Proteins, Imatinib, Follow-Up Studies, Surgery, Imatinib mesylate, BCR-ABL Positive, business, Myelogenous
Abstract

For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.

Published
2015

15. IMPACT OF KIT MUTATIONS IN ACUTE MYELOID LEUKAEMIA WITH INV(16)

Author

Cairoli, R, Beghini, A, Ripamonti, CB, Grillo, G, Nadali, G, Di Bona, E, Colapietro, P, Bertani, GB, Ravelli, E, Nador, G, Castagnola, C, Cattaneo, C, Ottaviani, E, Pioltelli, P, Viola, A, Cuneo, A, Ferrara, F, Martinelli, G, Lazzarino, M, Rossi, G, Pizzolo, G, Morra, E, Cairoli, R, Beghini, A, Ripamonti, C, Grillo, G, Nadali, G, Di Bona, E, Colapietro, P, Bertani, G, Ravelli, E, Nador, G, Castagnola, C, Cattaneo, C, Ottaviani, E, Pioltelli, P, Viola, A, Cuneo, A, Ferrara, F, Martinelli, G, Lazzarino, M, Rossi, G, Pizzolo, G, and Morra, E

Subjects
Hematology
Published
2008

16. Prevalence and prognostic impact of KIT mutations in acute myeloid leukaemia with INV(16)

Author

Cairoli, R, Beghini, A, Ripamonti, CB, Grillo, G, Nadali, G, Di Bona, E, Colapietro, P, Nichelatti, M, Ravelli, E, Nador, G, Cuneo, A, Castagnola, C, Viola, A, Ottaviani, E, Colarossi, S, Cattaneo, C, Parma, M, Pioltelli, P, Ferrara, F, Lazzarino, M, Rossi, G, Rodeghiero, F, Pizzolo, G, Martinelli, G, Morra, E, Cairoli, R, Beghini, A, Ripamonti, C, Grillo, G, Nadali, G, Di Bona, E, Colapietro, P, Nichelatti, M, Ravelli, E, Nador, G, Cuneo, A, Castagnola, C, Viola, A, Ottaviani, E, Colarossi, S, Cattaneo, C, Parma, M, Pioltelli, P, Ferrara, F, Lazzarino, M, Rossi, G, Rodeghiero, F, Pizzolo, G, Martinelli, G, and Morra, E

Subjects
Hematology
Published
2007

18. SIMILAR BUT NOT THE SAME: CHROMOSOMAL ABNORMALITIES T(8;21)(Q22;Q22) AND INV(16)(P13;Q22)/T(16;16)(P13;Q22) IDENTIFY SUBTYPES OF CORE BINDING FACTOR ACUTE MYELOID LEUKEMIA CHARACTERIZED BY DIFFERENT SURVIVAL AND PROGNOS- TIC FACTORS

Author

Mosna, Federico, Gottardi M, 1, Papayannidis C, 1, Di Bona E, 2, Tecchio, Cristina, Can doni A, 4, Forghieri F, 5, Galieni P, 6, Visani G, 7, Zambello R, 8, Volpato F, 9, Martinelli G, 1, and Gherlinzoni F, 2

Subjects
CORE BINDING FACTOR, ACUTE MYELOID LEUKEMIA
Published
2013

20. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance

Author

Avvisati, G, Lo Coco, F, Paoloni, Fp, Petti, Mc, Diverio, D, Vignetti, M, Latagliata, R, Specchia, G, Baccarani, M, Di Bona, E, Fioritoni, G, Marmont, F, Rambaldi, A, DI RAIMONDO, Francesco, Kropp, Mg, Pizzolo, G, Pogliani, Em, Rossi, G, Cantore, N, Nobile, F, Gabbas, A, Ferrara, F, Fazi, P, Amadori, S, Mandelli, F, Gimema, Aieop, and EORTC Cooperative Groups

Published
2011

21. 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

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, Francesco, DI BONA, E, Fazi, P, Peta, A, Bosi, A, Carella, Am, Fabbiano, F, Pogliani, Em, Petti, Mc, Amadori, S, Mandelli, F, and ITALIAN GIMEMA COOPERATIVE GROUP

Published
2010

24. The Italian Way of Treating Acute Promyelocytic Leukemia (APL), Final Act

Author

Avvisati, G., Petti, M. C., LO COCO, F., Testi, A. M., Fazi, P., Specchia, G., Malagola, M., DI BONA, E., Recchia, A., Marmont, F., Buelli, M., Lazzarino, M., DI RAIMONDO, Francesco, Leoni, F., Kropp, M. G., Veneri, D., Micolis, I., Rossi, G., Venditti, A., and Mandelli, F.

Published
2003

31. Treatment of aplastic anaemia with granulocyte-colony stimulating factor and risk of malignancy. Italian Aplastic Anaemia Study Group

Author

Locasciulli, A, Arcese, W, Locatelli, F, Di Bona, E, and Bacigalupo, A

Subjects
Adult, Male, Adolescent, Paroxysmal, Hemoglobinuria, Cyclosporine, Humans, Aged, Child, Mouth Neoplasms, Infant, Leukemia, Hemoglobinuria, Paroxysmal, Anemia, Aplastic, Treatment Outcome, Survival Analysis, Myelodysplastic Syndromes, Immunosuppressive Agents, Child, Preschool, Drug Therapy, Combination, Antilymphocyte Serum, Neoplasms, Granulocyte Colony-Stimulating Factor, Risk Factors, Follow-Up Studies, Middle Aged, Female, Drug Therapy, Preschool, Aplastic, Anemia, Combination, Settore MED/15 - Malattie del Sangue
Published
2001

36. Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

Author

de Latour, R. Peffault, Roth, A., Kulasekararaj, A. G., Han, B., Scheinberg, P., Maciejewski, J. P., Ueda, Y., de Castro, C. M., Di Bona, E., Fu, R., Zhang, L., Griffin, M., Langemeijer, S. M. C., Panse, J., Schrezenmeier, H., Barcellini, W., Mauad, V. A. Q., Schafhausen, P., Tavitian, S., and Beggiato, E.

Subjects
*PAROXYSMAL hemoglobinuria, *CLINICAL trials, *COMPLEMENT inhibition, *HEMOLYTIC anemia, *LACTATE dehydrogenase
Abstract

Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusions; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients received no transfusion; none of the patients in the second trial received transfusions. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia -- in whom iptacopan showed superiority to anti-C5 therapy -- and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.) [ABSTRACT FROM AUTHOR]

Published
2024
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37. Therapy-Related Myelodysplastic Syndrome (sMDS) /Acute Myelogenous Leukemia (sAML) in Acute Promyelocytic Leukemia (APL) Patients with Long-Lasting Molecular Remission: The GIMEMA Experience.

Author

Latagliata, R., Breccia, M., Fazi, P., Gubbiotti, S., Di Bona, E., Specchia, G., Chiarenza, A., Murru, R., Carella, A.M., Ferrara, F., Rossi, G., Melillo, L., Sica, S., Invernizzi, R., Cimino, G., Petti, M.C., Avvisati, G., Lo-Coco, F., and Mandelli, F.

Published
2005
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39. Real-world efficacy and safety of luspatercept and predictive factors of response in patients with lower risk myelodysplastic syndromes with ring sideroblasts

Author

Lanino, L., Restuccia, F., Perego, A., Ubezio, M., Fattizzo, B., Riva, M., Consagra, A., Musto, P., Cilloni, D., Oliva, E. N., Palmieri, R., Poloni, A., Califano, C., Capodanno, I., Itri, F., Elena, C., Fozza, C., Pane, F., Pelizzari, A. M., Breccia, M., Di Bassiano, F., Crisa, E., Ferrero, D., Giai, V., Barraco, D., Vaccarino, A., Griguolo, D., Minetto, P., Quintini, M., Paolini, S., Sanpaolo, G., Sessa, M., Bocchia, M., Di Renzo, N., Diral, E., Leuzzi, L., Genua, A., Guarini, A., Molteni, A., Nicolino, B., Occhini, U., Rivoli, G., Bono, R., Calvisi, A., Castelli, A., Di Bona, E., Di Veroli, A., Ferrara, F., Fianchi, L., Galimberti, S., Grimaldi, D., Marchetti, M., Norata, M., Frigeni, M., Sancetta, R., Selleri, C., Tanasi, I., Tosi, P., Turrini, M., Giordano, L., Finelli, C., Pasini, P., Naldi, I., Santini, V., and Della Porta, M. G.

40. Perspectives and Emotional Experiences of Patients With Chronic Myeloid Leukemia During ENESTPath Clinical Trial and Treatment-Free Remission: Rationale and Protocol of the Italian Substudy

Author

Elena Vegni, Chiara Elena, Gianantonio Rosti, Eros Di Bona, Simona Sica, Claudia Minotto, Gaetano La Barba, Sharon Supekar, Flavia Rivellini, Massimo Breccia, Luca Arcaini, Fabio Ciceri, I Capodanno, Sara Galimberti, Luigi Di Caprio, Antonio Cuneo, Alessandro Maggi, Paolo Sportoletti, Alessandra Iurlo, Giovanna Rege Cambrin, Enrico Capochiani, Francesco Albano, Lidia Borghi, Michele Baccarani, Massimiliano Bonifacio, Monica Crugnola, Borghi, L., Rosti, G., Maggi, A., Breccia, M., Di Bona, E., Iurlo, A., La Barba, G., Sportoletti, P., Albano, F., Galimberti, S., Rivellini, F., Cambrin, G. R., Capodanno, I., Cuneo, A., Bonifacio, M., Sica, S., Arcaini, L., Capochiani, E., Minotto, C., Ciceri, F., Crugnola, M., Di Caprio, L., Supekar, S., Elena, C., Baccarani, M., and Vegni, E.

Subjects
0301 basic medicine, Cancer Research, Pediatrics, medicine.medical_specialty, Randomization, Chronic myeloid leukemia, ENESTPath, emotional experience, mixed methods, nilotinib, psychological distress, quality of life, study protocol, Dysfunctional family, NO, 03 medical and health sciences, 0302 clinical medicine, Quality of life, medicine, Methods, RC254-282, business.industry, Myeloid leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Imatinib, Clinical trial, Distress, 030104 developmental biology, Nilotinib, Oncology, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian ‘patient’s voice CML’ substudy was to evaluate patients’ psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive BCR-ABL1+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed via patients’ emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination.NCT number: NCT01743989, EudraCT number: 2012-005124-15

Published
2021

41. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: The NEXT-in-CML study

Author

Anna Serra, Antonio Percesepe, Gabriele Gugliotta, Caterina Musolino, Gianni Binotto, Elisabetta Abruzzese, Immacolata Attolico, Gianantonio Rosti, Mario Annunziata, Rosaria Sancetta, Mariella Girasoli, Fabrizio Pane, Maria Antonella Laginestra, Sara Galimberti, Alessandra Iurlo, Stefania Stella, Sabrina Coluzzi, Simona Sica, Monica Bocchia, Marzia Salvucci, Francesca Lunghi, Fabio Stagno, Nicola Orofino, Stefano Pileri, Federica Sorà, Santa Errichiello, Elisabetta Calistri, Paolo Vigneri, Fausto Castagnetti, Michele Baccarani, Luana Bavaro, Michele Cavo, Eros Di Bona, Francesco Di Raimondo, Claudia Baratè, Margherita Martelli, Simona Soverini, Antonella Russo Rossi, Francesco Albano, Mariella D'Adda, Fabio Ciceri, Flavio Mignone, Elena Tenti, Caterina De Benedittis, Giuseppe Saglio, Isabella Capodanno, Giovanni Martinelli, Massimiliano Bonifacio, Luigi Scaffidi, Soverini, S., Bavaro, L., de Benedittis, C., Martelli, M., Iurlo, A., Orofino, N., Sica, S., Sora, F., Lunghi, F., Ciceri, F., Galimberti, S., Barate, C., Bonifacio, M., Scaffidi, L., Castagnetti, F., Gugliotta, G., Albano, F., Rossi, A. V. R., Stagno, F., di Raimondo, F., D'Adda, M., di Bona, E., Abruzzese, E., Binotto, G., Sancetta, R., Salvucci, M., Capodanno, I., Girasoli, M., Coluzzi, S., Attolico, I., Musolino, C., Calistri, E., Annunziata, M., Bocchia, M., Stella, S., Serra, A., Errichiello, S., Saglio, G., Pane, F., Vigneri, P., Mignone, F., Laginestra, M. A., Pileri, S. A., Percesepe, A., Tenti, E., Rosti, G., Baccarani, M., Cavo, M., Martinelli, G., Soverini, Simona, Bavaro, Luana, De Benedittis, Caterina, Martelli, Margherita, Iurlo, Alessandra, Orofino, Nicola, Sica, Simona, Sora, Federica, Lunghi, Francesca, Ciceri, Fabio, Galimberti, Sara, Baratè, Claudia, Bonifacio, Massimiliano, Scaffidi, Luigi, Castagnetti, Fausto, Gugliotta, Gabriele, Albano, Francesco, Russo Rossi, Antonella Vita, Stagno, Fabio, Di Raimondo, Francesco, D'Adda, Mariella, Di Bona, Ero, Abruzzese, Elisabetta, Binotto, Gianni, Sancetta, Rosaria, Salvucci, Marzia, Capodanno, Isabella, Girasoli, Mariella, Coluzzi, Sabrina, Attolico, Immacolata, Musolino, Caterina, Calistri, Elisabetta, Annunziata, Mario, Bocchia, Monica, Stella, Stefania, Serra, Anna, Errichiello, Santa, Saglio, Giuseppe, Pane, Fabrizio, Vigneri, Paolo G, Mignone, Flavio, Laginestra, Maria Antonella, Pileri, Stefano A, Percesepe, Antonio, Tenti, Elena, Rosti, Gianantonio, Baccarani, Michele, Cavo, Michele, and Martinelli, Giovanni

Subjects
Oncology, Male, Mutation rate, bcr-abl, Drug Resistance, Fusion Proteins, bcr-abl, Gene mutation, medicine.disease_cause, Settore MED/01 - STATISTICA MEDICA, Biochemistry, Adult, Aged, Aged, 80 and over, Drug Resistance, Neoplasm, Female, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Middle Aged, Mutation, Mutation Rate, Prospective Studies, Protein Kinase Inhibitors, hemic and lymphatic diseases, 80 and over, cml mutation, BCR-ABL mutations, Chronic, Prospective cohort study, Sanger sequencing, Leukemia, Chronic myeloid leukemia, Myeloid leukemia, Hematology, TKI, NGS, symbols, Human, medicine.medical_specialty, Immunology, symbols.namesake, CML, TKIs, BCR-ABL1, Chronic myeloid leukemia,TKI,BCR-ABL mutations,Sanger Sequencing,NGS, Internal medicine, medicine, business.industry, Fusion Proteins, Cell Biology, medicine.disease, Clinical trial, Prospective Studie, Sanger Sequencing, Neoplasm, BCR-ABL Positive, business, Myelogenous
Abstract

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Published
2020

42. Increased tumor burden in patients with chronic myeloid leukemia after 36 months of imatinib discontinuation

Author

Silvia Mori, Bruno Martino, Sarit Assouline, Micaela Bergamaschi, Eros Di Bona, Marcio Andrade-Campos, Chiara Elena, Patrizia Crivori, Ester Pungolino, Alessandra Iurlo, Antonella Gozzini, Philipp le Coutre, Elisa Diral, Elisabetta Abruzzese, Laura Antolini, Alessandra Pirola, Diletta Fontana, Fabio Stagno, Maria Luisa Bonanomi, Rocco Piazza, Carmen Fava, Carlo Gambacorti-Passerini, Jessica Petiti, Diral, E, Mori, S, Antolini, L, Abruzzese, E, Le Coutre, P, Martino, B, Pungolino, E, Elena, C, Bergamaschi, M, Assouline, S, Di Bona, E, Gozzini, A, Andrade-Campos, M, Stagno, F, Iurlo, A, Pirola, A, Fontana, D, Petiti, J, Bonanomi, M, Crivori, P, Piazza, R, Fava, C, and Gambacorti Passerini, C

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Adolescent, Immunology, Tumor burden, Antineoplastic Agents, Biochemistry, Young Adult, chronic myeloid leukemia, MED/15 - MALATTIE DEL SANGUE, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Recurrence free survival, Internal medicine, medicine, Humans, In patient, Aged, Aged, 80 and over, business.industry, Myeloid leukemia, Imatinib, clinical trial, Cell Biology, Hematology, Middle Aged, Prognosis, BCR-ABL protein, Tumor Burden, Discontinuation, Survival Rate, Withholding Treatment, Imatinib Mesylate, Female, business, Follow-Up Studies, Cohort study, medicine.drug, discontinuation
Abstract

TO THE EDITOR: The Imatinib Suspension and Validation (ISAV) study1 is a multicenter trial of imatinib discontinuation (ID) among patients with chronic myeloid leukemia (CML) in undetectable deep molecular remission (U-DMR). After 12 months of follow-up, 48% of patients relapsed (total n = 107), with the majority of relapses occurring within the first 9 months. An inverse relationship between patient age and risk of relapse was also observed at this timepoint. Here we report the final results of ISAV after a median follow-up of 49 months, as well as the dynamics of leukemic tumor load as determined by digital polymerase chain reaction (dPCR) in nonrelapsed patients. This trial is registered at www.clinicaltrials.gov (NCT01578213). Eligible patients were 18 years and older and had CML, either in chronic or accelerated phase, with U-DMR of at least 18 months’ duration and at least...

Published
2020

43. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia.

Author

Lo-Coco, F., Awisati, G., Vignett, M., Thiede, C., Orlando, S. M., lacobelli, 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, H. R., and Cazzola, M.

Subjects
*ACUTE promyelocytic leukemia, *TRETINOIN, *ARSENIC trioxide, *CANCER chemotherapy, *CANCER treatment
Abstract

The article discusses a study that compared the efficacy and toxicity of standard all-trans retinoic acid (ATRA) plus chemotherapy with ATRA plus arsenic trioxide in patients with low-to-intermediate-risk acute promyelocytic leukemia (APL). Findings show that ATRA plus arsenic trioxide may be superior to ATRA plus chemotherapy in the treatment of low-to-intermediate-risk APL. All 77 patients in the ATRA-arsenic trioxide group achieved complete remission.

Published
2013
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44. 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

Author

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

45. Increased Tumour Burden over a 36 Month Period in Chronic Myeloid Leukemia Patients Following Imatinib Discontinuation: Role of Digital PCR

Author

Chiara Elena, Eros Di Bona, Elisa Diral, Enrico Gottardi, Philipp le Coutre, Alessandra Pirola, Micaela Bergamaschi, Dong-Wook Kim, Jessica Petiti, Alessandra Iurlo, Maria Luisa Bonanomi, Rocco Piazza, Carmen Fava, Patrizia Crivori, Fabio Stagno, Carlo Gambacorti-Passerini, Sarit Assouline, Diral, E, Le Coutre, P, Gottardi, E, Elena, C, Bergamaschi, M, Assouline, S, Di Bona, E, Petiti, J, Stagno, F, Iurlo, A, Kim, D, Pirola, A, Bonanomi, M, Crivori, P, Piazza, R, Fava, C, and Gambacorti-Passerini, C

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Immunology, Tumor burden, Leukemia Myelogenous Chronic, BCR-ABL Positive, polymerase chain reaction, neoplasms, reverse transcriptase polymerase chain reaction, imatinib mesylate, protein-tyrosine kinase inhibitor, disease remission, Positive control, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, MED/15 - MALATTIE DEL SANGUE, hemic and lymphatic diseases, Internal medicine, medicine, Digital polymerase chain reaction, business.industry, Myeloid leukemia, Imatinib, Cell Biology, Hematology, Discontinuation, 030104 developmental biology, Imatinib mesylate, Functional status, business, 030215 immunology, medicine.drug
Abstract

Introduction. Discontinuation (D/C) of Imatinib or other TKIs in Chronic Myeloid Leukemia (CML) represents an important issue in the management of this disease. It is generally accepted that relapse develops (and treatment must be resumed) when patients (pts) lose Major Molecular Remission (MMR), i.e. when the amount of the BCR-ABL1 transcript, measured in peripheral blood by RT-PCR, exceeds 0.1 %. The Imatinib Suspension And Validation (ISAV) study, which started in 2011, enrolled pts with CML treated with Imatinib who showed no evidence of BCR-ABL1 transcript for at least 18 months before enrollment. Methods. A digital PCR (dPCR) for BCR-ABL1 was performed at the time of Imatinib D/C while a second dPCR was performed when non relapsed patients exited the study, 36 months later. dPCR experiments were performed by the QX200 system (BioRad) in the same lab and using the same methodology. The BCR-ABL1 fusion and ABL1 transcripts were quantified using DigiDrop P210 MasterMix and DigiDrop P210 Positive Control (Bioclarma), according to manufacturer's protocol. The target concentration in each sample was expressed as percentage of BCR-ABL1/ABL1. Results. A total of 107 pts were enrolled in the ISAV study. Relapses occurred in 54 pts (52%); among the 53 non relapsed pts, 41 (77%) presented at least one positive RT-PCR result following Imatinib D/C, and only 12 (23%) maintained PCR negativity throughout the duration of the study. Among the non-relapsed pts dPCR performed at treatment D/C showed positivity in 20.6% of cases (95% confidence interval [C.I.] 9-36%), while 91.1% of pts (95%, C.I. 80-97%) evaluated 36 months later showed a positive dPCR value, although no patient resumed treatment. The evaluation of non relapsed pts by dPCR showed that mean values at D/C were 0.00143% +/- 0.0006 (SE); when tested at study exit, the same pts showed average dPCR values of 0.0115 % +/- 0.002. This difference is statistically highly significant and corresponds to a change of approximately 1 log in the residual tumor burden: from 2x107 to 2x108 cells. There was no correlation between the results of RT-PCR performed during the study and the dPCR status at study exit: pts who tested negative by RT-PCR during the study were uniformly negative in dPCR at D/C but tested positive at study exit in 83.3% of cases; pts who showed at least on positive RT-PCR during the study showed positivity by dPCR in 25% at D/C and in 89.3% at study exit. Finally, half of the pts who tested negative by dPCR at study exit showed dPCR positivity when tested at the time of Imatinib D/C. Conclusions. These results show that during a three year period, the D/C of Imatinib led to the increase of approximately 1 log in the tumour burden of non-relapsed pts, although none of them lost MMR and resumed treatment. These data strongly indicate the need for a long-term monitoring of pts who D/C Imatinib; they also suggest that the functional status of residual CML cells rather than their number could represent the critical factor to predict the tumour load present after 3 years of Imatinib D/C. Disclosures Le Coutre: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Elena:Novartis: Consultancy; Pfizer: Consultancy. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Stagno:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding. Fava:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

Published
2019

46. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance

Author

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

47. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL)

Author

Eros Di Bona, Daniele Mattei, Renato Bassan, Anna Maria Scattolin, Alberto Bosi, Enrico Maria Pogliani, Elena Oldani, Elisabetta Terruzzi, Orietta Spinelli, Fabio Ciceri, Barbara Peruta, Alessandro Rambaldi, Andrea Gallamini, P. Fabris, Agostino Cortelezzi, Manuela Tosi, Giacomo Gianfaldoni, Tamara Intermesoli, Giuseppe Rossi, Erika Borlenghi, Giorgio Lambertenghi-Deliliers, Massimo Bernardi, Tiziano Barbui, Claudio Romani, Vincenzo Cassibba, Bassan, R, Spinelli, O, Oldani, E, Intermesoli, T, Tosi, M, Peruta, B, Rossi, G, Borlenghi, E, Pogliani, E, Terruzzi, E, Fabris, P, Cassibba, V, Lambertenghi Deliliers, G, Cortelezzi, A, Bosi, A, Gianfaldoni, G, Ciceri, F, Bernardi, M, Gallamini, A, Mattei, D, Di Bona, E, Romani, C, Scattolin, A, Barbui, T, Rambaldi, A, Pogliani, Em, Ciceri, Fabio, Scattolin, Am, and Rambaldi, A.

Subjects
Oncology, Male, Neoplasm, Residual, Transplantation Conditioning, Oncogene Proteins, Fusion, medicine.medical_treatment, Biochemistry, Translocation, Genetic, Risk Factors, MED/15 - MALATTIE DEL SANGUE, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Transplantation, Homologou, Hematology, Hazard ratio, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Chemotherapy regimen, Combined Modality Therapy, Survival Rate, Treatment Outcome, Female, Human, Adult, medicine.medical_specialty, Adolescent, Prognosi, Immunology, Young Adult, Acute lymphocytic leukemia, Internal medicine, medicine, Humans, Transplantation, Homologous, Aged, Chemotherapy, Antineoplastic Combined Chemotherapy Protocol, business.industry, Risk Factor, Cell Biology, medicine.disease, Minimal residual disease, Surgery, Transplantation, Prospective Studie, Adult Acute Lymphoblastic Leukemia, business, Stem Cell Transplantation
Abstract

Clinical risk classification is inaccurate in predicting relapse in adult patients with acute lymphoblastic leukemia, sometimes resulting in patients receiving inappropriate chemotherapy or stem cell transplantation (SCT). We studied minimal residual disease (MRD) as a predictive factor for recurrence and as a decisional tool for postconsolidation maintenance (in MRDneg) or SCT (in MRDpos). MRD was tested at weeks 10, 16, and 22 using real-time quantitative polymerase chain reaction with 1 or more sensitive probes. Only patients with t(9;22) or t(4;11) were immediately eligible for allogeneic SCT. Of 280 registered patients (236 in remission), 34 underwent an early SCT, 60 suffered from relapse or severe toxicity, and 142 were evaluable for MRD at the end of consolidation. Of these, 58 were MRDneg, 54 MRDpos, and 30 were not assessable. Five-year overall survival/disease-free survival rates were 0.75/0.72 in the MRDneg group compared with 0.33/0.14 in MRDpos (P = .001), regardless of the clinical risk class. MRD was the most significant risk factor for relapse (hazard ratio, 5.22). MRD results at weeks 16 to 22 correlated strongly with the earlier time point (P = .001) using a level of 10−4 or higher to define persistent disease. MRD analysis during early postremission therapy improves risk definitions and bolsters risk-oriented strategies. ClinicalTrials.gov identifier: NCT00358072.

Published
2009

48. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab

Author

Lucio Luzzatto, Patrizia Ricci, Giorgio Fratellanza, Anna Paola Iori, Angela Amendola, Antonio M. Risitano, Giacomo Gianfaldoni, Francesco Rodeghiero, Andrea Camera, Rosario Notaro, Filippo Barbano, Eros Di Bona, Fiorella Alfinito, Ludovica Marando, Bruno Rotoli, Carla Boschetti, Elisa Seneca, Bianca Serio, Carmine Selleri, Alberto Zanella, Danilo Ranaldi, Risitano, ANTONIO MARIA, Notaro, R, Marando, L, Serio, B, Ranaldi, D, Seneca, E, Ricci, P, Alfinito, Fiorella, Camera, A, Gianfaldoni, G, Amendola, A, Boschetti, C, Di Bona, E, Fratellanza, Giorgio, Barbano, F, Rodeghiero, F, Zanella, A, Iori, Ap, Selleri, Carmine, Luzzatto, L, and Rotoli, B.

Subjects
Hemolytic anemia, Male, medicine.medical_specialty, Erythrocytes, Cell Survival, Immunology, Hemoglobinuria, Paroxysmal, CD59, Antibodies, Monoclonal, Humanized, Biochemistry, Blood cell, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Hematology, biology, business.industry, Antibodies, Monoclonal, hemic and immune systems, Cell Biology, Complement C3, Eculizumab, medicine.disease, Flow Cytometry, Red blood cell, medicine.anatomical_structure, Paroxysmal nocturnal hemoglobinuria, biology.protein, Female, Immunotherapy, Antibody, business, circulatory and respiratory physiology, medicine.drug
Abstract

In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59−). The proportion of C3+ RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom 51Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess 51Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.

Published
2009

49. Prevalence and prognostic impact of KIT mutations in acute myeloid leukaemia with inv(16). A retrospective study

Author

Erika Ravelli, Giovanni Grillo, Enrico Di Bona, Emanuela Ottaviani, Gianbattista Bertani, Roberto Cairoli, Francesco Rodeghiero, Giovanni Martinelli, Antonio Cuneo, Mario Lazzarino, Pietro Pioltelli, Michele Nichelatti, Alessandro Beghini, Enrica Morra, Giuseppe Rossi, Felicetto Ferrara, Gianpaolo Nadali, Patrizia Colapietro, Giovanni Pizzolo, Carla B. Ripamonti, Cairoli, R, Beghini, A, Ripamonti, C, Grillo, G, Nadali, G, Di Bona, E, Colapietro, P, Nichelatti, M, Bertani, G, Ravelli, E, Cuneo, A, Ottaviani, E, Pioltelli, P, Ferrara, F, Lazzarino, M, Rossi, G, Rodeghiero, F, Pizzolo, G, Martinelli, G, and Morra, E

Subjects
Genetics, medicine.medical_specialty, brachial plexus neuritis, chemotherapy regimen, complete remission, follow-up, leukemia, myelocytic, acute, leukocyte count, mutation, polymerase chain reaction, screening, log rank test, business.industry, Incidence (epidemiology), Immunology, Retrospective cohort study, Cell Biology, Hematology, Biochemistry, Chemotherapy regimen, Gastroenterology, law.invention, Log-rank test, Exon, Exact test, law, Internal medicine, Mann–Whitney U test, Medicine, business, Polymerase chain reaction
Abstract

Introduction Several studies have recently pointed out the adverse impact of KIT mutations (mutKIT) on relapse incidence (RI) and overall survival (OS) in AML pts with t(8;21). By contrast, the prognostic significance of mutKIT in pts with inv(16) remains unclear. Purpose of this study is to evaluate the prevalence and the prognostic impact of mutKIT in inv(16)(p13q22). Patients and Methods Fifty adults with inv(16) AML at diagnosis (median age 46.6 yrs, range: 17–88; M/F: 30 /20), were centrally analyzed for mutKIT in exon 2, 8, 10, 11 and 17. Mutations were detected using sequencing and other sensitive assays such as ARMS (amplification refractory mutation system) PCR for D816Y and D816H and enzymatic digestion with HINFI for D816V and with Tsp509I for N822K. Results Data showed a prevalence of KIT mutation of 34% (17/50 pts). Among the mutKIT cases, we detected mutations in exon 17 (n=12), exon 8 (n= 4) and exon 10 (n=1). There was no difference between the mutKIT vs the unmutated (KIT-) patients in the median of WBC count at presentation (WBC 13.9 x109/L, range 4.4 to 277.5 vs 19.4 x109/L, range 2.5 to 130; Mann-Whitney U test: p = 0.649). Of the 42 patients (age < 60 years) who received intensive chemotherapy, 13 resulted mutKIT upon mutational screening. Complete remission (CR) was achieved in 13/13 (100%) mutKIT vs 27/29 (93%) KIT- patients (Fisher’s exact test: p > 0.999). At a median follow-up of 26 months (range: 2–144), 9/13 (69%) mutKIT and 8/27 (29%)KIT- pts relapsed;the Kaplan-Meier plots revealed KIT mutations to be a significant factor adversely affecting RI (log-rank test: p = 0.017) but not OS (61% in mutKIT vs 75% in KIT-;log-rank test: p = 0.331). Conclusion KIT mutations are associated with a greater probability of relapse following CR, without affecting OS, in AML pts with inv(16) aged

Published
2007

50. Gemtuzumab Ozogamicin (Mylotarg) as a single agent for moleculary relapsed acute promyelocytic leukemia

Author

Adriano Venditti, Erica Finolezzi, Mariagrazia Kropp, Massimo Breccia, Agostino Tafuri, Daniela Diverio, Franco Mandelli, Eros Di Bona, Concetta Micalizzi, Nélida I. Noguera, Francesco Lo-Coco, Giuseppe Cimino, Enrico Pogliani, Lo Coco, F, Cimino, G, Breccia, M, Noguera, N, Diverio, D, Finolezzi, E, Pogliani, E, Di Bona, E, Micalizzi, C, Kropp, M, Venditti, A, Tafuri, A, and Mandelli, F

Subjects
Oncology, Male, Time Factors, medicine.medical_treatment, Biochemistry, Antineoplastic Agent, chemistry.chemical_compound, Leukemia, Promyelocytic, Acute, Recurrence, MED/15 - MALATTIE DEL SANGUE, Reverse Transcriptase Polymerase Chain Reaction, Progressive multifocal leukoencephalopathy, Immunotoxins, Remission Induction, Antibodies, Monoclonal, Hematology, Middle Aged, Gemtuzumab, Leukemia, Treatment Outcome, Monoclonal, Disease Progression, Female, medicine.drug, Human, Acute promyelocytic leukemia, Adult, medicine.medical_specialty, Adolescent, Time Factor, Gemtuzumab ozogamicin, Immunology, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, Disease-Free Survival, Internal medicine, Calicheamicin, medicine, Humans, Aged, Chemotherapy, Aminoglycoside, business.industry, Cell Biology, medicine.disease, Surgery, Clinical trial, Aminoglycosides, chemistry, business, Settore MED/15 - Malattie del Sangue
Abstract

The anti-CD33 antibody calicheamicinconjugate gemtuzumab ozogamicin (GO) was used to treat 16 patients with acute promyelocytic leukemia (APL) who had relapsed at the molecular level. Of these patients, 8 were experiencing a first, 5 a second, 2 a third, and 1 a fourth relapse. GO was administered at 6 mg/m2 for 2 doses, and patients achieving a new molecular remission (MR) (ie, negativity of the reverse transcriptase-polymerase chain reaction [RT-PCR] test for PML/RARalpha) received a third dose. MR was obtained in 9 (91%) of 11 patients tested after 2 doses and in 13 (100%) of 13 patients tested after the third dose. Of the 3 remaining patients, 1 achieved MR after one GO administration and received no further therapy owing to hepatic toxicity, and 2 showed disease progression during treatment. Quantitative RT-PCR studies showed that responding patients experienced a dramatic decline (at least 2 logs) of the PML/RARalpha transcript after the first GO dose. Of 14 responders, 7 remained in sustained MR for a median of 15 months (range, 7-31 months) while 7 experienced relapse at 3 to 15 months. GO was administered again in 2 patients with relapse, and both obtained a new MR. These data indicate that GO is highly effective as a single treatment for patients with molecularly relapsed APL including those with very advanced disease.

Published
2004

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