Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005)

Summary

Primary objectives * To evaluate the efficacy and toxicity of a risk-adapted protocol that use idarubicin for induction and consolidation therapy in patients with APL. * To evaluate the impact of mitoxantrone reduction on the event-free, disease-free, and overall survival, as well as on the duration of remission and cumulative incidence of relapse in low- and intermediate-risk patients with APL. * To evaluate the impact of the addition of ara-C to idarubicin courses of consolidation for high-risk patients (administered as in the original GIMEMA protocols) on the event-free, disease-free, and overall survival, as well as on the duration of remission and cumulative incidence of relapse. * To evaluate the toxicity of the induction, consolidation, and maintenance chemotherapy in the whole series and in each treatment group in patients with APL. Secondary objectives • To compare all outcomes with those achieved with the PETHEMA LPA99 protocol.

Timeline

Start

2005-07

Primary completion

2012-04

Completion

2013-12

Publications

• Background Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002 Feb 1;99(3):759-67. doi: 10.1182/blood.v99.3.759.
• Background Ohno R, Asou N, Ohnishi K. Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate. Leukemia. 2003 Aug;17(8):1454-63. doi: 10.1038/sj.leu.2403031.
• Background Sanz MA, Martin G, Lo Coco F. Choice of chemotherapy in induction, consolidation and maintenance in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003 Sep;16(3):433-51. doi: 10.1016/s1521-6926(03)00040-9.
• Background Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, Omoto E, Akiyama H, Tsubaki K, Saito K, Kuriyama K, Oh H, Kitano K, Miyawaki S, Takeyama K, Yamada O, Nishikawa K, Takahashi M, Matsuda S, Ohtake S, Suzushima H, Emi N, Ohno R. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol. 1998 Jan;16(1):78-85. doi: 10.1200/JCO.1998.16.1.78.
• Background Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood. 1999 Jun 15;93(12):4131-43.
• Background Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999 Aug 15;94(4):1192-200.
• Background Lengfelder E, Reichert A, Schoch C, Haase D, Haferlach T, Loffler H, Staib P, Heyll A, Seifarth W, Saussele S, Fonatsch C, Gassmann W, Ludwig WD, Hochhaus A, Beelen D, Aul C, Sauerland MC, Heinecke A, Hehlmann R, Wormann B, Hiddemann W, Buchner T. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia. 2000 Aug;14(8):1362-70. doi: 10.1038/sj.leu.2401843.
• Background Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T, Diaz-Mediavilla J, Fioritoni G, Gonzalez JD, Liso V, Esteve J, Ferrara F, Bolufer P, Bernasconi C, Gonzalez M, Rodeghiero F, Colomer D, Petti MC, Ribera JM, Mandelli F. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000 Aug 15;96(4):1247-53.
• Background Sanz MA, Martin G, Gonzalez M, Leon A, Rayon C, Rivas C, Colomer D, Amutio E, Capote FJ, Milone GA, De La Serna J, Roman J, Barragan E, Bergua J, Escoda L, Parody R, Negri S, Calasanz MJ, Bolufer P; Programa de Estudio y Traitmiento de las Hemopatias Malignas. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004 Feb 15;103(4):1237-43. doi: 10.1182/blood-2003-07-2462. Epub 2003 Oct 23.
• Background Grimwade D, Gorman P, Duprez E, Howe K, Langabeer S, Oliver F, Walker H, Culligan D, Waters J, Pomfret M, Goldstone A, Burnett A, Freemont P, Sheer D, Solomon E. Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. Blood. 1997 Dec 15;90(12):4876-85.
• Background van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diaz MG, Malec M, Langerak AW, San Miguel JF, Biondi A. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999 Dec;13(12):1901-28. doi: 10.1038/sj.leu.2401592.
• Background Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, Pasqualucci L, Biondi A, Riganelli D, Orleth A, Liso A, Martelli MF, Pelicci PG, Pileri S. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997 Nov 15;90(10):4046-53.
• Background Gomis F, Sanz J, Sempere A, Plume G, Senent ML, Perez ML, Cervera J, Moscardo F, Bolufer P, Barragan E, Martin G, Sanz MA. Immunofluorescent analysis with the anti-PML monoclonal antibody PG-M3 for rapid and accurate genetic diagnosis of acute promyelocytic leukemia. Ann Hematol. 2004 Nov;83(11):687-90. doi: 10.1007/s00277-004-0902-7. Epub 2004 Jul 24.
• Martinez-Cuadron D, Montesinos P, Vellenga E, Bernal T, Salamero O, Holowiecka A, Brunet S, Gil C, Benavente C, Ribera JM, Perez-Encinas M, De la Serna J, Esteve J, Rubio V, Gonzalez-Campos J, Escoda L, Amutio ME, Arnan M, Arias J, Negri S, Lowenberg B, Sanz MA. Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy. Leukemia. 2018 Jan;32(1):21-29. doi: 10.1038/leu.2017.178. Epub 2017 Jun 6.
• Sanz MA, Montesinos P, Kim HT, Ruiz-Arguelles GJ, Undurraga MS, Uriarte MR, Martinez L, Jacomo RH, Gutierrez-Aguirre H, Melo RA, Bittencourt R, Pasquini R, Pagnano K, Fagundes EM, Vellenga E, Holowiecka A, Gonzalez-Huerta AJ, Fernandez P, De la Serna J, Brunet S, De Lisa E, Gonzalez-Campos J, Ribera JM, Krsnik I, Ganser A, Berliner N, Ribeiro RC, Lo-Coco F, Lowenberg B, Rego EM; IC-APL and PETHEMA and HOVON Groups. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies. Ann Hematol. 2015 Aug;94(8):1347-56. doi: 10.1007/s00277-015-2393-0. Epub 2015 May 15.
• Montesinos P, Rayon C, Vellenga E, Brunet S, Gonzalez J, Gonzalez M, Holowiecka A, Esteve J, Bergua J, Gonzalez JD, Rivas C, Tormo M, Rubio V, Bueno J, Manso F, Milone G, de la Serna J, Perez I, Perez-Encinas M, Krsnik I, Ribera JM, Escoda L, Lowenberg B, Sanz MA; PETHEMA; HOVON Groups. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens. Blood. 2011 Feb 10;117(6):1799-805. doi: 10.1182/blood-2010-04-277434. Epub 2010 Dec 8.
• Sanz MA, Montesinos P, Rayon C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, Gonzalez J, Diaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, Gonzalez JD, Lowenberg B; PETHEMA and HOVON Groups. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010 Jun 24;115(25):5137-46. doi: 10.1182/blood-2010-01-266007. Epub 2010 Apr 14.

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