Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic leukemia previously treated with ATRA and chemotherapy
Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21–128 months), the 4-year OS probability was 0.85 (95% CI 0.61–0.94), DFS was 0.74 (95% CI 0.49–0.88), and EFS 0.68 (95% CI 0.45–0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.
KeywordsAcute promyelocytic leukemia ATO ATRA Molecular relapse Stem cell transplant
LC, MB, FLC, MM, MD, DD, MR, and MTV collected and analyzed the data; LC, FLC, and MB wrote the paper; MB, LC, and FLC designed the study; TO, VA, LI, DD, and MD collected and analyzed sample and revised the manuscript.
This study received financial support from Associazione Italiana Ricerca sul Cancro (AIRC, IG N. 5916 to FLC and fellowship 19738 LC) and from Associazione italiana contro le Leucemie-Linfomi e Mieloma (AIL).
Compliance with ethical standards
Conflict of interest
LC received honorary for speaker’s bureau from TEVA; FLC and MB received honorary for speaker’s bureau and advisory board from TEVA.
- 2.Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, Fuerth B, Christofides A, Schuh AC (2014) A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol 21:234–250. https://doi.org/10.3747/co.21.2183 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Holter Chakrabarty JL, Rubinger M, Le-Rademacher J et al (2014) Autologous is superior to allogeneic hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant 20:1021–1025. https://doi.org/10.1016/j.bbmt.2014.03.025 CrossRefPubMedGoogle Scholar
- 6.Yanada M, Tsuzuki M, Fujita H, Fujimaki K, Fujisawa S, Sunami K, Taniwaki M, Ohwada A, Tsuboi K, Maeda A, Takeshita A, Ohtake S, Miyazaki Y, Atsuta Y, Kobayashi Y, Naoe T, Emi N, on behalf of the Japan Adult Leukemia Study Group (2013) Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 121:3095–3102. https://doi.org/10.1182/blood-2012-11-466862 CrossRefPubMedGoogle Scholar
- 8.Ganzel C, Mathews V, Alimoghaddam K, Ghavamzadeh A, Kuk D, Devlin S, Wang H, Zhang MJ, Weisdorf D, Douer D, Rowe JM, Polge E, Esteve J, Nagler A, Mohty M, Tallman MS (2016) Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplant 51:1180–1183. https://doi.org/10.1038/bmt.2016.96 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin M, Hunter A, Clark RE, Grimwade D, UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group (2015) Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 16:1295–1305. https://doi.org/10.1016/S1470-2045(15)00193-X CrossRefPubMedGoogle Scholar
- 10.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, Platzbecker U, Gruppo Italiano Malattie Ematologiche dell’Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance Leukemia (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369:111–121. https://doi.org/10.1056/NEJMoa1300874 CrossRefPubMedGoogle Scholar
- 12.van Dongen JJ, Macintyre EA, Gabert JA et al (1999) 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 13:1901–1928CrossRefGoogle Scholar
- 13.Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, Barbany G, Cazzaniga G, Cayuela JM, Cavé H, Pane F, Aerts JLE, de Micheli D, Thirion X, Pradel V, González M, Viehmann S, Malec M, Saglio G, van Dongen JJM (2003) Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe against Cancer program. Leukemia 17:2318–2357. https://doi.org/10.1038/sj.leu.2403135 CrossRefPubMedGoogle Scholar
- 15.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 F, Kropp MG, Pizzolo G, Pogliani EM, Rossi G, Cantore N, Nobile F, Gabbas A, Ferrara F, Fazi P, Amadori S, Mandelli F, for the GIMEMA, AIEOP, and EORTC Cooperative Groups (2011) AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 117:4716–4725. https://doi.org/10.1182/blood-2010-08-302950 CrossRefGoogle Scholar
- 16.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, Mandelli F, for the Italian GIMEMA Cooperative Group (2010) 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. Blood 116:3171–3179. https://doi.org/10.1182/blood-2010-03-276196 CrossRefGoogle Scholar
- 17.Latagliata R, Breccia M, Fazi P, Vignetti M, di Raimondo F, Sborgia M, Vincelli D, Candoni A, Salvi F, Rupoli S, Martinelli G, Kropp MG, Tonso A, Venditti A, Melillo L, Cimino G, Petti MC, Avvisati G, Lo-Coco F, Mandelli F, for the GIMEMA Acute Leukaemia Working Party (2011) GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors. Br J Haematol 154:564–568. https://doi.org/10.1111/j.1365-2141.2011.08593.x CrossRefPubMedGoogle Scholar
- 19.Petti MC, Pinazzi MB, Diverio D, Romano A, Petrucci MT, de Santis S, Meloni G, Tafuri A, Mandelli F, Lo Coco F (2001) Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg??? CMA-676). Br J Haematol 115:63–65. https://doi.org/10.1046/j.1365-2141.2001.03091.x CrossRefPubMedGoogle Scholar
- 20.Takeshita A, Shinjo K, Naito K, Matsui H, Sahara N, Shigeno K, Horii T, Shirai N, Maekawa M, Ohnishi K, Naoe T, Ohno R (2005) Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. Leukemia 19:1306–1311. https://doi.org/10.1038/sj.leu.2403807 CrossRefPubMedGoogle Scholar