Abstract
Acute promyelocytic leukemia (APL) is a subtype of acute leukemia characterized by a unique t(15;17) translocation generating the PML/RARA fusion gene and hybrid oncoprotein. Besides its critical role in leukemogenesis, this genetic aberration serves as a disease-specific biomarker for rapid diagnosis and monitoring of minimal residual disease (MRD). Moreover, PML/RARA is specifically targeted by All-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two agents that synergistically act to induce degradation of the oncoprotein. Large clinical studies including two randomized trials conducted in newly diagnosed APL patients have shown that the ATRA–ATO combination is superior to conventional ATRA and chemotherapy both in terms of efficacy and safety. Preliminary studies using oral formulations of arsenic and ATRA suggest that oral arsenic is as effective and manageable as intravenous ATO. Following early retrospective studies indicating the prognostic relevance of PML/RARA monitoring, several prospective studies were conducted in large cohorts of APL patients enrolled in clinical trials with the aim of better assessing the prognostic value of longitudinal PCR testing. The results consistently showed that molecular remission (defined as negativization of the PCR test for PML/RARA) correlates with a significantly decreased risk of relapse, whereas persistence of PCR positivity for PML/RARA after consolidation or conversion from negative to positive during follow-up is strongly associated with hematologic relapse. Based on these data, various groups started using pre-emptive salvage therapy for patients who persisted PCR-positive after frontline consolidation or converted from negative to positive PCR during follow-up. Finally, several expert panels have recommended that molecular remission should be considered a therapeutic objective in APL, and molecular response has been adopted as a study endpoint in modern clinical trials.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic Leukemia: where did we start, where are we now, and the future. Blood Cancer J. 2015. https://doi.org/10.1038/bcj.2015.25.
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.
Lo-Coco F, Ammatuna E. The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematology. 2006;2006:156–61.
Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011;29:495–503.
Montesinos P, González JD, González J, Rayón C, de Lisa E, Amigo ML, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol. 2010;28:3872–9.
Fenaux P, Wang ZZ, Degos L. Treatment of acute promyelocytic leukemia by retinoids. Curr Top Microbiol Immunol. 2007;313:101–28.
Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010;28:3866–71.
Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.
Ghavamzadeh A, Alimoghaddam K, Rostami S, Ghaffari SH, Jahani M, Iravani M, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011;29:2753–7.
de The H, Pandolfi PP, Chen Z. Acute promyelocytic leukemia: a paradigm for oncoprotein-targeted cure. Cancer Cell. 2017;32:552–60.
Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469–73.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21.
Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, et al. 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. 2015;16:1295–305.
Seftel MD, Barnett MJ, Couban S, Leber B, Storring J, Assaily W, et al. A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults. Curr Oncol. 2014;21:234–50.
O’Donnell MR, Tallman MS, Abboud CN, Altman JK, Appelbaum FR, Arber DA, et al. Acute myeloid leukemia, version 3.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2017;15:926–57.
Di Masi A, Leboffe L, De Marinis E, Pagano F, Cicconi L, Rochette-Egly C, et al. Retinoic acid receptors: from molecular mechanisms to cancer therapy. Mol Asp Med. 2015;41:1–115.
Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, et al. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997;90:4046–53.
Miller WHJ, Kakizuka A, Frankel SR, Warrell RPJ, DeBlasio A, Levine K, et al. Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1992;89:2694–8.
Lo Coco F, Diverio D, Pandolfi PP, Biondi A, Rossi V, Avvisati G, et al. Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet. 1992;340:1437–8.
Diverio D, Pandolfi PP, Biondi A, Avvisati G, Petti MC, Mandelli F, et al. Absence of reverse transcription-polymerase chain reaction detectable residual disease in patients with acute promyelocytic leukemia in long-term remission. Blood. 1993;82:3556–9.
Martinelli G, Remiddi C, Visani G, Farabegoli P, Testoni N, Zaccaria A, et al. Molecular analysis of PML-RAR alpha fusion mRNA detected by reverse transcription-polymerase chain reaction assay in long-term disease-free acute promyelocytic leukaemia patients. Br J Haematol. 1995;90:966–8.
Lallemand-Breitenbach V, Zhu J, Chen Z, de The H. Curing APL through PML/RARA degradation by As2O3. Trends Mol Med. 2012;18:36–42.
Laczika K, Mitterbauer G, Korninger L, Knobl P, Schwarzinger I, Kapiotis S, et al. Rapid achievement of PML-RAR alpha polymerase chain reaction (PCR)-negativity by combined treatment with all-trans-retinoic acid and chemotherapy in acute promyelocytic leukemia: a pilot study. Leukemia. 1994;8:1–5.
Huang W, Sun GL, Li XS, Cao Q, Lu Y, Jang GS, et al. Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood. 1993;82:1264–9.
Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter ‘AIDA’ trial. GIMEMA-AIEOP Multicent. Blood. 1998;92:784–9.
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;93:4131–43.
Jurcic JG. Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood. 2001;98:2651–6.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21:4642–9.
Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94:2225–9.
Esteve J, Escoda L, Martin G, Rubio V, Diaz-Mediavilla J, Gonzalez M, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia. 2007;21:446–52.
Lengfelder E, Lo-Coco F, Ades L, Montesinos P, Grimwade D, Kishore B, et al. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia. 2015;29:1084–91.
Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, et al. 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. 2003;17:2318–57.
Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel Y, Flora R, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–8.
Santamaria C, Chillon MC, Fernandez C, Martin-Jimenez P, Balanzategui A, Garcia Sanz R, et al. Using quantification of the PML-RARalpha transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia. Haematologica. 2007;92:315–22.
Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2009;106:3342–7.
Cicconi L, Divona M, Ciardi C, Ottone T, Ferrantini A, Lavorgna S, et al. PML-RARalpha kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy. Leukemia. 2016;30:1987–92.
Iland HJ, Collins M, Bradstock K, Supple SG, Catalano A, Hertzberg M, et al. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol. 2015;2:e357–66.
Zhu H, Wu D-P, Jin J, Li J, Ma J, Wang J, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013;31:4215–22.
Zhu H-H, Huang X-J. Oral arsenic and retinoic acid for non-high-risk acute promyelocytic leukemia. N Engl J Med. 2014;371:2239–41.
Chendamarai E, Balasubramanian P, George B, Viswabandya A, Abraham A, Ahmed R, et al. Role of minimal residual disease monitoring in acute promyelocytic leukemia treated with arsenic trioxide in frontline therapy. Blood. 2012;119:3413–9.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Cicconi, L., Fenaux, P., Kantarjian, H. et al. Molecular remission as a therapeutic objective in acute promyelocytic leukemia. Leukemia 32, 1671–1678 (2018). https://doi.org/10.1038/s41375-018-0219-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-018-0219-5
This article is cited by
-
Anti-tumor activity of all-trans retinoic acid in gastric-cancer: gene-networks and molecular mechanisms
Journal of Experimental & Clinical Cancer Research (2023)
-
Mineral medicine: from traditional drugs to multifunctional delivery systems
Chinese Medicine (2022)
-
Adefovir dipivoxil inhibits APL progression through degradation of the oncoprotein PML-RARA
Experimental Hematology & Oncology (2022)
-
Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia
Cell Death & Disease (2022)
-
PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα
Cellular and Molecular Life Sciences (2022)