Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Current Hematologic Malignancy Reports
Published in: Current Hematologic Malignancy Reports 2/2014

01-06-2014 | Acute Leukemias (R Stone, Section Editor)

Contemporary Treatment of APL

Authors: Elizabeth H. Cull, Jessica K. Altman

Published in: Current Hematologic Malignancy Reports | Issue 2/2014

Login to get access

Abstract

Acute promyelocytic leukemia (APL) is characterized by coagulopathy, leukopenic presentation and sensitivity to anthracyclines, all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). For the last 25 years, APL has been treated with a combination of ATRA and chemotherapy for induction followed by consolidation and maintenance therapy. This general treatment approach has resulted in cure rates of 80–90 %. ATO, originally approved in relapsed APL, has been incorporated into contemporary upfront treatment regimens with excellent response rates. Recent studies show that most patients with APL can be cured with ATRA and ATO alone, eliminating cytotoxic chemotherapy and resulting in superior outcomes compared to standard treatment. We will herein review historical treatment of APL, treatment considerations in specific patient populations, and therapeutic updates.
Literature
1.
Douer D. The epidemiology of acute promyelocytic leukemia. Balliere’s Best Pract Clin Hematol. 2003;16:357–67.CrossRef
2.
Estey E, Thall P, Kantarjian H, et al. Association between increased body mass index and a diagnosis of acute promyelocytic leukemia in patients with acute myeloid leukemia. Leukemia. 1997;11:1661–4.PubMedCrossRef
3.
Scaglioni PP, Pandolfi PP. The theory of APL revisited. Curr Top Microbiol Immunol. 2007;313:85–100.PubMed
4.
Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567–72.PubMed
5.
Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76:1704–9.PubMed
6.
Warrell Jr RP, Frankel SR, Miller Jr WH, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991;324:1385–93.PubMedCrossRef
7.
Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413–9.PubMed
8.
Fenaux P, Castaigne S, Dombret H, et al. All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood. 1992;80:2176–81.PubMed
9.
Kanamaru A, Takemoto Y, Tanimoto M, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group. Blood. 1995;85:1202–6.PubMed
10.
Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021–8.PubMedCrossRef
11.
Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002;99:759–67.PubMedCrossRef
12.••
Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369:111–21. Phase III trial that randomized standard risk patients with APL to treatment with ATRA/chemotherapy vs. ATRA/ATO. Results showed non-inferiority of ATRA/ATO regimen compared to ATRA/chemotherapy.PubMedCrossRef
13.
Fenaux P, Chastang C, Chevret S, et al. 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;94:1192–200.PubMed
14.
Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood. 1997;90:1014–21.PubMed
15.
Sanz MA, Martin G, Rayon C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015–21.PubMed
16.
Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993;82:3241–9.PubMed
17.
Ades L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111:1078–84.PubMedCrossRef
18.
Sanz MA, Lo Coco F, Martin G, et al. 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;96:1247–53.PubMed
19.
Sanz MA, Martin G, Gonzalez M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:1237–43.PubMedCrossRef
20.
Ades L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006;24:5703–10.PubMedCrossRef
21.
Nasr R, Guillemin MC, Ferhi O, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med. 2008;14:1333–42.PubMedCrossRef
22.
Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315–24.PubMed
23.
Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.PubMed
24.
Estey E, Garcia-Manero G, Ferrajoli A, 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.PubMedCrossRef
25.••
Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120:1570–80. They used a consolidation regimen of ATO/ATRA, eliminating chemotherapy from the consolidation phase and reported excellent response rates and OS.PubMedCrossRef
26.••
Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7. They added ATO to the consolidation phase and reported improved outcomes, particularly in high risk APL patients.PubMedCentralPubMedCrossRef
27.
Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504–10.PubMedCrossRef
28.
Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:5328–35.PubMedCentralPubMedCrossRef
29.
Iland HJ CM, Seymour J. The Australasian Leukaemia and lymphoma group APML4 trial - update on APL treatment down under [abstract]. In: 6th International Symposium on Acute Promyelocytic Leukemia Abstract Book 2013 Sept 29-Oct 2; Rome, Italy.
30.
31.
Sanz MA, Montesinos P, Rayon C, et al. 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;115:5137–46.PubMedCrossRef
32.•
Coutre S OM, Powell B, et al. A phase III randomized trial (S0521) of maintenance versus observation for patients with previously untreated low/intermediate risk acute promyelocytic leukemia. In: 6th International Symposium on Acute Promyelocytic Leukemia Abstract Book 2013 Sept 29-Oct 2. Phase III randomized trial that compared maintenance therapy to no maintenance therapy in standard risk patients and reported no differences in relapse rates or OS.
33.
de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–402.PubMedCrossRef
34.
Micol JB Raffoux E, Boissel N, et al. Do early events excluding patients with acute promyelocytic leukemia (APL) from trial enrollment modify treatment result evaluation? Real-life management of 100 patients referred to the University Hospital Saint-Louis between 2000 and 2010. Blood. 2010;116:473. ASH Annual Meeting Abstracts.
35.
Lehmann S, Ravn A, Carlsson L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia. 2011;25:1128–34.PubMedCrossRef
36.
Altman JK, Rademaker A, Cull E, et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res. 2013;37:1004–9.PubMedCrossRef
37.
Rahmé R, Thomas X, Recher C, et al. Early Deaths (ED) in Acute Promyelocytic Leukemia (APL) in France: a retrospective multicenter study in 355 patients (pts). Blood. 2012;120:890. ASH annual Meeting Abstracts.
38.
39.
Tallman MS, Brenner B, Serna Jde L, et al. Meeting report. Acute promyelocytic leukemia-associated coagulopathy, 21 January 2004, London, United Kingdom. Leuk Res. 2005;29:347–51.PubMedCrossRef
40.
Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood. 1998;91:3093–102.PubMed
41.
Kelaidi C, Ades L, Fenaux P. Treatment of acute promyelocytic leukemia with high white cell blood counts. Mediterr J Hematol Infect Dis. 2011;3:e2011038.PubMedCentralPubMedCrossRef
42.
Frankel SR, Eardley A, Lauwers G, et al. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med. 1992;117:292–6.PubMedCrossRef
43.
Kelaidi C, Chevret S, De Botton S, et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol. 2009;27:2668–76.PubMedCrossRef
44.
Vahdat L, Maslak P, Miller Jr WH, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994;84:3843–9.PubMed
45.
de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006;20:35–41.PubMedCrossRef
46.
Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.PubMedCrossRef
47.
Breccia M, Carmosino I, Diverio D, et al. Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count. Br J Haematol. 2003;120:266–70.PubMedCrossRef
48.
Lengfelder E, Hofmann WK, Nolte F. Management of elderly patients with acute promyelocytic leukemia: progress and problems. Ann Hematol. 2013;92:1181–8.PubMedCentralPubMedCrossRef
49.
Park JH, Qiao B, Panageas KS, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 2011;118:1248–54.PubMedCentralPubMedCrossRef
50.
Ades L, Chevret S, De Botton S, et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia. 2005;19:230–3.PubMedCrossRef
51.
Ono T, Takeshita A, Kishimoto Y, et al. Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia. Cancer Sci. 2012;103:1974–8.PubMedCrossRef
52.
Sanz MA, Vellenga E, Rayon C, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood. 2004;104:3490–3.PubMedCrossRef
53.
Latagliata R, Breccia M, Fazi P, et al. GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long-term results and prognostic factors. Br J Haematol. 2011;154:564–8.PubMedCrossRef
54.
Zhang Y, Zhang Z, Li J, et al. Long-term efficacy and safety of arsenic trioxide for first-line treatment of elderly patients with newly diagnosed acute promyelocytic leukemia. Cancer. 2013;119:115–25.PubMedCrossRef
55.
Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004;104:1995–9.PubMedCrossRef
56.
Breccia M, Cimino G, Diverio D, et al. Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica. 2007;92:1273–4.PubMedCrossRef
57.
Lo-Coco F, Orlando SM, Platzbecker U. Treatment of acute promyelocytic leukemia. N Engl J Med. 2013;369:1472.PubMedCrossRef
58.
Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341–8.PubMedCrossRef
59.
Au WY, Lie AK, Chim CS, et al. Arsenic trioxide in comparison with chemotherapy and bone marrow transplantation for the treatment of relapsed acute promyelocytic leukaemia. Ann Oncol. 2003;14:752–7.PubMedCrossRef
60.
Raffoux E, Rousselot P, Poupon J, et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol. 2003;21:2326–34.PubMedCrossRef
61.
Shigeno K, Naito K, Sahara N, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol. 2005;82:224–9.PubMedCrossRef
62.
Aribi A, Kantarjian HM, Estey EH, et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer. 2007;109:1355–9.PubMedCrossRef
63.
Lu J, Huang X, Bao L, et al. Treatment outcomes in relapsed acute promyelocytic leukemia patients initially treated with all- retinoic acid and arsenic compound-based combined therapies. Oncol Lett. 2014;7:177–82.PubMedCentralPubMed
64.
Thirugnanam R, George B, Chendamarai E, et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009;15:1479–84.PubMedCrossRef
65.
de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol. 2005;23:120–6.PubMedCrossRef
66.
Pemmaraju N, Tanaka MF, Ravandi F, et al. Outcomes in patients with relapsed or refractory acute promyelocytic leukemia treated with or without autologous or allogeneic hematopoietic stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2013;13:485–92.PubMedCrossRef
67.••
Zhu HH, Wu DP, Jin 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;31:4215–21. This is a randomized controlled trial comparing outcomes with IV arsenic vs. a novel form of oral arsenic. Demonstrated no difference in outcomes with the new formulation.PubMedCrossRef
68.
Ozpolat B, Lopez-Berestein G, Adamson P, et al. Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. J Pharm Pharm Sci. 2003;6:292–301.PubMed
69.
Tsimberidou AM, Tirado-Gomez M, Andreeff M, et al. Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma. 2006;47:1062–8.PubMedCrossRef
70.
Jain P, Kantarjian H, Estey E et al. Single-Agent Liposomal All-Trans-Retinoic Acid as Initial Therapy for Acute Promyelocytic Leukemia: 13-Year Follow-Up Data. Clin Lymphoma Myeloma Leuk 2013.
71.
Warrell Jr RP. Retinoid resistance in acute promyelocytic leukemia: new mechanisms, strategies, and implications. Blood. 1993;82:1949–53.PubMed
72.
Shao W, Benedetti L, Lamph WW, et al. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML-RAR alpha mutation. Blood. 1997;89:4282–9.PubMed
73.
Ohnishi K. PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. Int J Clin Oncol. 2007;12:313–7.PubMedCrossRef
74.
Tobita T, Takeshita A, Kitamura K, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997;90:967–73.PubMed
75.
Naina HV, Levitt D, Vusirikala M, et al. Successful treatment of relapsed and refractory extramedullary acute promyelocytic leukemia with tamibarotene. J Clin Oncol. 2011;29:e534–6.PubMedCrossRef
76.
Di Veroli A, Ramadan SM, Divona M, et al. Molecular remission in advanced acute promyelocytic leukaemia after treatment with the oral synthetic retinoid Tamibarotene. Br J Haematol. 2010;151:99–101.PubMedCrossRef
Metadata
Title
Contemporary Treatment of APL
Authors
Elizabeth H. Cull
Jessica K. Altman
Publication date
01-06-2014
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 2/2014
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-014-0205-6

Other articles of this Issue 2/2014

Current Hematologic Malignancy Reports 2/2014 Go to the issue

Acute Leukemias (F Ravandi, Section Editor)

Recent Discoveries in Molecular Characterization of Acute Myeloid Leukemia

Acute Leukemias (R Stone, Section Editor)

The Use of Molecular Genetics to Refine Prognosis in Acute Myeloid Leukemia

ACUTE LEUKEMIAS (R STONE, SECTION EDITOR)

Novel Antibody Therapy in Acute Lymphoblastic Leukemia

Acute Leukemias (R Stone, Section Editor)

FLT3 Inhibitors in AML: Are We There Yet?

ACUTE LEUKEMIAS (F RAVANDI, SECTION EDITOR)

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in First Complete Remission: Are We Closer to Knowing Who Needs It?

Acute Leukemias (F Ravandi, Section Editor)

Is Targeted Therapy Feasible in Acute Myelogenous Leukemia?

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits