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
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial

Authors: Li Zhang, Yao Zou, Yumei Chen, Ye Guo, Wenyu Yang, Xiaojuan Chen, Shuchun Wang, Xiaoming Liu, Min Ruan, Jiayuan Zhang, Tianfeng Liu, Fang Liu, Benquan Qi, Wenbin An, Yuanyuan Ren, Lixian Chang, Xiaofan Zhu

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children.

Methods

We performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years.

Results

Among the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months.

Conclusions

Overall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses.

Trial registration

ClinicalTrials.gov (NCT01191541, retrospectively registered on 18 August 2010).
Literature
1.
Sanz MA, Montesinos P, Vellenga E, Rayón C, de la Serna J, Parody R, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA group. Blood. 2008;112:3130–4.CrossRefPubMed
2.
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leaukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.CrossRefPubMed
3.
Chen SJ, Zhou GB, Zhang XW, Mao JH, de Thé H, Chen Z. From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood. 2011;117:6425–37.CrossRefPubMedPubMedCentral
4.
Zhou J, Zhang Y, Li J, Li X, Hou J, Zhao Y, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010;115:1697–702.CrossRefPubMed
5.
Daver N, Kantarjian H, Marcucci G, Pierce S, Brandt M, Dinardo C, et al. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. Br J Haematol. 2015;168:646–53.CrossRefPubMed
6.
Cicconi L, Lo-Coco F. Current management of newly diagnosed acute promyelocytic leukemia. Ann Oncol. 2016;27:1474–81.CrossRefPubMed
7.
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.CrossRefPubMed
8.
Lo-Coco F, Di Donato L, GIMEMA, Schlenk RF, German–Austrian acute myeloid leukemia study group and study alliance leukemia. Targeted therapy alone for acute Promyelocytic leukemia. N Engl J Med. 2016;374:1197–8.CrossRefPubMed
9.
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, 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.CrossRefPubMedPubMedCentral
10.
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.CrossRefPubMed
11.
Iland HJ, Collins M, Bradstock K, Supple SG, Catalano A, Hertzberg M, Australasian Leukaemia and lymphoma Group, 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.CrossRefPubMed
12.
Cheng Y, Zhang L, Wu J, Lu A, Wang B, Liu G. Long-term prognosis of childhood acute promyelocytic leukaemia with arsenic trioxide administration in induction and consolidation chemotherapy phases: a single-Centre experience. Eur J Haematol. 2013;91:483–9.CrossRefPubMed
13.
Creutzig U, Dworzak MN, Bochennek K, Faber J, Flotho C, Graf N, et al. First experience of the AML-berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid. Pediatr Blood Cancer. 2017;64(8) https://​doi.​org/​10.​1002/​pbc.​26461.
14.
Zhang L, Zhao H, Zhu X, Chen Y, Zou Y, Chen X. Retrospective analysis of 65 Chinese children with acute promyelocytic leukemia: a single center experience. Pediatr Blood Cancer. 2008;51:210–5.CrossRefPubMed
15.
Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, et al. High dose ara- C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009;23:2248–58.CrossRefPubMed
16.
Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, 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.CrossRefPubMed
17.
Adès L, Chevret S, Raffoux E, Guerci-Bresler A, Pigneux A, Vey N, et al. Long-term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and Daunorubicin in the treatment of nonelderly APL patients. Am J Hematol. 2013;88:556–9.CrossRefPubMed
18.
Gore SD, Gojo I, Sekeres MA, Morris L, Devetten M, Jamieson K, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol. 2010;28:1047–53.CrossRefPubMedPubMedCentral
19.
van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. 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;13:1901–28.CrossRefPubMed
20.
Gabert J, Beillard E, van der Velden VH, 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.CrossRefPubMed
21.
Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European working party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer cytogenetics group and BIOMED 1 European Community-concerted action "molecular cytogenetic diagnosis in Haematological malignancies". Blood. 2000;96:1297–308.PubMed
22.
Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017;35:605–12.CrossRefPubMed
23.
Head D, Kopecky KJ, Weick J, Files JC, Ryan D, Foucar K, et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood. 1995;86:1717–28.PubMed
24.
Bally C, Fadlallah J, Leverger G, Bertrand Y, Robert A, Baruchel A, et al. Outcome of acute promyelocytic leukemia (APL) in children and adolescents: an analysis in two consecutive trials of the European APL Group. J Clin Oncol. 2012;30:1641–6.CrossRefPubMed
25.
Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002;99:759–67.CrossRefPubMed
26.
Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, 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
27.
Lou Y, Ma Y, Suo S, Ni W, Wang Y, Pan H, et al. Prognostic factors of patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide-based frontline therapy. Leuk Res. 2015;39:938–44.CrossRefPubMed
28.
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 U S A. 2009;106:3342–7.CrossRefPubMedPubMedCentral
29.
Firkin F. Carcinogenic risk of retained arsenic after successful treatment of acute promyelocytic leukemia with arsenic trioxide: a cause for concern? Leuk Lymphoma. 2014;55:977–8.CrossRefPubMed
Metadata
Title
Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial
Authors
Li Zhang
Yao Zou
Yumei Chen
Ye Guo
Wenyu Yang
Xiaojuan Chen
Shuchun Wang
Xiaoming Liu
Min Ruan
Jiayuan Zhang
Tianfeng Liu
Fang Liu
Benquan Qi
Wenbin An
Yuanyuan Ren
Lixian Chang
Xiaofan Zhu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4280-2

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Research article

Diagnostic role of circulating extracellular matrix-related proteins in non-small cell lung cancer

Research article

Changes in ovarian cancer survival during the 20 years before the era of targeted therapy

Research article

Temporal and geographic variation in the systemic treatment of advanced prostate cancer

Research article

Analysis of microarrays of miR-34a and its identification of prospective target gene signature in hepatocellular carcinoma

Correction

Correction to: A systematic comparison of copy number alterations in four types of female cancer

Research article

A systematic review of non-standard dosing of oral anticancer therapies
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits