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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000023
MYELOID DISEASE: Edited by Martin S. Tallman

ATRA + ATO: has a new standard of care been established in low-risk acute promyelocytic leukaemia?

Breccia, Massimoa; Cicconi, Laurab,c; Lo-Coco, Francescob,c

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aDepartment of Hematology, Sapienza University, Rome

bDepartment of Biomedicine and Prevention, University Tor Vergata

cLaboratory of Neuro-Oncohematology, Santa Lucia Foundation, Rome, Italy

Correspondence to Francesco Lo Coco, MD, Department of Biomedicine and Prevention, University Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Tel: +39 06 20903220; e-mail: francesco.lo.coco@uniroma2.it

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Abstract

Purpose of review

Arsenic trioxide (ATO) has been shown to be the most effective single agent in acute promyelocytic leukaemia (APL) and has been approved for the treatment of relapsed patients both in the US and Europe. The role of ATO in front-line therapy of APL is under investigation.

Recent findings

Pilot studies using ATO with or without all-trans retinoic acid (ATRA) have been carried out in newly diagnosed APL patients with the aim to reduce the short and long-term toxic effects of chemotherapy and to improve clinical outcome. Especially in patients with non-high-risk APL, the ATRA + ATO approach allowed significant increase in event-free survival and overall survival rates compared to standard ATRA and chemotherapy. This has been demonstrated by pilot studies and, more recently, by a randomized comparative multi-centre study conducted in Italy and Germany.

Summary

The ATO + ATRA strategy for APL may provide the first paradigm of acute leukaemia curability by targeted agents and without chemotherapy. However, longer follow-up of available studies and independent confirmation of the Italian–German findings are awaited to firmly establish this paradigm. Finally, extension of this approach to other patient categories such as high-risk, elderly and children will need to be explored in the near future.

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INTRODUCTION

Acute promyelocytic leukaemia (APL) is a distinct subset of acute myeloid leukaemia (AML) characterized by consistent biologic and clinical features [1]. The current standard treatment for APL consists of an association of all-trans retinoic acid (ATRA) and simultaneous anthracycline-based chemotherapy with or without cytarabine. This combination results in complete remission rates of 80–95% and long-term remission rates exceeding 80%. In spite of these impressive improvements, approximately 20% of patients receiving modern ATRA and chemotherapy undergo disease relapse, thereby requiring salvage therapy [1,2].

Arsenic trioxide (ATO) has also been shown to be highly effective in APL and has initially been tested in patients relapsing after ATRA and chemotherapy [3▪]. Distinct from ATRA, which binds the retinoic acid receptor alpha (RARA) moiety of the promyelocytic leukaemia protein (PML)/RARA oncoprotein, ATO targets PML and has different, dose-dependent mechanisms of action, inducing partial differentiation at lower doses and apoptosis at higher concentration [4▪,5▪]. The European LeukemiaNet recommendations indicate that ATO should be considered as the first option in patients who relapse after standard ATRA and chemotherapy [6].

Several pilot studies have more recently tested the efficacy and safety of ATO in newly diagnosed patients both as single agent or in combination with ATRA with or without chemotherapy [3▪,7▪]. A recent multi-centre randomized trial conducted in Italy and Germany by the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA), AML Study Group (AMLSG) and Study Alliance Leukaemia (SAL) cooperative groups has shown that the ATO and ATRA combination is at least not inferior to standard ATRA and chemotherapy for 2-year event-free survival (EFS) in non-high-risk APL [8▪]. As a consequence, the recently updated National Comprehensive Cancer Network (NCCN) guidelines positioned the Italian–German ATO and ATRA combination as the first recommended option in front-line treatment for low/intermediate-risk patients and for high-risk patients who are not able to tolerate standard therapy including anthracyclines [9▪▪]. Here, we review the most recent clinical results using ATO in newly diagnosed patients and discuss the potential role of the ATO–ATRA combination as the new standard of care in newly diagnosed APL.

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ATO AS FRONT-LINE TREATMENT

A preliminary Indian experience in 72 newly diagnosed patients treated with ATO as single agent was reported in 2006 [10]. In this prospective non-randomized study, patients received ATO induction therapy at the dose of 10 mg/day and, after achieving complete remission, a 4-week consolidation course followed by a maintenance programme with 10 days/month of ATO for a total of 6 months. Patients who developed leucocytosis during ATO treatment received anthracyclines (11%) or hydroxyurea (more than 70%). The rate of complete molecular response after induction was 20%, and the majority of patients converted to a PCR-negative status after consolidation. At a median follow-up of 25 months, the 3-year EFS, disease-free survival (DFS) and overall survival (OS) were 74.8, 87.2 and 86%, respectively, with better outcomes being observed in patients with non-high-risk disease (defined in this investigation as those with initial leucocyte count below 5 × 109/l). At 60 months, the 5-year OS, EFS and DFS were 74.2, 69 and 80%, respectively. The long-term follow-up data further support the notion that ATO has potent anti-leukaemic efficacy as single agent in APL [11].

In another non-comparative prospective trial reported from Iran, 94 newly diagnosed patients were treated with ATO monotherapy. The induction cycle included ATO 0.15 mg/kg daily until complete remission and was followed in those who achieved complete remission by a 28-day consolidation cycle with the same ATO schedule [12]. Complete remission rate was 86.3% with a median time to complete remission of 30 days. Twelve patients died in the induction phase mainly because of haemorrhagic complications and APL differentiation syndrome. The reported 2-year DFS was 63.7% and 3-year OS was 87.6%. A long-term update with 197 newly diagnosed patients was then reported in 2011 by the same Iranian group [13]. An identical ATO induction schedule was followed by one to four consolidation cycles, with the last two administered 1 and 2 years after the second consolidation course. Complete remission rate was 85.8%, but early death and remission failure were commonly observed among high-risk patients. The 5-year DFS and OS rates were 66.7 and 64.4%, respectively. Despite the increase of consolidation cycles up to four courses in the updated report, improvement in DFS, but not long-term OS, was reported [13].

Although not extensively explored given the rarity of the disorder in the elderly population, ATO was reported to be effective also in this subset of APL patients. A long-term follow-up (median of 99 months) of 33 elderly patients treated with ATO as single agent for induction and post-remission therapy was recently reported by Chinese investigators at the Harbin Medical University. Complete remission rate was 87.9% and 10-year OS was 69.3% with a cause-specific survival of 84.8%. No significant increased risk of chronic arsenicosis or second malignancies was reported during this long follow-up [14▪]. The results of studies using ATO in front-line therapy of APL are summarized in Table 1[8▪,15–18,19▪▪,20,21,22▪▪].

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STUDIES ON THE ATO + ATRA COMBINATION IN FRONT-LINE TREATMENT

A randomized trial with ATO and ATRA as front-line therapy for APL was first reported by a Chinese group in 2004 [15]. Sixty-one newly diagnosed patients were randomized to receive ATRA alone, ATO alone (0.16 mg/kg) or the association of both agents as remission induction therapy. No clinical differences were reported at baseline among patients randomized in the three different groups. Similar complete remission rates were described among the three groups: 95% in the ATRA group, 90% in the ATO group and 95.2% in the combination arm. However, a significant different median time to achieve complete remission was reported: 40.5 days (range 25–65 days) in the ATRA group, 31 days (range 28–38 days) in the ATO group and 25.5 days (range 18–35 days) in the combination group. Moreover, a difference was also detected in median decrease of PML/RARA transcripts, which was significantly more pronounced in the combination therapy arm. As post-remission therapy, all patients received three chemotherapy courses and thereafter five courses of maintenance therapy with ATRA and low-dose chemotherapy ± ATO. Median DFS was 13, 16 and 20 months for ATRA, ATO and combination groups, respectively, and none of the patients relapsed in the ATRA + ATO group, whereas 26% and 11% of patients relapsed in the ATRA and ATO group, respectively [15]. An update of the study with a long-term follow-up of 70 months reported estimated 5-year EFS and OS rates for all patients of 89.2% and 91.7%, respectively. An analysis of prognostic factors for response to ATO-based therapy indicated that outcome was not influenced by initial white blood cell count, PML/RARA isoform type or FLT3 (Fms-related tyrosine kinase 3) mutations [16].

The ATO + ATRA combinatorial approached for newly diagnosed APL was also explored by investigators at the MD Anderson Cancer Center (MDACC) [17]. A total of 44 patients were enrolled in this study: 25 low-risk patients received ATO (0.15 mg/kg daily, 10 days after beginning of ATRA) and ATRA until achievement of complete remission as induction therapy, followed by four 28-day consolidation cycles with the same induction schedule. Nineteen high-risk patients received the identical ATO and ATRA combination with the addition of gemtuzumab ozogamicin at the dose of 9 mg/m2, administered only on day 1. Overall complete remission rate was 89% (96% in low-risk and 79% in high-risk patients). Differentiation syndrome was observed in six patients (three low-risk and three high-risk patients). Relapses were detected in three high-risk patients (after 9, 9 and 15 months, respectively, whereas none of the low-risk patients relapsed after a median time of 16 months, and all remained in sustained molecular remission. Ten elderly patients (aged >60 years) included in the study responded to this combination and only one of them relapsed during follow-up. In 2011, the same MDACC group reported an extended study on 82 patients treated with this ATRA + ATO combination [18]. A first cohort of 65 low and intermediate-risk patients received the combination of the two drugs with ATO started at day 10, whereas the second group of 17 patients received ATRA and ATO concomitantly from day 1. High-risk patients received gemtuzumab ozogamicin on day 1 as in the previous study. Response rate was 92% with an early death rate of 8.5% and three patients experienced relapse. The estimated 3-year OS and EFS rates were 85% [18].

Another Chinese study published in 2009 confirmed the efficacy of the chemotherapy-free combination of ATRA + ATO. The combination was used by Dai et al.[20] as remission induction in 90 newly diagnosed patients, but the two agents were combined with chemotherapy in the post-remission phase. A significantly shorter median time to complete remission was observed in the ATRA + ATO group (31 days) as compared to the ATRA group (39 days), and the combination was also associated with better relapse-free survival (RFS) as compared to standard therapy (3-year RFS 92.9 vs. 72.4%).

Other recent studies have reported on the combination of ATO and ATRA as front-line therapy in association with chemotherapy given during either induction or consolidation. The Australasian group reported the results of studies using the APML4 phase II trial that used ATO in association with anthracycline chemotherapy and ATRA for remission induction [19▪▪]. This schedule was followed by two consolidation cycles of ATO and ATRA without any further chemotherapy. The early death rate was 3.2%. All patients who started consolidation achieved complete molecular remission. Two-year freedom from relapse (FFR) was 97.5%, failure-free survival (FFS) 88.1% and OS 93.2%. The use of ATO in both induction and consolidation showed an improvement in FFR and FFS together with a substantial reduction in anthracycline exposure [19▪▪].

The efficacy of a combination therapy with ATO, ATRA and chemotherapy was also investigated, though in a retrospective study, by the Chinese group. Induction therapy with ATO and ATRA was followed by three courses of consolidation with chemotherapy and 2 years of maintenance with sequential administration of ATO/ATRA. One hundred and thirty-seven patients were enrolled and the reported complete remission rate was 93.4% with an early death rate of 6.6%. After a median follow-up of 35 months, five relapses were recorded of which three were isolated central nervous system relapses. Considering low/intermediate and high-risk patients, the 5-year OS rates were 98.9 and 97.4%, respectively, whereas EFS rates were 98.7 and 87.9%, respectively [21].

Most recently, a multi-centre randomized study conducted in China reported on the comparison of an oral ATO formulation vs. intravenous ATO in newly diagnosed patients with APL. Patients in the two arms received after induction the same chemotherapy-based consolidation, and were successively re-allocated to the initial randomly selected option (i.e. oral ATO + ATRA vs. intravenous ATO + ATRA) that was given as maintenance. The results showed impressively high remission and survival rates (OS: 99 vs. 96.6% at 3 years, respectively) with no differences in the two groups [22▪▪]. The most relevant findings of the studies with the ATO + ATRA combination are reported in Table 1.

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RANDOMIZED ATO + ATRA VS. ATRA + CHEMOTHERAPY

Recently, a randomized Italian–German multi-centre study compared ATO and ATRA therapy vs. the standard ATRA and chemotherapy as front-line treatment in low and intermediate-risk APL. Patients in the experimental arm received the MDACC approach with ATO started together with ATRA on day 1 (see [18]). Patients enrolled in the standard arm received ATRA and idarubicn (AIDA) induction, consolidation and maintenance schedule for low and intermediate risk. Primary endpoint of the study was EFS at 2 years. One hundred and sixty-two patients were enrolled in Italy and Germany by the GIMEMA, AMLSG and SAL multi-centre groups. No significant differences were reported in terms of complete remission rates after induction by analysing 156 evaluable patients (complete remission was 100 and 95% in the experimental and standard arms, respectively). Four patients in the standard arm died during induction, two of them due to differentiation syndrome; one patient in the experimental arm and three in the standard arm died during consolidation. As regards toxicity, grade 3/4 neutropenia and thrombocytopenia were recorded more frequently in the standard arm, whereas grade 3/4 hepatic abnormalities occurred more often in the ATRA + ATO group. At a median follow-up of 34 months, the primary endpoint was achieved with significantly higher 2-year EFS in the ATRA + ATO arm as compared to standard chemotherapy (97 vs. 86%). In addition, the 2-year OS probability was significantly higher for patients in the ATRA + ATO arm (99 vs. 91%), whereas the 2-year cumulative incidence of relapse (CIR) was not different between the two groups [8▪].

An independent randomized study very similar to the above Italian–German study has been conducted in parallel by the UK National Cancer Research Institute (NCRI). In this trial, newly diagnosed APL patients were randomized to receive ATO + ATRA or the AIDA protocol. The study also included high-risk patients who were given gemtuzumab ozogamicin on day 1 as in the MDACC study. The result of this investigation should be available soon.

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ATO + ATRA AS THE NEW STANDARD OF CARE: WHAT REMAINS TO BE ESTABLISHED?

The results of the GIMEMA–AMLSG–SAL randomized study provided further evidence of the efficacy of the ATO + ATRA combination in non-high-risk newly diagnosed patients, suggesting that chemotherapy may be avoided in this subset. On the basis of the results of this randomized study, the US NCCN AML panel has recently included the ATO + ATRA protocol in the therapeutic options for initial treatment of low or intermediate-risk APL patients together with the standard AIDA regimen, and ATRA and daunorubicin and cytarabine [9▪▪]. The experts positioned this combination as first recommended option and suggested this as a valid alternative to standard approach also for those high-risk patients who cannot tolerate anthracycline-containing regimens.

Some issues still remain a matter of debate and need to be addressed. First, till date, only one randomized trial has been reported on the presumed advantage of the ATRA + ATO combination in standard-risk newly diagnosed patients. A successive analysis of these results on a longer-term follow-up and results from a similar trial conducted independently in the UK are awaited to draw firm conclusions on the possibility to avoid chemotherapy in these patients. The NCRI study, in particular, should also clarify whether the ATRA + ATO combination (with minimal chemotherapy) represents a valid therapeutic approach in the high-risk patient setting as well. Finally, differences in direct cost between ATO and chemotherapy exist in different countries and a comprehensive cost–effect study would be important to compare both approaches and their feasibility in countries with different resources and income [23▪].

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CONCLUSION

The introduction of targeted therapy with ATRA in combination with chemotherapy has dramatically changed the prognosis of APL patients. The subsequent use of risk-adapted therapeutic strategies adjusted to the relapse risk has contributed to reduce toxicity in different patient subgroups. Recently, ATO has been shown to be effective and synergistic with ATRA in both relapsed and newly diagnosed patients, carrying the advantage of considerably reduced toxicity, particularly in terms of myelosuppression and risk of secondary leukaemia. A randomized comparative study of ATRA + ATO vs. ATRA + chemotherapy has shown that the former strategy is at least not inferior and possibly superior to standard ATRA and chemotherapy for non-high-risk patients. Long-term follow-up of this study and forthcoming results of a recently closed similar study conducted in the UK will establish whether APL is cured by targeted therapy only and without cytotoxic treatments. Finally, other trials are warranted to assess the efficacy and safety of the ATRA + ATO combination in other clinical settings, including children and elderly patients with this disease.

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Acknowledgements

This study is partially supported by AIRC (Associazione Italiana per la Ricerca sul Cancro).

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Conflicts of interest

F.L.C. has received honoraria as a speaker from Lundbeck and Teva. For the remaining authors, there are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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REFERENCES

1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008; 111:2505–2515.

2. Sanz MA, Lo Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011; 29:495–503.

3▪. Breccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother. 2012; 13:1031–1043.

An updated review summarizing clinical results with ATO in both newly diagnosed and relapsed APL patients.


4▪. Lallemand-Breitenbach V, Zhu J, Chen Z, de Thé H. Tends Mol Med. 2012; 18:36–42.

This is a comprehensive review on the mechanisms of action of ATO in APL.


5▪. Tomita A, Kiyoi H, Naoe T. Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As203) in acute promyelocytic leukemia. Int J Hematol. 2013; 97:717–725.

Together with reviewing mechanisms of action of both ATRA and ATO, this study discusses the molecular and cellular basis for resistance to either agent.


6. 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; 113:1875–1891.

7▪. Iland HJ, Seymour JF. Role of arsenic trioxide in acute promyelocytic leukemia. Curr Treat Options Oncol. 2013; 14:170–184.

Most recent studies using ATO in front-line therapy of APL are discussed in this study.


8▪. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369:111–121.

This is the first randomized study comparing a chemotherapy-free approach with ATRA + ATO with standard ATRA and chemotherapy for newly diagnosed APL. The results suggest that non-high-risk APL is curable without chemotherapy.


9▪▪. O’Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 2.2013. J Nat Compr Cancer Netw. 2013; 11:1047–1055.

Updated recommendations from a panel of US experts for the treatment of AML including newly diagnosed APL.


10. Mathews V, George B, Lakshmi KM, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006; 107:2627–2632.

11. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia. Long-term follow-up data. J Clin Oncol. 2010; 28:3866–3871.

12. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006; 17:131–134.

13. Ghavamzadeh A, Alimoghaddam K, Rostami S, et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011; 29:2753–2757.

14▪. 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; 119:115–125.

The study shows that ATO-induced remission holds in the long run and carries limited toxicity also in the elderly, which is a patient subset particularly vulnerable to the toxic effect of chemotherapy.


15. 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 USA. 2004; 101:5328–5335.

16. Hu J, Liu YF, Wu CF, 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; 106:3342–3347.

17. 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; 107:3469–3473.

18. 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; 27:504–510.

19▪▪. 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; 120:1570–1580.

This study shows that the ATRA + ATO combination coupled with reduced anthracycline amounts results in high rates of prolonged remission. Thus, combining the three most effective anti-APL agents allows using limited chemotherapy. This strategy might be appropriate in particular for high-risk disease, which is a patient category in which some small chemotherapy doses may not be avoidable.


20. Dai CW, Zhang GS, Shen JK, et al. Use of all-trans retinoic acid in combination with arsenic trioxide for remission induction in patients with newly diagnosed acute promyelocytic leukemia and for consolidation/maintenance in CR patients. Acta Haematol. 2009; 121:1–8.

21. Lou Y, Qian W, Meng H, et al. High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia. Leuk Res. 2013; 37:37–42.

22▪▪. 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 randomised controlled trial. J Clin Oncol. 2013; 31:4215–4221.

This large prospective randomized study shows that an oral formulation of ATO is equally effective and shows similar toxicity profile as compared to intravenous ATO. These results hold promise to treat APL patients in the future (at least after induction) completely on an outpatient basis.


23▪. Sanz MA, Iacoboni G, Montesinos P. Acute promyelocytic leukemia: do we have a new front-line standard of treatment? Curr Oncol Rep. 2013; 15:445–449.

Most recent review article which critically considers the latest chemotherapy-free options for APL in comparison with more established results with ATRA and chemotherapy.


Keywords

acute promyelocytic leukemia; all-trans retinoic acid; arsenic trioxide

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