Arsenic Trioxide in the Management of APL: Proceed With Caution

In this excellent review of acute promyelocytic leukemia (APL) treatment, the authors highlight opportunities offered by incorporating arsenic trioxide (ATO) into the therapeutic armamentarium. ATO, the most effective single agent for APL, has unquestionably emerged as the most exciting “new drug” in the treatment of this disease. Nevertheless, we must distinguish between actual therapeutic achievements of ATO and its potential use. Particular considerations of available data on ATO suggest that a cautionary attitude is warranted in relation to its role in front-line therapy.

First, the positive results reported with ATO given with or without all-trans retinoic acid (ATRA), to minimize or even eliminate cytotoxic chemotherapy, have only been reported by single institutions in relatively small and noncomparative studies. Interestingly, early studies with ATO carried out in China,[1] Iran,[2] and India[3] were designed to replace chemotherapy for economic reasons, ATO being cheaper than ATRA plus chemotherapy, whereas studies at M.D. Anderson Cancer Center (MDACC)[4] were conceived to minimize late chemotherapy-related toxicity, mainly long-term complications such as cardiomyopathy and therapy-related acute myeloid leukemia or myelodysplastic syndromes (t-AML/MDS). Reasons leading to use of ATO in less privileged countries may not apply to developed Western countries, where ATO is significantly more expensive than chemotherapy. As to issues leading to exploration of ATO in front-line therapy at MDACC, it also should be noted that none of the aforementioned long-term complications is recognized as a major problem in APL and may have been overestimated in the literature. Two large series have recently reported a relatively low incidence of t-AML/MDS, which in the worst incidence is 2.2% at 6 years. The incidence of cardiomyopathy related to anthracycline use has not yet been studied systematically and with appropriate methodology; apparently, however, it does not have a high clinical relevance. Therefore, it actually is too challenging to demonstrate a significant reduction in the incidence of these complications with strategies based on ATO to minimize or eliminate chemotherapy. Needless to say, a significant reduction of these complications, yet to be demonstrated, should be coupled to absence of other long-term complications that have also been associated with environmental exposure to arsenic derivatives,[5] in particular an increased incidence of malignancies, especially cutaneous squamous cell carcinoma, lung cancer, and hepatocellular carcinoma, but also after ATO treatment for APL.[6] Keeping in mind these considerations, recent recommendations of the European LeukemiaNet[7] regarding the place that ATO should have in current treatment of newly diagnosed APL remain valid. These recommendations are: 1) clinical trials should compare efficacy, safety, and cost-effectiveness of ATO-based regimens versus a standard ATRA-plus-anthracycline chemotherapy approach; 2) ATO-based approaches should be used for patients with severe comorbidities who are unfit for chemotherapy; and 3) ATO-based regimens would be effective in curing many APL patients in countries where locally produced arsenic compounds provide a more affordable treatment approach than ATRA plus chemotherapy.

In contrast to results reported by the US Intergroup,[8] in which addition of ATO in consolidation to standard induction and consolidation therapy significantly improved event-free survival (EFS) and disease-free survival in adults with newly diagnosed APL, a recent study by the French-Belgian-Swiss group[9] was unable to demonstrate such benefit for ATO combined with standard consolidation therapy. In this study, patients < 70 years with white blood cell (WBC) count < 10 × 10⁹/L at presentation who achieved complete remission (CR) with ATRA and a ‘3 + 7’ schedule of idarubicin plus cytarabine were randomized to receive two consolidation courses of idarubicin plus cytarabine, 25 days of ATO, or 15 days of ATRA. No statistical differences in cumulative incidence of relapse, EFS, and overall survival (OS) were seen between the three therapeutic options. On the other hand, patients with a presenting WBC count > 10 × 10⁹/L were randomly assigned to receive or not receive 25 days of arsenic trioxide, 5 days a week for 5 weeks, together with idarubicin plus cytarabine for consolidation therapy. This comparison showed a similar cumulative incidence of relapse in both arms, while there was a trend toward a lower EFS and OS in the ATO arm, coupled with a significant increase in the number of days with neutropenia and hospitalization. The apparently contradictory results of both studies may be explained by the different way in which ATO was added to standard consolidation therapy: Two cycles of ATO were given after induction and before consolidation therapy in the US Intergroup study, whereas ATO was combined simultaneously with chemotherapy consolidation in the French-Belgian-Swiss trial.

Finally, although there is a general consensus that cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, it is hard to predict a benefit in this respect from use of new therapeutic strategies. It is more likely that implementing effective supportive measures to counteract the coagulopathy during induction therapy may reduce rates of early death during induction. Further, increased healthcare provider awareness of and expertise in APL, thereby avoiding delayed diagnosis and late referral to specialized centers, may have a significant impact on pretherapy deaths.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES
1. 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.

2. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131-4.

3. 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;107:2627-32.

4. 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.

5. Rahman MM, Sengupta MK, Ahamed S, et al. Murshidabad-one of the nine groundwater arsenic affected districts of West Bengal, India. Part I. Magnitude of contamination and population at risk. Clin Toxicol. 2005;43:823-34.

6. Au W-Y, Kumana CR, Lam Ch-W, et al. Solid tumors subsequent to arsenic trioxide treatment for acute promyelocytic leukemia. Leuk Res. 2007;31:105-8.

7. 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.

8. 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.

9. Adès L, Raffoux E, Chevret S, et al. Arsenic trioxide (ATO) in the consolidation treatment of newly diagnosed APL-first interim analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL Group. Presented at the 53rd ASH Annual Meeting and Exposition. Orlando, FL, December 47, 2010, abstract 505. Available at http://ash.confex.com/ash/2010/webprogram/Paper30338.html. Accessed June 27, 2011.