Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia
Lo-Coco F, Avvisati G, Vignetti M, et al.; Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia.
N Engl J Med. 2013 Jul 11;369(2):111-21. [Full Text]
Summary by Mandy Reyes
For decades ATRA has been part of the standard of care for treatment of Acute Promyelocytic Leukemia (APL). However, ATRA treatment alone is often not able to maintain complete remission of the disease and is associated with two adverse outcomes: differentiation syndrome and secondary resistance resulting in relapse [1,2]. To remedy this, chemotherapy was included, most notably Anthracyclines, as they have demonstrated effectiveness in APL in the past .
After multiple trials a general treatment protocol was formed: ATRA with Anthracyclines as induction therapy, consolidation therapy then low dose-chemotherapy plus ATRA . Given the known adverse effects of chemotherapy additional agents have been investigated to replace it and Arsenic Trioxide (ATO) was one of those investigational agents.
Study design and Patient population
Patients aged 18-71 with low-moderate risk newly diagnosed APL, as defined by white blood cell count > 10, were eligible. Notably excluded was high risk APL and patient with previously diagnosed APL who may be on second or third line treatment. Patients with poor baseline renal function (Creatinine >3), liver dysfunction (Bilirubin >3) and poor functional status WHO >2 were also excluded.
Prior to enrollment, patient’s required confirmation of APL with either PML-RARA fusion gene with T(15;17) translocation with RT-PCR and FISH (or karotyping) or via indirect immunofluroescence to detect the microspeckled PML pattern.
This study was a multicenter, randomized control open label trial that was not sponsored by the pharmaceutical industry. Initial randomization was performed on the basis of morphologic features. There was no significant difference between the treatment groups. Once randomized, all patients who received at least one dose of the treatment were included in the study (156 patients).
The primary outcomes included the two year event-free survival rate and the two-year disease free survival rate. Comparisons were made for non0inferiority and superiority of the ATRA-ATO regimen.
Major secondary outcomes included remission rate and two-year cumulative incidence of relapse. Major safety outcomes involved evaluation of myelosuppression, hepatic toxicity, QTc prolongation, and infection rate.
The two year event-free survival rate was 97% in the ATRA-ATO group and 86% in the control ATRA-chemotherapy group (95% CI 2-22, P< 0.001 for non-inferiority and P=0.02 for superiority). Alternatively, the two-year disease free survival rate was similar with 97% (95% CI 94-100) in ATRA-ATO group and 90% (95% CI 84-97) in ATRA-chemotherapy group (P=0.11).
Complete remission occurred in all 77 patients in ARTA-ATO patients and 75/79 (95%) patients receiveing ATRA-chemotherapy (P=0.12). The two-year cumulative incidence of relapse was similar between groups with 1% (95% CI, 0 to 4) in the ATRA–ATO group and 6% (95% CI, 0 to 11) in the ATRA–chemotherapy (P=0.2).
Forty-three of 68 patients (63%) in the ATRA–ATO while only 4 of 69 (6%) patients in the ATRA–chemotherapy had grade 3 or 4 hepatotoxic effects (P<0.001). Twelve patients in ATRA-arsenic (16%) and no patients in ATRA-chemotherapy group had QTc prolongation. ATRA-chemotherapy had significantly more hematologic toxicity (neutropenia and thrombocytopenia), more mucositis and more frequent infections.
This 2103 study demonstrated ATRA plus ATO as a non-inferior and perhaps safer alternative treatment of APL compared to the traditional ARTA plus anthracycline and ARTA plus methotrexate for maintenance therapy. The panel at European LeukemiaNet in 2019 found ATRA plus ATO to be the new standard of care for non-high risk APL .
In this study, the ATRA-ATO was only evaluated in newly diagnosed APL and not refractory, relapsed or high risk disease. ATO had already been proven to be successful in the treatment of refractory cases in China almost 2 decades prior to this study; however, remission with ATO monotherapy was not sustained and liver and cardiac toxicity (Qtc prolongation) was noted . Another consideration is that patients with a FLT3 mutations seem to have inferior overall survival with ATRA-ATO . Currently the TUD-APOLLO-064 study is evaluating ATRA-ATO therapy in high risk APL (NCT 02688140).
Monoclonal antibodies are also on the horizon. For example, Gemtuzumab Ozogamicin was successful in the treatment of APL, though toxicity has limited its use .
Other retinoid compounds have been identified such as Huangdai oral tablet that produced 100% response rate with low toxicity  but there are patients with “complex karyotypes” (presence or absence of certain mutations) that affects prognosis . New clinical targets include FLT3 kinase inhibitors, CD25 expression and even investigations into microRNA  with multiple other investigations ongoing. While ATO is an additional tool for APL, further investigation continues into this disease with more candidates and more targeted therapy is sure to follow.
- Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990 Nov 1;76(9):1704-9. PMID: 2224119.
- Rego EM, De Santis GC. Differentiation syndrome in promyelocytic leukemia: clinical presentation, pathogenesis and treatment. Mediterr J Hematol Infect Dis. 2011;3(1):e2011048. doi: 10.4084/MJHID.2011.048. Epub 2011 Oct 24. PMID: 22110898; PMCID: PMC3219650.
- Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood. 1973 Apr;41(4):489-96. PMID: 4510926.
- Degos, L., Wang, Z. All trans retinoic acid in acute promyelocytic leukemia. Oncogene 20, 7140–7145 (2001). https://doi.org/10.1038/sj.onc.1204763
- Miguel A. Sanz, Pierre Fenaux, Martin S. Tallman, Elihu H. Estey, Bob Löwenberg, Tomoki Naoe, Eva Lengfelder, Hartmut Döhner, Alan K. Burnett, Sai-Juan Chen, Vikram Mathews, Harry Iland, Eduardo Rego, Hagop Kantarjian, Lionel Adès, Giuseppe Avvisati, Pau Montesinos, Uwe Platzbecker, Farhad Ravandi, Nigel H. Russell, Francesco Lo-Coco; Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood 2019; 133 (15): 1630–1643. doi: https://doi.org/10.1182/blood-2019-01-894980
- Huan SY, Yang CH, Chen YC. Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy. Leuk Lymphoma. 2000 Jul;38(3-4):283-93. doi: 10.3109/10428190009087019. PMID: 10830735.
- Poiré X, Moser BK, Gallagher RE, Laumann K, Bloomfield CD, Powell BL, Koval G, Gulati K, Holowka N, Larson RA, Tallman MS, Appelbaum FR, Sher D, Willman C, Paietta E, Stock W. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma. 2014 Jul;55(7):1523-32. doi: 10.3109/10428194.2013.842985. Epub 2014 Feb 4. PMID: 24160850; PMCID: PMC4273565.
- Ravandi F, Estey EH, Appelbaum FR, Lo-Coco F, Schiffer CA, Larson RA, Burnett AK, Kantarjian HM. Gemtuzumab ozogamicin: time to resurrect? J Clin Oncol. 2012 Nov 10;30(32):3921-3. doi: 10.1200/JCO.2012.43.0132. Epub 2012 Sep 17. PMID: 22987091; PMCID: PMC4874205.
- Xiang Y, Wang XB, Sun SJ, Guo AX, Wei AH, Cheng YB, Huang SL. [Compound huangdai tablet as induction therapy for 193 patients with acute promyelocytic leukemia]. Zhonghua Xue Ye Xue Za Zhi. 2009 Jul;30(7):440-2. Chinese. PMID: 19954593.
- Mrózek K, Marcucci G, Nicolet D, Maharry KS, Becker H, Whitman SP, Metzeler KH, Schwind S, Wu YZ, Kohlschmidt J, Pettenati MJ, Heerema NA, Block AW, Patil SR, Baer MR, Kolitz JE, Moore JO, Carroll AJ, Stone RM, Larson RA, Bloomfield CD. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012 Dec 20;30(36):4515-23. doi: 10.1200/JCO.2012.43.4738. Epub 2012 Sep 17. PMID: 22987078; PMCID: PMC3518729.
- Wiernik PH. Inching toward cure of acute myeloid leukemia: a summary of the progress made in the last 50 years. Med Oncol. 2014 Aug;31(8):136. doi: 10.1007/s12032-014-0136-z. Epub 2014 Jul 22. PMID: 25048723.