Side effects associated with treatment of Acute Promielocytic Leukemia: systematic review




Therapeutics; Hematologic agents; Acute myeloid leukemia.


Acute Promyelocytic Leukemia (APL) is a type of cancer that mainly attacks blood cells and requires intensive treatments that damage and directly affect health. The treatments used to control APL associated with drugs affect the individual, manifesting side effects. This systematic review aimed to analyze the side effects associated with the treatments used for APL. For this, a systematic review was conducted according to the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). The literature search was carried out in the following databases: PubMed and Web of Science using combinations of the following keywords in English and Portuguese: acute myeloid leukemia, promyelocytic leukemia, M3, treatment, side effects and drugs. Studies that met the following criteria were included in the systematic review: (I) the participants were diagnosed with APL, (II) the patients underwent a treatment protocol for the pathology, (III) the side effects associated with the treatment were described. A total of 31 articles were selected for inclusion in the systematic review. The most frequent side effects associated with the treatment of APL found were: skin reactions, gastrointestinal discomfort, nausea, vomiting and migraine. Based on the results found in this systematic review, it was observed that some side effects frequently appear in patients with APL, regardless of the type of treatment used, namely: nausea, vomiting, skin reactions, migraine and gastrointestinal discomfort.


Aldapt, M. B., Kassem, N., Al-Okka, R., Ghasoub, R., Soliman, D., Abdulla, M. A., Mudawi, D., Ibrahim, F. & Yassin, M. A. (2018). Thrombocytosis in a male patient with acute promyelocytic leukaemia during all-trans retinoic (ATRA) acid treatment. Acta Biomed, 89 (3), 33-7.

Almeida, S. C. Leucemia promielocítica aguda: clínica diagnóstico e abordagem [tese]. Universidade de Coimbra; 2015.

Beaumont, M., Sanz, M., Carli, P. M., Maloisel, F., Thomas, X., Detourmignies, L., Guerci, A., Gratecos, N., Rayon, C., Miguel, J. S., Odriozola, J., Cahn, J. Y., Huguet, F., Vekhof, A., Stamatoulas, A., Dombret, H., Capote, F., Esteve, J., Stoppa, A. M. & Fenaux, P. (2015). Therapy-related acute promyelocytic leukemia. Journal of Clinical Oncology, 21 (11), 2123-37.

Bennett, J. M., Catovsky, D., Daniel, M. T., Flandrin, G., Galton, D. A., Gralnick, H. R. & Sultan, C. (1985). Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Annals of Internal Medicine,103 (4), 620-5.

Buligon, M. P., Mielke, J. C., Chiesa, J. & Ferrazo, K. L. (2018). Rare labial ulcer related to the use of all-trans retinoic acid in a patient with acute promyelocytic leukemia. Special Care Dentistry, 38 (4), 234-8.

Candoni, A., Damiani, D., Michelutti, A., Masolini, P., Michieli. M., Michelutti, T., Geromin, A. & Fanin, R. (2003). Clinical characteristics, prognostic factors and multidrug-resistance related protein expression in 36 adult patients with acute promyelocytic leukemia. European Journal of Haematology, 71 (1), 1-8.

Charles, K. S., Kanaa, M., Winfield, D. A. & Reilly, J. T. (2000). Scrotal ulceration during all-trans retinoic (ATRA) therapy for acute promyelocytic leukaemia. Clinical & Laboatory Haematology, 22 (3), 171-4.

Chim, C. S., Liang, R., Kwong, Y. L., Lie, A. K. W., Todd, D. & Chan, T. K. (2008). Treatment of de novo acute myeloid leukaemia in Hong Kong: a twenty‐year experience (1975 to 1996). Australian and New Zealand Journal of Medicine, 29 (5), 726-30.

Choi, S., Kim, H. S., Jung, C. S., Jung, S. W., Lee, Y. J., Rheu, J. K., Jo, J. R. & Lee, N. H. (2011). Reversible Symptomatic Myocarditis Induced by All-Trans Retinoic Acid Administration during Induction Treatment of Acute Promyelocytic Leukemia: Rare Cardiac Manifestation as a Retinoic Acid Syndrome. Journal of Cardiovasc Ultrasound, 19 (2), 95-8.

Dai, C. W., Zhang, G. S., Shen, J. K., Zheng, W. L., Pei, M. F., Xu, Y. X., Cao, Y. X., Yi, Y., Yang, J. J., Peng, H. L., Zhong, H. Y. & Li, R. J. (2009). 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 Haematologica, 121 (1), 1-8.

Dasanu, C. A., Ichim, T. E. & Alexandrescu, D. T. (2013). Muehrcke's lines (Leukonychia striata) due to transretinoic acid therapy for acute promyelocytic leukemia. Journal of Oncology Pharmacy Practice, 19 (4), 377-9.

De Kouchkovsky, I. & Abdul-Hay, M. (2016). Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer Journal, 6 (7), e441.

Di Bona, E., Avvisati, G., Castaman, G., Luce, V. M., De Sanctis, F., Rodeghiero, F. & Mandeli, F. (2000). Early Haemorrhagic morbidity and mortality during remission induction whit or whitout all-trans retinoic acid in acute promyelocytic leukemia. British Journal of Haematology, 108 (4), 689-95.

Douer, D., Estey, E., Santillana, S., Bennett, J. M., Lopez-Bernstein, G., Boehm, K. & Williams, T. (2001). Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood, 97 (1), 73-80.

Estey, E., Koller, C., Cortes, J., Reed, P., Freireich, E., Giles, F. & Kantarjian, H. (2001). Treatment of newly-diagnosed acute promyelocytic leukemia with liposomal all-trans retinoic acid. Leukemia & Lymphoma, 42 (3), 309-16.

Fröhling, S., Scholl, C., Gilliland, D. G. & Levine, R. L. (2005). Genetics of myeloid malignancies: pathogenetic and clinical implications. Journal of Clinical Oncolgy, 23 (26), 6285-95.

Gallipoli, P. & Drummond, M. W. (2009) Pseudotumour cerebri as a manageable side effect of prolonged all-trans retinoic acid therapy in an adult patient with acute promyelocytic leukaemia. European Journal of Haematology, 82 (3), 242-3.

Karathedath, S., Rajamani, B. M., Aalam, S. M. M., Abraham, A., Varatarajhan, S., Kishnamurthy, P., Mathews, V., Velayudhan, S. R. & Balasubramanian, P. (2017). Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2. PLoS One, 12 (5), e0177227.

Labrador, J., Puig, N., Ortín, A., Gutierrez, N. C. & González-Díaz, M. (2012). Multiple cranial neuropathy and intracranial hypertension associated with all-trans retinoic acid treatment in a young adult patient with acute promyelocytic leukemia. International Journal of Hematology, 96 (3), 383-5.

Lane, S. W. & Gilliland, D. G. (2010). Leukemia stem cells. Seminar in Cancer Biology, 20 (2), 71-6.

Lazo, G., Kantarjian, H., Estey, E., Thomas, D., O’Brien, S. & Cortes, J. (2003). Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M. D. Anderson experience. Cancer, 97 (9), 2218-24.

Leal, A. M., Kumeda, C. A. & Velloso, E. D. R. P. (2009). Características genéticas da leucemia promielocítica aguda de novo. Revista Brasileira de Hematologia e Hemoterapia, 31 (6), 1-9.

Leblebjian, H., DeAngelo, D. J., Skirvin, J. A., Stone, R. M., Wadleigh, M., Werner, M., Neuberg, D. S., Bartel, S. & McDonnell, A. M. (2013). Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia. Leukemia Research, 37 (7), 747-51.

Lengfelder, E., Reichert, A., Schoch, C., Haase, D., Haferlach, T., Löffler, H., Staib, P., Heyll, A., Seifarth, W., Saussele, C., Fonatsch, C., Gassmann, W., Ludwig, W. D., Hochhaus, A., Beelen, D., Aul, C., Sauerland, M. C., Heinecke, A., Hehlmann, R., Wörmann, B., Hiddemann, W. & Büchner, T. (2000). Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. Leukemia, 14 (8), 1362-70.

Lin, C. P., Huang, M. J., Chang, I. Y., Lin, W. Y. & Sheu, Y. T. (2000). Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leukemia & Lymphoma, 38 (1-2), 195-8.

Liu, Y., He, P., Cheng, X. & Zhang, M. (2015). Long-term outcome of 31 cases of refractory acute promyelocytic leukemia treated with compound realgar natural indigo tablets administered alternately with chemotherapy. Oncology Letters, 10 (2), 1184-90.

Lu, D. P., Qiu, J. Y., Jiang, B., Wang, Q., Liu, K. Y., Liu, Y. R. & Chen, S. S. (2002). Tetra- arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report. Blood, 99 (9), 3136-43.

Machner, B., Neppert, B., Paulsen, M., Hofmann, C., Sander, T. & Helmchen, C. (2018). Pseudotumor cerebri as a reversible side effect of all-trans retinoic acid treatment in acute promyelocytic leukaemia. European Journal of Neurology, 15 (7), 68-9.

Matthew, J. P., Joanne, E. M., Patrick, M. B., Isabelle, B., Tammy, C. H., Cynthia, D. M., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder. E. W., Mayo-Wilson, E., McDonald, S., McGuinness, L. A., Stewart, L. A., Thomas, J., Tricco, A. C., Welch, V. A., Whiting, P. & Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 29, 372:n71.

Mayorga, J., Richardson-Hardin, C. & Dicke, K. A. (2002). Arsenic trioxide as effective therapy for relapsed acute promyelocytic leukemia. Clinical Journal of Oncology Nursing, 6 (6), 341-6.

Nascimento, C. A. D., Cartaxo, C. M. B., Lopes, K. A. M., Buhatsky, M. & Batista, A. F. (2016). Leucemia mieloide aguda (LMA): as condições psicológicas do paciente adulto. Psicologia em Revista, 22 (2), 1677-1168.

Ohnishi K, Yoshida H, Shigeno K, Nakamura S, Fujisawa S, Naito K., Shinjo, K., Fujita, Y., Matsui, H., Sahara, N., Takeshita, A., Satoh, H., Terada, H. & Ohno, R. (2002). Arsenic trioxide therapy for relapsed or refractory japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia, 16 (4), 617-22.

Ortiz, J. V., Assunção, B. M. B. L., Crosbie, M. S. & De Freitas, F. A. (2017). Cardiotoxicidade por antraciclinas em pacientes com leucemia aguda: uma revisão de literatura. Revista Pleiade, 11 (21), 5-16.

Park, C. J., Bae, Y. D., Choi, J. Y., Heo, P. S., Lee, K. S., Park, Y. S. & Lee, J. A. (2001). Sweet’s syndrome during the treatment of acute promyelocytic leukemia with all- trans retinoic acid. The Korean Journal of Internal Medicine, 16 (3), 218-21.

Pavithran, K., Arjun, R., Aruna, R. & Thomas, M. (2004). Scrotal ulceration during induction therapy of acute promyelocytic leukemia with ATRA. American Journal of Hematology, 75 (4), 260-1.

Paydas, S., Yavuz, S., Disel, U., Sahin, B., Canbolat, T. & Tuncer, I. (2003). Vasculitis associated with all trans retinoic acid (ATRA) in a case with acute promyelocytic leukemia. Leukemia & Limphoma, 44 (3), 547-8.

Rubira, C. M. F. & Santos, P. S. S. Manejo da mucosite oral quimioinduzida em criança com leucemia Mielóide aguda. In: Congresso Odontológico de Bauru; 2019; Bauru.

Sarturi, B. F., Bittencourt, R. I., Spindler, B. M., Contin, L. C. Z., Soares, T. B., Paiva, M. F., Burin, M. M. & Daudt, L. E. Avaliação de cardiotoxicidade pós uso de antraciclina em pacientes com leucemia mielóide aguda entre os anos de 2007 a 2013. In: 34ª Semana Científica do Hospital de Clínicas de Porto Alegre; 2014; Porto Alegre.

Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM., Shi, J. Y., Zheng, P. Z., Yan, H., Liu, Y. F., Chen, Y., Shen, Y., Wu, W., Tang, W., Waxman, S., Thé, H. D., Wang, Z. Y., Chen, S. J. & Chen, Z. (2204). All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proceedings of the National Academy of Sciences, 101 (15), 5328-35.

Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E., Stone, R. M., Kalaycio, M., Scheinberg, D. A., Steinherz, P., Sievers, E. L., Coutré, S., Dahlberg, S., Ellison, R. & Warrell, R. P. (2001). United states multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. Journal of Clinical Oncology, 19 (18), 3852-60.

Tao, S., Wang, C., Chen, Y., Deng, Y., Song, L., Shi, Y., Lin, L., Ding, B., He, Z. & Yu, L. (2018). Long-term effect of all-trans retinoic acid and arsenic trioxide sequential maintenance in patients with acute promyelocytic leukemia. Leukemia & Lymphoma, 60 (3), 711-9.

Wang, H., Xi, S., Liu, Z., Yang, Y., Zheng, Q., Wang, F., Xu, Y., Wang, Y., Zheng, Y. & Sun, G. (2011). Arsenic methylation metabolism and liver injury of acute promyelocytic leukemia patients undergoing arsenic trioxide treatment. Environmental Toxicology, 28 (5), 267-75.

Yang, X., Xu, J., Yang, J., Zhou, Y., Mei, Y., Yang, T. & Zhang, Y. (2018). Unilateral macular choroidal neovascularization—a rare manifestation in acute myelocytic leukemia. Medicine, 97 (16), e0344.

Zhu, C., Guo-Qiyang, C., Zhi-Xiang, S., Sai-Juan, C. & Zhen-Yi, W. (2001). Treatment of acute promyelocytic leukemia with arsenic compounds: In vitro and in vivo studies. Seminars in Hematology, 38 (1), 26-36.



How to Cite

SALLES FILHO, A. S.; CAMPOS, H. O. Side effects associated with treatment of Acute Promielocytic Leukemia: systematic review. Research, Society and Development, [S. l.], v. 11, n. 3, p. e45711326914, 2022. DOI: 10.33448/rsd-v11i3.26914. Disponível em: Acesso em: 16 jul. 2024.



Health Sciences