HOW WE TREATED ACUTE PROMYELOCYTIC LEUKEMIA: WHERE WE ARE NOW?
Keywords:
Acute Promyelocytic Leukemia, PML - RARα fusion protein, early death, all trans retinoic acidAbstract
Acute Promyelocytic Leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), accounting for about 15% of AML cases. APL is a distinct clinical entity characterized by a marked tendency towards coagulopathy, hemorrhage and early death, characterized by a block in differentiation where leukemic cells are halted at the promyelocytic stage. A characteristic balanced chromosomal translocation between chromosomes 15 and 17 t (15;17)) (q24; q21) is seen in 95% of cases – the translocation results in the formation of the PML - RARα fusion protein. The introduction of retinoic acid (RA) and arsenic trioxide (ATO) has been responsible for initially remarkable cure rates. Our retrospective-prospective study was performed at our Clinic, from Jan 2004 until Dec 2022. Included were 56 patients with demographic characteristic (male - 27, female - 29), at the age of 15 to 77 years (median range 45) with APL, according to FAB and WHO regimens for diagnosis with confirmed molecular diagnosis. Risk stratification was done for the patients according to Sanz risk score, WBC, PL and clinical presentation of the disease. The overall survival shown that 30 patients (53.6%) are alive and 26 (46.4%) had death outcome. Relating the treatments, 5 patients (8,9%) died before starting the chemo treatment. The early death was observed in 16 patients (61.5%), and in 10 patients (38.5%) death occurred after 30 days of diagnosis. The main reason of mortality was also analyzed. To prevent ED prior to treatment, suspected APL patients should be immediately hospitalized, treated as medical emergency.
References
Mantha S, Taliman MS, Soff GA. What’s new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia? Curr Opin Hematol 2016; 23(2): 121-126. Do: 10.1097/MOH.0000000000000221.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33(4): 451-458. doi: 10.1111/j.1365-2141.1976.tb03563.x.
Sanz MA, Montesinos P, Rayón C, Holowiecka A, De la Serna J, Milone G, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010; 115(25): 5137-5146. doi: 10.1182/blood-2010-01-266007.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114(5): 937-951. doi: 10.1182/blood-2009-03-209262.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the world health organization classification of myeloid neoplasms and acute leukemia. Blood (2016) 127(20): 2391-2405. doi: 10.1182/blood-2016-03-643544.
Yanada M, Matsushita T, Asou N, Kishimoto Y, Tsuzuki M, Maeda Y, et al. Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome. European Journal of Haematology 2007; 78(3): 213-219. doi: 10.1111/j.1600-0609.2006.00803.x.
Ahmad EI, Akl H, Hashem ME, Elgohary TAM. The biological characteristics of adult CD34+ acute promyelocytic leukemia. Medical Oncology 2012; 29(2): 1119-1126. doi: 10.1007/s12032-011-9895-y.
Albano F, Mestice A, Pannunzio A, Lanza F, Martino B, Pastore D, et al. The biological characteristics of CD34+ CD2+ adult acute promyelocytic leukemia and the CD34- CD2- hypergranular (M3) and microgranular (M3v) phenotypes. Haematologica 2006; 91(3): 311-316. PMID: 16531253.
Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Marie-François G. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 1973; 41(4): 489-496. PMID: 4510926.
De Thé, H., Le Bras, M., Lallemand-Breitenbach, V., 2012. The cell biology of disease: acute promyelocytic leukemia, arsenic, and PML bodies. J Cell Biol. 198, 11–21. Available at: https://doi.org/10.1083/jcb.201112044.
Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111(5): 2505-2515. doi: 10.1182/blood-2007-07-102798.
Asou N, Adachi K, Tamura J, Kanamaru A, Kageyama S, Hiraoka A, et al. Analysis of prognostic factors in newly diagnosed patients with acute promyelocytic leukemia: the APL92 study of the Japan Adult Leukemia Study Group (JALSG). Cancer Chemother Pharmacol 2001; 48(Suppl 1): S65-S71. https://doi.org/10.1007/s002800100308.
Choudhry A, DeLoughery TG. Bleeding and thrombosis in acute promyelocytic leukemia. Am J Hematol 2012; 87(6): 596-603. doi: 10.1002/ajh.23158.
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(5): 646-653. doi: 10.1111/bjh.13189.
Karim F, Shaikh U, Adil SN, Khurshid M. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre. Singapore Med J 2014; 55(8): 443-447. doi: 10.11622/smedj.2014105.
Zhu H, Hu J, Chen L, Zhou W, Li X, Wang L, et al. “The 12-year follow-up of survival, chronic adverse effects and retention of arsenic in patients with acute promyelocytic leukemia. Blood 2016; 128(11):1525-8. doi: 10.1182/blood-2016-02-699439.
Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, et al. “Long term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide and gemtuzumab”. Blood 2017; 129(10): 1275-1283. doi: 10.1182/blood-2016-09-736686.
Platzebecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vigneti 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(6): 605-612. doi: 10.1200/JCO.2016.67.1982.
Iland HJ, Collins M, Bradstock K, Supple SG, Catalano A, Hertzberg M, et al. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukemia in the Australasian leukemia and lymphoma group (ALLG) APML4 study: A non-randomised phase 2 trial. Lancet Haematol 2015; 2(9): e357-e366. doi: 10.1016/S2352-3026(15)00115-5.
Watts JM, Tallman MS. Acute promyelocytic leukemia: what is the new standard of care? Blood Rev 2014; 28(5), 205-212. doi: 10.1016/j.blre.2014.07.001.
McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA, et al. “Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica (2023)samo vo 2012 go naogjam, neznam od kade 2023 2012; 97(1):133-136. doi: 10.3324/haematol.2011.046490.
Chang H, Kuo MC, Shih LY, Dunn P, Wang PN, Wu JH, et al. Clinical bleeding events and laboratory coagulation profiles in acute promyelocytic leukemia. Eur J Haematol 2012; 88(4): 321-328. doi: 10.1111/j.1600-0609.2011.01747.x.
Siddikuzzaman, Guruvayoorappan C, Berlin Grace VM. All trans retinoic acid and cancer. Immunopharmacology and immunotoxicology 2011; 33(2): 241-249. doi: 10.3109/08923973.2010.521507.
Di Bona E, Avvisati G, Castaman G, Luce Vegna M, De Sanctis V, Rodeghiero F, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol 2000; 108(4): 689-695. doi: 10.1046/j.1365-2141.2000.01936.x.
Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon 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, 1247-1253. https://doi.org/10.1182/blood.V96.4.1247.
Rego EM, Kim HT, Ruiz-Arguelles GJ, Undurraga MS,Uriarte Mdel R, Jacomo, RH, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 2013; 121(11): 1935-1943. doi: 10.1182/blood-2012-08-449918.
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.
Rogers JE, Yang D. Differentiation syndrome in patients with acute promyelocytic leukemia. J Oncol Pharm Pract 2012; 18(1): 109-114. doi: 10.1177/1078155211399163.
Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood 2019; 133(15): 1630-1643. doi: 10.1182/blood-2019-01-894980.
Lo-Coco F, Avvisati G,Vignetti M, Thiede C, Orlando S, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369(2): 111-121. doi: 10.1056/nejmoa1300874.
Douer D, Zickl L, Schiffer C, Appelbaum F, Feusner J, Shepard L, et al. Late relapses following all-trans retinoic acid for cute prmyelocytic leukemia are uncommon, resond well to salvage therapy and occur independently of prognostic factors at diagnosis: Long-term follow up of north American intergroup study I0129. Blood 2011; 118(21): 83. doi: 10.1182/blood.V118.21.83.83.
Crespo-Solis E, Contreras-Cisneros, J, Demichelis-Gomez R, Rosas-Lopez A, Vera-Zertuche JM, Aguayo A, et al. Survival and treatment response in adults with acute promyelocytic leukemia treated with a modified International Consortium on Acute Promyelocytic Leukemia protocol. Rev Bras Hematol Hemoter 2016; 38(4): 285-290. doi: 10.1016/j.bjhh.2016.08.002.
Iyer SG, Elias L, Stanchina M, Watts J. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances and future directions. Front in Oncol 2023; 12: 1062524. doi 10.3389/fonc.2022.1062524.
Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011; 118(5): 1248-1254. doi: 10.1182/blood-2011-04-346437.
Paulson K, Serebrin A, Lambert P, Bergeron B, Everett J, Kew A, et al. Acute promyelocytic leukemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukemia referral centers: a pan-Canadian epidemiological study. Br J Haematol 2014; 166: 660-666. doi: 10.1111/bjh.12931.
Thomas, X. Acute Promyelocytic Leukemia: A History over 60 Years-From the Most Malignant to the most Curable Form of Acute Leukemia. Oncology and Therapy 2019; 7: 33-65. https://doi.org/10.1007/s40487-018-0091-5.
Rahmé R, Thomas X, Recher C, Vey N, Delaunay J, Deconinck E, et al. Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. Leukemia 2014; 28: 2422-2424. https://doi.org/10.1038/leu.2014.240.
Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. Australasian Leukemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012; 120(8): 1570-1580. doi: 10.1182/blood-2012-02-410746.
Sanz MA, Montesinos P. Risk-adapted treatment for low and intermediate-risk acute promyelocytic leukemia. Clin Lymph Myeloma Leuk 2010; 10(suppl 3): S130-S134. doi: 10.3816/CLML.2010.s.025.
Serefhanoglu S, Buyukasik Y, Goker H, Sayinalp N, Haznedaroglu IC, Aksu S, et al. Clinical features and outcomes of 49 Turkish patients with acute promyelocytic leukemia who received ATRA and anthracyclines (PETHEMA protocol) therapy. Leuk Res 2010; 34(12): e317-e319. doi: 10.1016/j.leukres.2010.07.027.
Jillella AP, Kota VK. The global problem of early deaths in acute promyelocytic leukemia: a strategy to decrease induction mortality in the most curable leukemia. Blood Rev 2018; 32(2): 89-95. doi: 10.1016/j.blre.2017.09.001.
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 mono-chemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 2008; 112(8): 3130-3134. https://doi.org/ 10.1182/blood-2008-05-159632.
Downloads
Published
Versions
- 2023-07-06 (2)
- 2023-06-16 (1)
