Current treatment strategy of acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL has changed from the worst among the AMLs to currently the best. The application of all-trans retinoic acid (ATRA) in the induction therapy of APL decreases the high mortality of newly diagnosed patients, thereby significantly improving the response rate. ATRA combined with anthracycline-based chemotherapy is the current standard treatment, and for high-risk patients, high doses cytarabine have a beneficial effect on relapse prevention. In recent years, the indications of arsenic trioxide (ATO) therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL. The introduction of both ATRA and ATO represents great achievements in translational medicine. In this review article, we discuss the therapeutic strategies for this disease, including the initial approaches to newly diagnosed patients, prevention, and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

Keywords

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

References

[1] Chen SJ, Zelent A, Tong JH, Yu HQ, Wang ZY, Derré J, Berger R, Waxman S, Chen Z. Rearrangements of the retinoic acid receptor alpha and promyelocytic leukemia zinc finger genes resulting from t(11;17)(q23;q21) in a patient with acute promyelocytic leukemia. J Clin Invest 1993; 91(5): 2260-2267

[2] Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor alpha to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 1997; 17(1): 109-113

[3] Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996; 87(3): 882-886

[4] Arnould C, Philippe C, Bourdon V, Gr goire MJ, Berger R, Jonveaux P. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor alpha in acute promyelocytic-like leukaemia. Hum Mol Genet 1999; 8(9): 1741-1749

[5] Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, Iland H. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood 2007; 110(12): 4073-4076

[6] Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M. The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica 2008; 93(9): 1414-1416

[7] Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY. Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997; 89(9): 3354-3360

[8] Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, Corso D, DeBlasio A, Gabrilove J, Scheinberg DA, Pandolfi PP, Warrell RP Jr. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339(19): 1341-1348

[9] Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, Shaji RV, Srivastava VM, Srivastava A, Chandy M. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107(7): 2627-2632

[10] Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 1973; 41(4): 489-496

[11] Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99(3): 759-767

[12] Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72(2): 567-572

[13] De Botton S, Dombret H, Sanz M, Miguel JS, Caillot D, Zittoun R, Gardembas M, Stamatoulas A, Condé E, Guerci A, Gardin C, Geiser K, Makhoul DC, Reman O, de la Serna J, Lefrere F, Chomienne C, Chastang C, Degos L, Fenaux P, European APL Group. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. Blood 1998; 92(8): 2712-2718

[14] de Botton S, Chevret S, Coiteux V, Dombret H, Sanz M, San Miguel J, Caillot D, Vekhoff A, Gardembas M, Stamatoulas A, Conde E, Guerci A, Gardin C, Fey M, Cony Makhoul D, Reman O, de la Serna J, Lefrere F, Chomienne C, Degos L, Fenaux P; European APL group. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia 2003; 17(2): 339-342

[15] Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Link H, Guerci A, Duarte M, Daniel MT, Bowen D, .Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82(11): 3241-3249

[16] Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E, Fey M, Rayon C, Huguet F, Sotto JJ, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, Miguel JS, Link H, Desablens B, Stamatoullas A, Deconinck E, Maloisel F, Castaigne S, Preudhomme C, Degos L for the European APL Group. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999; 94(4): 1192-1200

[17] Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, Ogden A, Weinstein H, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100(13): 4298-4302

[18] Asou N, Adachi K, Tamura U, Kanamaru A, Kageyama S, Hiraoka A, Omoto E, Akiyama H, Tsubaki K, Saito K, Kuriyama K, Oh H, Kitano K, Miyawaki S, Takeyama U, Yamada O, Nishikawa K, Takahashi M, Matsuda S, Ohtake H, Ohno R. 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

[19] Sanz MA, Montesinos P, Vellenga E, Rayón C, de la Serna J, Parody R, Bergua JM, León A, Negri S, González M, Rivas C, Esteve J, Milone G, González JD, Amutio E, Brunet S, García-Laraña J, Colomer D, Calasanz MJ, Chillón C, Barragán E, Bolufer P, Lowenberg B. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 2008; 112(8): 3130-3134

[20] Adès L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S, Recher C, Thomas X, Rayon C, Castaigne S, Tournilhac O, de Botton S, Ifrah N, Cahn JY, Solary E, Gardin C, Fegeux N, Bordessoule D, Ferrant A, Meyer-Monard S, Vey N, Dombret H, Degos L, Chevret S, Fenaux P; European APL Group. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 2010; 115(9): 1690-1696

[21] Asou N, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, Tsuzuki M, Horikawa K, Matsuda M, Shinagawa K, Kobayashi T, Ohtake S, Nishimura M, Takahashi M, Yagasaki F, Takeshita A, Kimura Y, Iwanaga M, Naoe T, Ohno R ; Japan Adult Leukemia Study Group. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARα transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood 2007; 110(1): 59-66

[22] Zhang P, Wang SY, Hu LH. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol (Zhonghua Xue Ye Xue Za Zhi) 1996; 17: 58-62 (in Chinese)

[23] Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, Wu W, Zhang FQ, Chen Y, Zhou L, Li JM, Zeng XY, Yang RR, Yuan MM, Ren MY, Gu FY, Cao Q, Gu BW, Su XY, Chen GQ, Xiong SM, Zhang TD, Waxman S, Wang ZY, Chen Z, Hu J, Shen ZX, Chen SJ. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94(10): 3315-3324

[24] Shigeno K, Naito K, Sahara N, Kobayashi M, Nakamura S, Fujisawa S, Shinjo K, Takeshita A, Ohno R, Ohnishi K. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol 2005; 82(3): 224-229

[25] Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutré S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19(18): 3852-3860

[26] Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R, Mossavi A, Baybordi E, Khodabadeh A, Iravani M, Bahar B, Mortazavi Y, Totonchi M, Aghdami N. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol 2006; 17(1): 131-134

[27] Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, Han ZG, Ni JH, Shi GY, Jia PM, Liu MM, He KL, Niu C, Ma J, Zhang P, Zhang TD, Paul P, Naoe T, Kitamura K, Miller W, Waxman S, Wang ZY, de The H, Chen SJ, Chen Z. Use of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia (APL): I. As₂O₃ exerts dose-dependent dual effects on APL cells. Blood 1997; 89(9): 3345-3353

[28] Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, Rousselot P, Robledo-Sarmiento M, Lallemand-Breitenbach V, Gourmel B, Vitoux D, Pandolfi PP, Rochette-Egly C, Zhu J, de Thé H. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 2008; 14(12): 1333-1342

[29] Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, Liang WX, Song AX, Lallemand-Breitenbach V, Jeanne M, Zhang QY, Yang HY, Huang QH, Zhou GB, Tong JH, Zhang Y, Wu JH, Hu HY, de Thé H, Chen SJ, Chen Z. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 2010; 328(5975): 240-243

[30] George B, Mathews V, Poonkuzhali B, Shaji RV, Srivastava A, Chandy M. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience. Leukemia 2004; 18(10): 1587-1590

[31] Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, Jin XL, Tang W, Li XS, Xong SM, Shen ZX, Sun GL, Ma J, Zhang P, Zhang TD, Gazin C, Naoe T, Chen SJ, Wang ZY, Chen Z. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As₂O₃) in the treatment of acute promyelocytic leukemia: As₂O₃ induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood 1996; 88(3): 1052-1061

[32] Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos L, Kogan SC, Bishop JM, de Thé H. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 1999; 189(7): 1043-1052

[33] Jing Y, Wang L, Xia L, Chen GQ, Chen Z, Miller WH, Waxman S. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 2001; 97(1): 264-269

[34] Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, Zhou J, Zhu J, Raught B, de Thé H. Arsenic degrades PML or PML-RARαthrough a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 2008; 10(5): 547-555

[35] Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. 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(9): 3342-3347

[36] Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De Thé H, Wang ZY, Chen SJ, Chen Z. 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(15): 5328-5335

[37] Ravandi F, Estey E, Jones D, Faderl S, O’Brien S, Fiorentino J, Pierce S, Blamble D, Estrov Z, Wierda W, Ferrajoli A, Verstovsek S, Garcia-Manero G, Cortes J, Kantarjian H. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27(4): 504-510

[38] Dai CW, Zhang GS, Shen JK, Zheng WL, Pei MF, Xu YX, Cao YX, Yi Y, Yang JJ, Peng HL, Zhong HY, Li RJ. 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): 1-8

[39] Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116(19): 3751-3757

[40] Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, Díaz-Mediavilla J, Fioritoni G, González JD, Liso V, Esteve J, Ferrara F, Bolufer P, Bernasconi C, Gonzalez M, Rodeghiero F, Colomer D, Petti MC, Ribera JM, Mandelli F. 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(4): 1247-1253

[41] Kelaidi C, Chevret S, De Botton S, Raffoux E, Guerci A, Thomas X, Pigneux A, Lamy T, Rigal-Huguet F, Meyer-Monard S, Chevallier P, Maloisel F, Deconinck E, Ferrant A, Fegueux N, Ifrah N, Sanz M, Dombret H, Fenaux P, Adès L. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol 2009; 27(16): 2668-2676

[42] Ito S, Ishida Y, Oyake T, Satoh M, Aoki Y, Kowata S, Uchiyama T, Enomoto S, Sugawara T, Numaoka H, Suzuki K, Murai K. Clinical and biological significance of CD56 antigen expression in acute promyelocytic leukemia. Leuk Lymphoma 2004; 45(9): 1783-1789

[43] Avvisati G, Petti MC, Lo-Coco F, Vegna ML, Amadori S, Baccarani M, Cantore N, Di Bona E, Ferrara F, Fioritoni G, Gallo E, Invernizzi R, Lazzarino M, Liso V, Mariani G, Ricciuti F, Selleri C, Sica S, Veneri D, Mandelli F for the Italian Cooperative Group GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto). Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up. Blood 2002; 100(9): 3141-3146

[44] Adès L, Chevret S, Raffoux E, de Botton S, Guerci A, Pigneux A, Stoppa AM, Lamy T, Rigal-Huguet F, Vekhoff A, Meyer-Monard S, Maloisel F, Deconinck E, Ferrant A, Thomas X, Fegueux N, Chomienne C, Dombret H, Degos L, Fenaux P ; European Acute Promyelocytic Leukemia Group. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006; 24(36): 5703-5710

[45] Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, Vellenga E, Guerci A, Pigneux A, Huguet F, Rayon C, Stoppa AM, de la Serna J, Cahn JY, Meyer-Monard S, Pabst T, Thomas X, de Botton S, Parody R, Bergua J, Lamy T, Vekhoff A, Negri S, Ifrah N, Dombret H, Ferrant A, Bron D, Degos L, Fenaux P. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 2008; 111(3): 1078-1084

[46] Sanz MA, Montesinos P, Rayón C, Holowiecka A, de la Serna J, Milone G, de Lisa E, Brunet S, Rubio V, Ribera JM, Rivas C, Krsnik I, Bergua J, González J, Díaz-Mediavilla J, Rojas R, Manso F, Ossenkoppele G, González JD, Lowenberg B on behalf of the PETHEMA and HOVON Groups. 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

[47] Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, Ludwig WD, Staib P, Aul C, Grüneisen A, Kern W, Reichle A, Serve H, Berdel WE, Braess J, Spiekermann K, Wörmann B, Sauerland MC, Heinecke A, Hiddemann W, Hehlmann R, Büchner T. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia 2009; 23(12): 2248-2258

[48] Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E, Pogliani EM, Di Bona E, Micalizzi C, Kropp M, Venditti A, Tafuri A, Mandelli F. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004; 104(7): 1995-1999

[49] Estey EH, Giles FJ, Beran M, O’Brien S, Pierce SA, Faderl SH, Cortes JE, Kantarjian HM. Experience with gemtuzumab ozogamycin (“mylotarg”) and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002; 99(11): 4222-4224

[50] de Botton S, Fawaz A, Chevret S, Dombret H, Thomas X, Sanz M, Guerci A, San Miguel J, de la Serna J, Stoppa AM, Reman O, Stamatoulas A, Fey M, Cahn JY, Sotto JJ, Bourhis JH, Parry A, Chomienne C, Degos L, Fenaux P. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 2005; 23(1): 120-126

[51] Lo-Coco F, Romano A, Mengarelli A, Diverio D, Iori AP, Moleti ML, De Santis S, Cerretti R, Mandelli F, Arcese W. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia 2003; 17(10): 1930-1933

[52] Thirugnanam R, George B, Chendamarai E, Lakshmi KM, Balasubramanian P, Viswabandya A, Srivastava A, Chandy M, Mathews V. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009; 15(11): 1479-1484

[53] Kohno A, Morishita Y, Iida H, Yanada M, Uchida T, Hamaguchi M, Sawa M, Sugiura I, Yamamoto K, Mizuta S, Sao H, Naoe T, Miyamura K; Nagoya Blood and Marrow Transplantation Group. Hematopoietic stem cell transplantation for acute promyelocytic leukemia in second or third complete remission: a retrospective analysis in the Nagoya Blood and Marrow Transplantation Group. Int J Hematol 2008; 87(2): 210-216

[54] de la Serna J, Montesinos P, Vellenga E, Rayón C, Parody R, León A, Esteve J, Bergua JM, Milone G, Debén G, Rivas C, González M, Tormo M, Díaz-Mediavilla J, González JD, Negri S, Amutio E, Brunet S, Lowenberg B, Sanz MA. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008; 111(7): 3395-3402

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg