Abstract
The incidence of therapy-related acute promyelocytic leukemia (t-APL) is apparently rising. We systematically reviewed the English literature until March 15, 2013, and collected a total of 326 t-APL cases, with the following results: (1) t-APL affects predominantly middle-aged adults with a median age at diagnosis of 47 years and a female-to-male ratio of 1.7:1; (2) after an incidence peak at 2 years following the completion of treatment for the primary antecedent disease, the risk of developing t-APL quickly diminishes with time; (3) the four most common primary antecedent conditions are breast cancer, hematological malignancies, multiple sclerosis, and genitourinary malignancies; (4) topoisomerase II inhibitors and radiation represent the most common potential risk factors; (5) despite different DNA damage “hot spot” sites, t-APL has no significant clinicopathologic differences from de novo APL (dn-APL); (6) t(15;17) is the sole cytogenetic abnormality in the vast majority of patients; (7) only a small minority of cases have a myelodysplastic or pancytopenic preleukemic phase; (8) more than one-third of patients come to medical attention incidentally (i.e., due to laboratory abnormalities), while the most common symptom is mucocutaneous bleeding, and 79 % have clinical DIC; and (9) the remission rate of t-APL is about 80 %, similar to dn-APL.
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References
Duffield AS, Aoki J, Levis M, Cowan K, Gocke CD, Burns KH, et al. Clinical and pathologic features of secondary acute promyelocytic leukemia. Am J Clin Pathol. 2012;137:395–402.
Dayyani F, Kantarjian H, O’Brien S, Pierce S, Jones D, Faderl S, et al. Outcome of therapy-related acute promyelocytic leukemia with or without arsenic trioxide as a component of frontline therapy. Cancer. 2011;117:110–5.
Yin CC, Glassman AB, Lin P, Valbuena JR, Jones D, Luthra R, et al. Morphologic, cytogenetic, and molecular abnormalities in therapy-related acute promyelocytic leukemia. Am J Clin Pathol. 2005;123:840–8.
Au WY, Lam P, Shek TW. Uncommon presentations of some common malignancies: case 2. Nasopharyngeal carcinoma followed by secondary acute promyelocytic leukemia presenting with respiratory distress. J Clin Oncol. 2005;23:1314–5.
Pulsoni A, Pagano L, Lo Coco F, Avvisati G, Mele L, di Bona E, et al. Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience. Blood. 2002;100:1972–6.
Takeyama K, Seto M, Uike N, Hamajima N, Ino T, Mikuni C, et al. Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. Int J Hematol. 2000;71:144–52.
Bennett M. A case of myelocytic leukemia simulating the mouse model diseases. J Surg Oncol. 1970;2:239–43.
Beaumont M, Sanz M, Carli PM, Maloisel F, Thomas X, Detourmignies L, et al. Therapy-related acute promyelocytic leukemia. J Clin Oncol. 2003;21:2123–37.
Mauritzson N, Albin M, Rylander L, Billström R, Ahlgren T, Mikoczy Z, et al. Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976–1993 and on 5098 unselected cases reported in the literature. 1974–2001. Leukemia. 2002;16:2366–78.
Michels SD, McKenna RW, Arthur DC, Brunning RD. Therapy-related acute myeloid leukemia and myelodysplastic syndrome: a clinical and morphologic study of 65 cases. Blood. 1985;65:1364–72.
Dann EJ, Rowe JM. Biology and therapy of secondary leukemias. Best Pract Res Clin Haematol. 2001;14:119–37.
Elliott MA, Letendre L, Tefferi A, Hogan WJ, Hook C, Kaufmann SH, et al. Therapy-related acute promyelocytic leukemia: observations relating to APL pathogenesis and therapy. Eur J Haematol. 2012;88:237–43.
Ogami A, Morimoto A, Hibi S, Todo S, Sugimoto T, Mori K, et al. Secondary acute promyelocytic leukemia following chemotherapy for non-Hodgkin’s lymphoma in a child. J Pediatr Hematol Oncol. 2004;26:427–30.
Bhavnani M, Azzawi SA, Yin JA, Lucas GS. Therapy-related acute promyelocytic leukaemia. Br J Haematol. 1994;86:231–2.
Larson RA, Le Beau MM. Prognosis and therapy when acute promyelocytic leukemia and other “good risk” acute myeloid leukemias occur as a therapy-related myeloid neoplasm. Mediterr J Hematol Infect Dis. 2011;3:e2011032.
Ammatuna E, Montesinos P, Hasan SK, Ramadan SM, Esteve J, Hubmann M, et al. Presenting features and treatment outcome of acute promyelocytic leukemia arising after multiple sclerosis. Haematologica. 2011;96:621–5.
Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes Chromosomes Cancer. 2002;33:395–400.
Ono M, Watanabe T, Shimizu C, et al. Therapy-related acute promyelocytic leukemia caused by hormonal therapy and radiation in a patient with recurrent breast cancer. Jpn J Clin Oncol. 2008;38:567–70.
Papa G, Mauro FR, Anselmo AP, Hiramoto N, Goto Y, Yonemori K, et al. Acute leukaemia in patients treated for Hodgkin’s disease. Br J Haematol. 1984;58:43–52.
Grünwald HW, Rosner F. Acute myeloid leukemia following treatment of Hodgkin’s disease: a review. Cancer. 1982;50:676–83.
Liu M, Liu J, Liu L, Yu L, Shi B, Ye L, et al. A case report of acute myeloid leukemia after liver transplantation. Acta Haematol. 2013;129:225–8.
Doti CA, Gondolesi GE, Sheiner PA, Emre S, Miller CM, Aledort LM. Leukemia after liver transplant. Transplantation. 2001;72:1643–6.
Camós M, Esteve J, Rimola A, Grande L, Rozman M, Colomer D, et al. Increased incidence of acute myeloid leukemia after liver transplantation? Description of three new cases and review of the literature. Transplantation. 2004;77:311–3.
Pascual AM, Téllez N, Boscá I, Mallada J, Belenguer A, Abellán I, et al. Revision of the risk of secondary leukaemia after mitoxantrone in multiple sclerosis populations is required. Mult Scler. 2009;15:1303–10.
Sheer D, Solomon E, Greaves MF, Lister TA. 15/17 chromosome translocation in acute promyelocytic leukemia. Cancer Genet Cytogenet. 1982;5:353–4.
Voltz R, Starck M, Zingler V, Strupp M, Kolb HJ. Mitoxantrone therapy in multiple sclerosis and acute leukaemia: a case report out of 644 treated patients. Mult Scler. 2004;10:472–4.
Xue Y, Lu D, Guo Y, Lin B. Specific chromosomal translocations and therapy-related leukemia induced by bimolane therapy for psoriasis. Leuk Res. 1992;16:1113–23.
Amadori S, Papa G, Anselmo AP, Fidani P, Mandelli F, Biagini C. Acute promyelocytic leukemia following ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and radiotherapy for Hodgkin’s disease. Cancer Treat Rep. 1983;67:603–4.
Pedersen-Bjergaard J. Acute promyelocytic leukemia with t(15;17) following inhibition of DNA topoisomerase II. Ann Oncol. 1995;6:751–3.
Wang JC, Caron PR, Kim RA. The role of DNA topoisomerases in recombination and genome stability: a double-edged sword? Cell. 1990;62:403–6.
Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352:1529–38.
Deweese JE, Osheroff N. The DNA cleavage reaction of topoisomerase, II: wolf in sheep’s clothing. Nucleic Acids Res. 2009;37:738–48.
Mays AN, Osheroff N, Xiao Y, Wiemels JL, Felix CA, Byl JA, et al. Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia. Blood. 2010;115:326–30.
Hasan SK, Ottone T, Schlenk RF, Xiao Y, Wiemels JL, Mitra ME, et al. Analysis of t(15;17) chromosomal breakpoint sequences in therapy-related versus de novo acute promyelocytic leukemia: association of DNA breaks with specific DNA motifs at PML and RARA loci. Genes Chromosomes Cancer. 2010;49:726–32.
Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C, et al. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112:3383–90.
Kudo K, Yoshida H, Kiyoi H, Numata S, Horibe K, Naoe T. Etoposide-related acute promyelocytic leukemia. Leukemia. 1998;12:1171–5.
Naoe T, Kudo K, Yoshida H, Horibe K, Ohno R. Molecular analysis of the t(15;17) translocation in de novo and secondary acute promyelocytic leukemia. Leukemia. 1997;11(Suppl 3):287–8.
Joannides M, Mays AN, Mistry AR, Hasan SK, Reiter A, Wiemels JL, et al. Molecular pathogenesis of secondary acute promyelocytic leukemia. Mediterr J Hematol Infect Dis. 2011;3:e2011045.
Hasan SK, Buttari F, Ottone T, Voso MT, Hohaus S, Marasco E, et al. Risk of acute promyelocytic leukemia in multiple sclerosis: coding variants of DNA repair genes. Neurology. 2011;76:1059–65.
Ellis R, Boggild M. Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it? Mult Scler. 2009;15:505–8.
Praga C, Bergh J, Bliss J, Bonneterre J, Cesana B, Coombes RC, et al. Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol. 2005;23:4179–91.
Pedersen-Bjergaard J, Daugaard G, Hansen SW, Philip P, Larsen SO, Rørth M. Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. Lancet. 1991;338:359–63.
Gershkevitsh E, Rosenberg I, Dearnaley DP, Trott KR. Bone marrow doses and leukaemia risk in radiotherapy of prostate cancer. Radiother Oncol. 1999;53:189–97.
Ottone T, Cicconi L, Hasan SK, Lavorgna S, Divona M, Voso MT, et al. Comparative molecular analysis of therapy-related and de novo acute promyelocytic leukemia. Leuk Res. 2012;36:474–8.
Sanz MA, Lo Coco F, Martín G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leucemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96:1247–53.
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113:1875–91.
Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011;29:495–503.
Breccia M, Lo-Coco F. Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease. Expert Opin Pharmacother. 2012;13:1031–43.
Lo-Coco F, Avvisati G, Orlando SM, Ferrara F, Vignetti M, Fazi P, et al. ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non-high risk acute promyelocytic leukemia (APL): results of the phase III, prospective, randomized, intergroup APL0406 study led by the Italian-German cooperative groups GIMEMA-SAL-AMLSG. ASH Annual Meeting 2012.
Ramadan SM, Di Veroli A, Camboni A, Breccia M, Iori AP, Aversa F, et al. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era. Haematologica. 2012;97:1731–5.
Schoch C, Haferlach T, Hasse D, Fonatsch C, Löffler H, Schlegelberger B, et al. Patients with de novo acute myeloid 1eukaemia and complex karyotype aberrations have a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol. 2001;112:118–26.
Wiernik PH, Sun Z, Gundacker H, Dewald G, Slovak ML, Paietta E, et al. Prognostic implications of additional chromosome abnormalities among patients with de novo acute promyelocytic leukemia with t(15;17). Med Oncol. 2012;29:2095–101.
Douer D, Zickl LN, Schiffer CA, Appelbaum FR, Feusner JH, Shepherd L, et al. All-trans retinoic acid and late relapses in acute promyelocytic leukemia: Very long-term follow-up of the North American Intergroup Study I0129. Leuk Res 2013 (in press).
Hall MJ, Li L, Wiernik PH, Olopade OI. BRCA2 mutation and the risk of hematologic malignancy. Leuk Lymphoma. 2006;47:765–7.
Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ. Altered myeloid development and acute leukemia in transgenic mice expressing PML–RAR alpha under control of cathepsin G regulatory sequences. Blood. 1997;89:376–87.
Brown D, Kogan S, Lagasse E, Weissman I, Alcalay M, Pelicci PG, et al. A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1997;94:2251–6.
Minucci S, Monestiroli S, Giavara S, Ronzoni S, Marchesi F, Insinga A, et al. PML–RAR induces promyelocytic leukemia with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood. 2002;100:2989–95.
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Rashidi, A., Fisher, S.I. Therapy-related acute promyelocytic leukemia: a systematic review. Med Oncol 30, 625 (2013). https://doi.org/10.1007/s12032-013-0625-5
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DOI: https://doi.org/10.1007/s12032-013-0625-5