In the 2016 revision of the World Health Organization classification the term therapy-related myeloid neoplasia (t-MN) defines a subgroup of acute myeloid leukemia (AML) comprising patients who develop myelodysplastic syndrome (MDS-t) or acute myeloid leukemia (AML-t) after treatment with cytotoxic and/or radiation therapy for various malignancies or autoimmune disorders. We report the case of a 36 year old patient with t-MN (t-MDS) after achieving complete remission (CR) of a PML-RARA positive acute promyelocytic leukemia (APL) at 32 months after diagnosis. Initially classified as low risk APL and treated according to the AIDA protocol - induction and 3 consolidation cycles - the patient achieved a complete molecular response in September 2013 and started maintenance therapy. On follow-up PML-RARA transcript remained negative. In January 2016 leukopenia and thrombocytopenia developed and a peripheral blood smear revealed hypogranular and agranular neutrophils. Immunophenotyping in the bone marrow aspirate identified undifferentiated blast cells that did not express cytoplasmic myeloperoxidase. The cytogenetic study showed normal karyotype. The molecular biology tests not identified PMLRARA transcript. A diagnosis of t-MDS (AREB-2 - WHO 2008) was established. Treatment of AML was started with 2 “3+7” regimens and 1 MEC cycle. Two months from diagnosis, while in CR, an allogeneic HSCT from an unrelated HLA compatible donor was performed after myeloablative regimen. An unfavorable clinical evolution was followed by death on day 9 after transplantation. The occurrence of t-MNs during CR of APL represents a particular problem in terms of follow-up and differential diagnosis of relapse and constitutes a dramatic complication for a disease with a favorable prognosis.
This work was supported by the grants PN 41-087 /PN2-099 from the Romanian Ministry of Research and Technology
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1. Vardiman JW Arber DA Brunning RD Larson RA Matutes E Baumann I et al. Therapy - related myeloid neoplasms in: Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H Thiele J Vardiman JW editors. WHO classification of Tumours of Haematopoietic and Lymphoid Tissues. Fourth Ed. Lyon France: IARC Press 2008: 127-129.
2. Arber DA Orazi A Hasserjian R Thiele J Borowitz MJ Michelle M et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391-2405. DOI: 10.1182/blood-2016-03-643544
4. Heuser M. Therapy-related myeloid neoplasms: does knowing the origin help to guide treatment? Hematology Am Soc Hematol Educ Program. 2016 Dec;(1):24-32. DOI: 10.1182/asheducation-2016.1.24
5. Churpek JE Marquez R Neistadt B Claussen K Lee MK Churpek MM et al. Inherited mutations in cancer succeptibility genes are common among survivors of breast cancer who develop therapy - related leukemia. Cancer. 2016 Jan;122(2):304-11. DOI: 10.1002/ cncr.29615
6. Kayser S Dohner K Krauter J Köhne CH Horst HA Held G et al. The impact of therapy - related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011 Feb; 117(7):2137-45. DOI: 10.1182/blood-2010-08-301713
7. Montesinos P Gonzalez JD Gonzalez J Rayo’n C de Lisa E Amigo ML et al. Therapy - Related Myeloid Neoplasms in patients with acute promyelocytic leukemia treated with all- trans retinoic acid and anthracycline based chemotherapy. J Clin Oncol. 2010 Aug;28(24):3872-9. DOI: 10.1200/JCO.2010.29.2268
8. Lo-Coco F Cicconi L Breccia M. Current standard treatment of acute promyelocytic leukemia. British Journal of Haematology. 2016 Mar;172(6):841-4. DOI: 10.1111/bjh.13890
9. Zeidan AM Gore SD. New strategies in acute promyelocytic leukemia: Moving to an Entirely Oral Chemotherapy-Free Upfront Management Approach. Clinical Cancer Research. 2014 Oct; 20(19):4985-93. DOI: 10.1158/1078-0432.CCR-13-2725
10. Tomita A Kiyoi H NaoeT. Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O 3) in acute promyelocytic leukemia. Int J Hematol. 2013 Jun;97(6):717-25. DOI: 10.1007/ s12185-013-1354-4
11. Wang ZY Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008 March; 111(5):2505-14. DOI: 10.1182/blood-2007-07-102798
12. Sanz MA Lo Coco F Martin 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 leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000 Aug; 96:1247-53.
13. Sanz MA Grimwade D Tallman MS Lowenberg B Fenaux P Estey EH et al. Management of acute promyelocytic leukemia: recommandations from an expert panel on behalf of the European Leukemia Net. Blood 2009 Feb;113(9):1875-91. DOI: 10.1182/ blood-2008-04-150250
14. Sanz MA Lo-Coco F. Modern Approaches to Treating Acute Promyelocytic Leukemia. J Clin Oncol. 2011 Feb;29(5):495-503. DOI: 10.1200/JCO.2010.32.1067
15. Lo-Coco F Avvisati G Vignetti M Breccia M Gallo E Rambaldi A et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010 Oct; 116(17):3171-9. DOI: 10.1182/ blood-2010-03-276196
16. Lo-Coco F Avvisati G Vignetti M Thiede C Orlando SM Iacobelli S et al. Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. N Engl J Med 2013 Jul;369(2):111-21. DOI: 10.1056/ NEJMoa1300874
17. Platzbecker U Avvisati G Cicconi L Thiede C Paoloni F Vignetti 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 2016 Jul;1-14.
18. Burnett AK Russell NH Hills RK Bowen D Kell J Knapper S et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised controlled phase 3 trial. The Lancet Oncology 2015 Oct;16(13): 1295-305. DOI: 10.1016/S1470-2045(15)00193-X
19. Imagawa J Harada Y Shimomura T Tanaka H Okikawa Y Hyodo H et al. Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia. Blood 2010 Dec; 116(26):6018-22. DOI: 10.1182/ blood-2010-06-289389
20. Eghtedar A Rodriquez I Kantarjian H O’Brien S Daver N Manero GG et al. Incidence of secondary neoplasms in patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus chemotherapy or with all-trans retinoic acid pluss arsenic trioxide. Leuk. Lymphoma 2015 May;56(5):1342-5. DOI: 10.3109/10428194.2014.953143
21. Latagliata R Petti MC Fenu S Mancini M Spiriti MAE Breccia M et al. Therapy-related myelodysplastic syndrome- acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Blood 2002 Feb; 99(3):822-4. DOI: 10.1182/blood.V99.3.822
22. 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 alltrans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood.2010 Jun;115(25):5137-46. DOI: 10.1182/ blood-2010-01-266007
23. Panizo C Patino A Lecumberri R Calasanz MJ Odero MD Bendandi M et al. Secondary myelodysplastic syndrome after treatment for promyelocytic leukemia: clinical and genetic features of two cases. Cancer Genetics and Cytogenetics 2003 Jul; 143(2):178-81. DOI: 10.1016/S0165-4608(02)00859-2
24. Lobe I Rigal-Huguet F Vekhoff A Desablens B Bordessoule D Mounier C et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia. 2003 Aug;17(8):1600-4. DOI: 10.1038/sj.leu.2403034
25. Coliţă A Nicoară S Butoianu E Munteanu N Ursea C Poppa C et al. Acute promyelocytic leukemia. A study of 119 cases and a review of the literature. Rev Med Interna Neurol Psihiatr Neurochir Dermatovenerol Med Interna. 1988 Jan-Feb;40(1):21-32.
26. Colita A Vasilache D Gheorghe A Jardan C Jardan D Dragomir M et al. Acute promyelocytic leukemia: the importance of the laboratory examination for the diagnosis and the dynamic following of the answer to the treatment. Romanian Review of the Laboratory Medicine 2013 Jun; 21(2/4):S60.
27. Coombs CC Tavakkoli M Tallman MS: Acute promyelocytic leukemia: where did we start where are we now and the future. Blood Cancer Journal 2015 Feb;5 e304. DOI: 10.1038/bcj.2015.25
28. Schmiegelow K Al - Modhwahii Andersen MK Behrendtz M Forestier E Hasle H et al. Methotrexate (6- mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia. Results from the NOPHO ALL- 92 study. Blood 2009;113:6077-884. DOI: 10.1182/blood-2008-11-187880
29. Döhner H Estey E Grimwade D Amadori S Appelbaum FR Büchner T et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017 Jan;129(4):424-47. DOI: 10.1182/blood-2016-08-733196
30. Watts JM Tallman MS. Acute promyelocytic leukemia: What is the new standard of care? Blood Rev 2014 Sep; 28(5):205-12. DOI: 10.1016/j.blre.2014.07.001
31. Esteve J Escoda L Martín G Rubio V Díaz- Mediavilla J González M et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracyclinebased chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 2007 Mar;21(3):446-52. DOI: 10.1038/sj.leu.2404501