Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy:
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- 作者：Antonio R. Lucena-Araujo (1) (2)
Haesook T. Kim (3)
Rafael H. Jacomo (1) (2)
Raul A. Melo (4)
Rosane Bittencourt (5)
Ricardo Pasquini (6)
Katia Pagnano (7)
Evandro M. Fagundes (8)
Maria de Lourdes Chauffaille (9)
Carlos S. Chiattone (10)
Ana Silvia Lima (1) (2)
Guillermo Ruiz-Argüelles (11)
Maria Soledad Undurraga (12)
Lem Martinez (13)
Hau C. Kwaan (14)
Robert Gallagher (15)
Charlotte M. Niemeyer (16)
Stanley L. Schrier (17)
Martin S. Tallman (18)
David Grimwade (19)
Arnold Ganser (20)
Nancy Berliner (21)
Raul C. Ribeiro (22)
Francesco Lo-Coco (23) (24)
Bob L?wenberg (25)
Miguel A. Sanz (26)
Eduardo M. Rego (1) (2) (27) - 关键词：Acute promyelocytic leukemia ; IC ; APL ; FLT3 ; ITD mutations ; Developing countries ; ATRA
- 刊名：Annals of Hematology
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：93
- 期：12
- 页码：2001-2010
- 全文大小：408 KB
- 参考文献：1. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60?years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372-380 CrossRef
2. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909-918 CrossRef
3. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al (2002) Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 99:4326-335 CrossRef
4. Chillon MC, Fernandez C, Garcia-Sanz R, Balanzategui A, Ramos F, Fernandez-Calvo J et al (2004) FLT3-activating mutations are associated with poor prognostic features in AML at diagnosis but they are not an independent prognostic factor. Hematol J 5:239-46 CrossRef
5. Kainz B, Heintel D, Marculescu R, Schwarzinger I, Sperr W, Le T et al (2002) Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16). Hematol J 3:283-89 CrossRef
6. Moreno I, Martin G, Bolufer P, Barragan E, Rueda E, Roman J et al (2003) Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 88:19-4
7. Schnittger S, Bacher U, Haferlach C, Kern W, Alpermann T, Haferlach T (2011) Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA. Haematologica 96:1799-807 matol.2011.049007" target="_blank" title="It opens in new window">CrossRef
8. Noguera NI, Breccia M, Divona M, Diverio D, Costa V, De SS et al (2002) Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16:2185-189 CrossRef
9. de Lourdes CM, Borri D, Proto-Siqueira R, Moreira ES, Alberto FL (2008) Acute promyelocytic leukemia with t(15;17): frequency of additional clonal chromosome abnormalities and FLT3 mutations. Leuk Lymphoma 49:2387-389 CrossRef
10. Au WY, Fung A, Chim CS, Lie AK, Liang R, Ma ES et al (2004) FLT-3 aberrations in acute promyelocytic leukaemia: clinicopathological associations and prognostic impact. Br J Haematol 125:463-69 CrossRef
11. Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E (2005) de BS et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia 19:1153-160 CrossRef
12. Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF et al (2005) Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 106:3768-776 CrossRef
13. Hasan SK, Sazawal S, Dutta P, Pillai LS, Kumar B, Chaubey R et al (2007) Impact of FLT3 internal tandem duplications on Indian acute promyelocytic leukemia patients: prognostic implications. Hematology 12:99-01 CrossRef
14. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K et al (1997) Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 11:1447-452 m (3)
Rafael H. Jacomo (1) (2)
Raul A. Melo (4)
Rosane Bittencourt (5)
Ricardo Pasquini (6)
Katia Pagnano (7)
Evandro M. Fagundes (8)
Maria de Lourdes Chauffaille (9)
Carlos S. Chiattone (10)
Ana Silvia Lima (1) (2)
Guillermo Ruiz-Argüelles (11)
Maria Soledad Undurraga (12)
Lem Martinez (13)
Hau C. Kwaan (14)
Robert Gallagher (15)
Charlotte M. Niemeyer (16)
Stanley L. Schrier (17)
Martin S. Tallman (18)
David Grimwade (19)
Arnold Ganser (20)
Nancy Berliner (21)
Raul C. Ribeiro (22)
Francesco Lo-Coco (23) (24)
Bob L?wenberg (25)
Miguel A. Sanz (26)
Eduardo M. Rego (1) (2) (27)
1. Medical School of Ribeir?o Preto, Ribeirao Preto, Brazil
2. Center for Cell Based Therapy, Ribeirao Preto, Brazil
3. Dana-Farber Cancer Institute, Boston, MA, USA
4. Funda??o HEMOPE, Recife, Brazil
5. Federal University of Rio Grande do Sul, Porto Alegre, Brazil
6. Federal University of Paraná, Curitiba, Brazil
7. University of Campinas, Campinas, Brazil
8. Federal University of Minas Gerais, Belo Horizonte, Brazil
9. Federal University of Sao Paulo, Sao Paulo, Brazil
10. Santa Casa Medical School, Sao Paulo, Brazil
11. Clínica Ruiz de Puebla, Puebla, Mexico
12. Hospital del Salvador, Santiago, Chile
13. Asociación Espa?ola Primera de Socorros Mutuos, Montevideo, Uruguay
14. Northwestern University Feinberg School of Medicine, Chicago, IL, USA
15. Albert Einstein Cancer Center, New York, NY, USA
16. University Medical Center, Freiburg, Germany
17. Stanford University, Stanford, CA, USA
18. Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, New York, NY, USA
19. King’s College London School of Medicine, London, UK
20. Hannover Medical School, Hannover, Germany
21. Harvard Medical School, Boston, MA, USA
22. St. Jude Children’s Research Hospital, Memphis, TN, USA
23. University Tor Vergata, Rome, Italy
24. Santa Lucia Foundation, Rome, Italy
25. Erasmus University Medical Center, Rotterdam, The Netherlands
26. Valencia University Medical School, Valencia, Spain
27. Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of S?o Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14048-900, Brazil - ISSN：1432-0584
文摘
Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20?%). FLT3-ITD mutations were associated with higher white blood cell counts (P--.0001), relapse-risk score (P--.0007), higher hemoglobin levels (P--.0004), higher frequency of the microgranular morphology (M3v) subtype (P--.03), and the short PML/RARA (BCR3) isoform (P--.0001). After a median follow-up of 38?months, FLT3-ITDpositive patients had a lower 3-year overall survival rate (62?%) compared with FLT3-ITDnegative patients (82?%) (P--.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95?% confidence interval [CI] 1.17-.89; P--.017). Nevertheless, complete remission (P--.07), disease-free survival (P--.24), and the cumulative incidence of relapse (P--.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.