Clinical Oncology Letters
https://clinicaloncologyletters.com/article/doi/10.4322/col.2018.005
Clinical Oncology Letters
Artigo Original

Desfecho e preditores de resposta aos inibidores de Tirosinoquinase de 2a geração em pacientes com Leucemia Mielóide Crônica em fase crônica resistentes ao Imatinibe

Outcome and predictors of response to second generation tyrosine kinase inhibitors in patients with Chronic Myeloid Leukemia in chronic phase resistant to Imatinibe

Fernanda da Cunha Vieira, Debora Bonito, Davimar M. Borducchi, Auro del Giglio, Patrícia Weinschenker Bollmann

Downloads: 0
Views: 1496

Resumo

Objetivo: Avaliar o desfecho de pacientes com Leucemia Mielóide Crônica (LMC) em fase crônica (FC) em uso de inibidor de tirosino-quinase (ITKs) de segunda geração após falha com imatinibe e validar o escore de Hammersmith como preditor de resposta da terapia de segunda linha neste grupo de pacientes. Métodos: Entre maio de 2009 e dezembro de 2013, 63 pacientes tratados no serviço de Hematologia do Hospital Mário Covas com LMC em uso de imatinibe foram acompanhados. Destes, 25 pacientes falharam ao imatinibe e receberam tratamento com inibidores de segunda linha. Avaliações periódicas foram realizadas para definição de resposta, incluindo exame clínico, hemograma, cariótipo de medula óssea e pesquisa da proteína BCR-ABL por técnica de reverse transcriptase PCR. Os critérios de resposta do Leukemia Net foram adotados. O escore prognóstico de Hammersmith foi aplicado nos pacientes que iniciaram terapia de segunda linha. Resultados: Com mediana de follow-up de 20,2 meses, 9 pacientes apresentaram resposta citogenética completa, sendo 8 com Resposta Molecular Maior. Onze pacientes apresentaram progressão. O tempo mediano de Sobrevida Livre de Progressão foi 9,5 meses (IC95% 0-23,9). Quando o escore de Hammersmith foi aplicado na nossa população de 20 pacientes, 2 deles eram de baixo risco, 10 de risco intermediário e 8 de alto risco. Conclusão: Metade dos pacientes puderam ser resgatados com ITK de segunda geração apósfalha com imatinibe. Quanto ao escore de Hammersmith, este não conseguiu prever a resposta à terapia na nossa coorte de pacientes, provavelmente pela amostra por ser pequena.

Palavras-chave

Leucemia Mieloide Crônica; Inibidor de Tirosinoquinase; Imatinibe

Abstract

Objective: To evaluate the outcome of patients with Chronic Myeloid Leukaemia (CML) in chronic phase in use of a second generation tyrosine kinase inhibitor (TKIs) following imatinib failure and to validate the Hammersmith score as a predictor of therapy response of this second group of patients. Methods: Between May 2009 and December 2013, 63 patients treated at the hematology department of the Mário Covas Hospital with CML using imatinib were followed. Of these, 25 patients failed to imatinib and received treatment with second-line inhibitors. Periodic evaluations were performed to define response, including clinical examination, blood count, bone marrow karyotype and BCR-ABL protein by reverse transcriptase PCR. The Leukemia Net response criteria were adopted. The Hammersmith prognostic score was applied to patients who started second-line therapy. Results: With a median follow-up of 20.2 months, 9 patients presented complete cytogenetic response, 8 of which with Major Molecular Response. Eleven patients presented progression of disease. The median time to Progression Free Survival was 9.5 months (95% CI 0-23.9). When the Hammersmith score was applied in our population of 20 patients, 2 of them were classified as low risk, 10 as intermediate risk and 8 as high risk. Conclusion: Half of patients could be rescued with second generation TKI after imatinib failure. As for Hammersmith's score, it could not predict the response to therapy in our cohort of patients, probably because the sample was small.

Keywords

Chronic Myeloid Leukemia; Tyrosine kinase inhibitor; Imatinib

Referências

1. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207-19. http://dx.doi.org/10.7326/0003-4819-131-3-199908030-00008. PMid:10428738.

2. Druker BJ, Guilhot F, O’Brien SG. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-17. http://dx.doi.org/10.1056/NEJMoa062867. PMid:17151364.

3. Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26(20):3358-63. http://dx.doi.org/10.1200/JCO.2007.15.8154. PMid:18519952.

4. Volpe G, Panuzzo C, Ulisciani S, Cilloni D. Imatinib resistance in CML. Cancer Lett. 2009;274(1):1-9. http://dx.doi.org/10.1016/j.canlet.2008.06.003. PMid:18653275.

5. Chauffaille MLLF. Leucemia mielóde crônica: tratamento baseado em evidências. Diagn Tratamento. 2009;14(2):62-5.

6. Tam CS, Kantarjian H, Garcia-Manero G, et al. Failure to achieve a major cytogenetic response by 12 months defines inadequate response in patients receiving nilotinib or dasatinib as second or subsequent line ther- apy for chronic myeloid leukemia. Blood. 2008;112(3):516-8. http://dx.doi.org/10.1182/blood-2008-02-141580. PMid:18492956.

7. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789-99. PMid:6584184.

8. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst. 1998;90(11):850-8. http://dx.doi.org/10.1093/jnci/90.11.850. PMid:9625174.

9. Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686-92. http://dx.doi.org/10.1182/blood-2010-12-319038. PMid:21536864.

10. Milojkovic D, Nicholson E, Apperley JF, et al. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica. 2010;95(2):224-31. http://dx.doi.org/10.3324/haematol.2009.012781. PMid:19833633.

11. Druker BJ, O’Brien SG, Cortes J, Radich J. Chronic myel-ogenous leukemia. ASH Education Book. Dec 2002;6(10):111-35.

12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic Myeloid Leukemia. 2009;2(1):1-11.

13. Saad ED, Hoff PM, Carnelós RP, Katz A, Novis YAS, Pietrocola M, et al. Critérios Comuns de Toxicidade do Instituto Nacional de Câncer dos Estados Unidos. Rev Bras Cancerol. 2002;48(1):63-96.

14. Cortes JE, Egorin MJ, Guilhot F, Molimard M, Mahon FX. Pharmacokinetic/pharmacodynamic correlation and bloodlevel testing in imatinib therapy for chronic myeloid leukemia. Leukemia. 2009;23(9):1537-44. http://dx.doi.org/10.1038/leu.2009.88. PMid:19404318.

15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809-20. http://dx.doi.org/10.1182/blood-2006-02-005686. PMid:16709930.

16. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. http://dx.doi.org/10.1056/NEJMoa022457. PMid:12637609.

17. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349(15):1423-32. http://dx.doi.org/10.1056/NEJMoa030513. PMid:14534335.

18. Baccarani M, Deininger M, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872. http://dx.doi.org/10.1182/blood-2013-05-501569. PMid:23803709.

19. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200-6. http://dx.doi.org/10.1038/leu.2008.84. PMid:18401416.

20. Apperley JF, Cortes JE, Kim DW, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol. 2009;27(21):3472-9. http://dx.doi.org/10.1200/JCO.2007.14.3339. PMid:19487385.

21. Cortes J, Kim DW, Raffoux E, et al. Efficacy and safety of dasatinib in imatinib-resistant or - intolerant patients with chronic myeloid leukemia in blast phase. Leukemia. 2008;22(12):2176-83. http://dx.doi.org/10.1038/leu.2008.221. PMid:18754032.

22. Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109(12):5143-50. http://dx.doi.org/10.1182/blood-2006-11-056028. PMid:17317857.

23. Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow- up of a randomized phase 2 study (STARTR). Cancer. 2009;115(18):4136-47. http://dx.doi.org/10.1002/cncr.24504. PMid:19536906.

24. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542-51. http://dx.doi.org/10.1056/NEJMoa055104. PMid:16775235

25. Giles FJ, Larson RA, Kantarjian HM, et al. Nilotinib in Patients (pts) with Philadelphia Chromosome-Positive (Ph+) Chronic Myelogenous Leukemia in Blast Crisis (CML-BC) Who Are Resistant or Intolerant to Imatinib. Blood. 2007;110(11):1025. [abstract].

26. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117(4):1141-5. http://dx.doi.org/10.1182/blood-2010-03-277152. PMid:21098399.

27. Coutre PD, Giles F, Hochhaus A, et al. Nilotinib in Chronic Myeloid Leukemia Patients in Accelerated Phase (CML-AP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study [abstract]. Blood. 2008;112(11):3229.

28. Ottmann OG, Larson RA, Kantarjian HM, et al. Nilotinib in Patients (pts) with Relapsed/ Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Who Are Resistant or Intolerant to Imatinib. Blood. 2007;110(11):2815. [abstract].

5cdafc8d0e8825ee5986c887 col Articles
Links & Downloads

Clin Onc Let

Share this page
Page Sections