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Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life

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Abstract

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8–14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

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References

  1. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, Baccarani M, Deininger MW, Cervantes F, Fujihara S, Ortmann CE, Menssen HD, Kantarjian H, O'Brien SG, Druker BJ, IRIS Investigators (2017) Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med 376:917–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saussele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R (2013) European leukemia net recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, Cervantes F (1984) Prognostic discrimination in ‘good-risk’ chronic granulocytic leukemia. Blood 63:789–799

    CAS  PubMed  Google Scholar 

  4. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 90:850–858

    Article  CAS  PubMed  Google Scholar 

  5. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, Guilhot F, Porkka K, Ossenkoppele G, Lindoerfer D, Simonsson B, Pfirrmann M, Hehlmann R (2011) Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 118:686–692

    Article  CAS  PubMed  Google Scholar 

  6. Geelen IGP, Sandin F, Thielen N, Janssen JJWM, Hoogendoorn M, Visser O, Cornelissen JJ, Hoglund M, Westerweel PE (2018) Validation of the EUTOS long-term survival score in a recent independent cohort of “real world” CML patients. Leukemia 32:2299–2303

    Article  PubMed  Google Scholar 

  7. O’Brien S, Radich JP, Abboud CN, Akhtari M, Altman JK, Berman E, DeAngelo D, Deininger M, Devine S, Fathi AT, Gotlib J, Jagasia M, Kropf P, Moore JO, Pallera A, Pinilla-Ibarz J, Reddy VV, Shah NP, Smith BD, Snyder DS, Wetzler M, Gregory K, Sundar H, Ntational comprehensive cancer network (2013) National comprehensive cancer network. Clinical practice guidelines in oncology. Chronic myelogenous leukemia, version 1.2014. J Natl Compr Cancer Netw 11:1327–1340

    Article  Google Scholar 

  8. Cross NC, White HE, Colomer D et al (2015) Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia 29:999–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649–655

    Article  CAS  PubMed  Google Scholar 

  10. Gail MH (2005) Cumulative incidence rate. Encyclopedia of Biostatistics

  11. Kaplan EL, Meyer P (1958) Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–465

    Article  Google Scholar 

  12. Bland JM, Altman DG (2004) The logrank test. BMJ. 328(7447):1073

    Article  PubMed  PubMed Central  Google Scholar 

  13. Goodman SN (1993) P value hypothesis and likelihood: implications for epidemiology of a neglected historical debate. A J Epidemiol 137:485–496

    Article  CAS  Google Scholar 

  14. Pfirrmann M, Hochhaus A, Lauseker M, Saußele S, Hehlmann R, Hasford J (2011) Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia. Leukemia 25:1433–1438

    Article  CAS  PubMed  Google Scholar 

  15. Gooley TA, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 18:695–706

    Article  CAS  Google Scholar 

  16. Hochhaus A, Saussele S, Rosti G et al (2017) Chronic myeloid leukaemia: ESMO Clinical Practice. Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28(Supplement 4):iv41–iv51

    Article  CAS  Google Scholar 

  17. Kantarjian H, O’Brien S, Garcia-Manero G et al (2012) Very long-term follow-up results of imatinib Mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy. Cancer 118(12):3116–3122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Castagnetti F, Gugliotta G, Breccia M et al (2016) The EUTOS long-term survival score is predictive for response and outcome in CML patients treated frontline with nilotinib-based regimens. Abstract. S434:EHA

  19. Molica M, Canichella M, Alunni Fegatelli D, Colafigli G, Massaro F, Latagliata R, Foà R, Breccia M (2017) The EUTOS long-term survival score accurately predicts the risk of death in chronic myeloid leukaemia patients treated outside of clinical trials. Am J Hematol 92(12):E661–E664

    Article  PubMed  Google Scholar 

  20. Pagnano KB, Miranda EC, Seguro FS et al (2017) E14a2 and e14a2+e13a2 BCR-ABL transcripts are associated with earlier cytogenetic and molecular response rates in CML-CP treated with imatinib. Blood 130:1596

    Google Scholar 

  21. Jain P, Kantarjian H, Patel KP, Gonzalez GN, Luthra R, Shamanna RK, Sasaki K, Jabbour E, Romo CG, Kadia TM, Pemmaraju N, Daver N, Borthakur G, Estrov Z, Ravandi F, OBrien S, Cortes J (2016) Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood 127(10):1269–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C, Fabarius A, Proetel U, Schnittger S, Haferlach C, Krause SW, Schubert J, Einsele H, Hanel M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Hofmann WK, Hochhaus A, Muller MC, for the SAKK and the German CML Study Group (2014) Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib. Haematologica 99(9):1441–1447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Castagnetti F, Gugliotta G, Breccia M, Iurlo A, Levato L, Albano F, Vigneri P, Abruzzese E, Rossi G, Rupoli S, Cavazzini F, Martino B, Orlandi E, Pregno P, Annunziata M, Usala E, Tiribelli M, Sica S, Bonifacio M, Fava C, Gherlinzoni F, Bocchia M, Soverini S, Bochicchio MT, Cavo M, Giovanni M, Saglio G, Pane F, Baccarani M, Rosti G, on behalf of the GIMEMA CML Working Party (2017) The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol 92(8):797–805

    Article  CAS  PubMed  Google Scholar 

  24. Rousselot P, Cony-Makhoul P, Nicolini F, Mahon FX, Berthou C, Réa D, Reiffers J, Bornand A, Saint-Jean O, Guilhot J, Guilhot F, on behalf of the French Intergroup For Chronic Myelogenous Leukemia (Fi-LMC) (2013) Long-term safety and efficacy of imatinib mesylate (Gleevec®) in elderly patients with chronic phase chronic myelogenous leukemia: results of the AFR04 study. Am J Hematol 88(1):1–4

    Article  CAS  PubMed  Google Scholar 

  25. Young-Woong W, DongWook K, Sung-Eun L et al (2013) Safety and efficacy of imatinib in elderly patients with chronic-phase chronic myeloid leukemia: analysis of outcome for < 60 years versus ≥ 60 years. Blood 122:4039

    Google Scholar 

  26. Latagliata R, Ferrero D, Iurlo A, Cavazzini F, Castagnetti F, Abruzzese E, Fava C, Breccia M, Annunziata M, Stagno F, Tiribelli M, Binotto G, Mansueto G, Gozzini A, Russo S, Cavalli L, Montefusco E, Gugliotta G, Cedrone M, Russo Rossi A, Avanzini P, Pregno P, Mauro E, Spadea A, Celesti F, Giglio G, Isidori A, Crugnola M, Calistri E, Sorà F, Storti S, D’Addosio A, Rege-Cambrin G, Luciano L, Alimena G (2013) Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study. Drugs Aging 30(8):629–637

    Article  CAS  PubMed  Google Scholar 

  27. Hughes T, Saglio G, Kantarjian H et al (2014) Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 123:1353–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Sullivan B, Briggs NE, Hertzberg M, Seymour JF, Reynolds J, Hughes TP (2013) Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood 121(19):3818–3824

    Article  CAS  PubMed  Google Scholar 

  29. Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, Clark RE, Apperley JF, Milojkovic D, Bua M, Pavlu J, Paliompeis C, Reid A, Rezvani K, Goldman JM, Foroni L (2012) Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30:232–238

    Article  CAS  PubMed  Google Scholar 

  30. Hanfstein B, Muller MC, Hehlmann R et al (2012) Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 26:2096–2102

    Article  CAS  PubMed  Google Scholar 

  31. Castagnetti F, Gugliotta G, Breccia M et al (2015) Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib. Leukemia 29(9):1823–1831

    Article  CAS  PubMed  Google Scholar 

  32. Buiatti E, Crocetti E, Acciai S, Gafà L, Falcini F, Milandri C, Rosa ML (1997) Incidence of second primary cancers in three Italian population-based cancer registries. Eur J Cancer 33(11):1829–1834

    Article  CAS  PubMed  Google Scholar 

  33. Verma D, Kantarjian H, Strom SS, Rios MB, Jabbour E, Quintas-Cardama A, Verstovsek S, Ravandi F, O'Brien S, Cortes J (2011) Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies. Blood 118(16):4353–4358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Miranda MB, Lauseker M, Kraus MP, Proetel U, Hanfstein B, Fabarius A, Baerlocher GM, Heim D, Hossfeld DK, Kolb HJ, Krause SW, Nerl C, Brümmendorf TH, Verbeek W, Fauser AA, Prümmer O, Neben K, Hess U, Mahlberg R, Plöger C, Flasshove M, Rendenbach B, Hofmann WK, Müller MC, Pfirrmann M, Hochhaus A, Hasford J, Hehlmann R, Saußele S (2016) Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV. Leukemia 30(6):1255–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pilot PR, Sablinska K, Owen S, Hatfield A (2006) Epidemiological analysis of second primary malignancies in more than 9500 patients treated with imatinib. Leukemia 20(1):148

    Article  CAS  PubMed  Google Scholar 

  36. Ribeiro AL, Marcolino MS, Bittencourt HNS, Barbosa MM, Nunes MCP, Xavier VF, Clementino NCD (2008) An evaluation of the cardiotoxicity of imatinib mesylate. Leuk Res 32(12):1809–1814

    Article  CAS  PubMed  Google Scholar 

  37. Estabragh ZR, Knight K, Watmough SJ, Lane S, Vinjamuri S, Hart G, Clark RE (2011) A prospective evaluation of cardiac function in patients with chronic myeloid leukaemia treated with imatinib. Leuk Res 35(1):49–51

    Article  CAS  PubMed  Google Scholar 

  38. Hatfield A, Owen S, Pilot PR (2007) In reply to “Cardiotoxicity of the cancer therapeutic agent imatinib mesylate”. Nat Med 13(1):13–13 author reply 16

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy

    Matteo Molica, Gioia Colafigli, Emilia Scalzulli, Sofia Chiatamone Ranieri, Lorenzo Rizzo, Daniela Diverio, Roberto Latagliata, Robin Foà & Massimo Breccia

  2. Department of Statistical Sciences, Sapienza University, Rome, Italy

    Danilo Alunni Fegatelli

  3. Data Center and Health Outcomes Research Unit, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy

    Fabio Efficace

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Contributions

MB designed the study, wrote and revised the manuscript; MM collected data and wrote the manuscript; DAF and FE analyzed data; ES, LR, RL, and SCR followed patients; DD and GC performed molecular analysis; RF critically revised the paper and approved the final version.

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Correspondence to Massimo Breccia.

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The authors declare that they have no conflict of interest.

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All procedures performed in this study were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments.

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Molica, M., Colafigli, G., Scalzulli, E. et al. Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life. Ann Hematol 98, 1891–1904 (2019). https://doi.org/10.1007/s00277-019-03706-x

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