Nilotinib-Chemotherapy in CML Myeloid BP or Bcr-abl(+) AML

Summary

The current standard therapy in previously untreated adults with chronic phase (CP) of CML is imatinib and the result of long-term follow-up of IRIS study proves that imatinib for CML CP is reasonable therapy.(1, 2) However, some patients were initially diagnosed as advanced CML, accelerated phase (AP) or blastic phase (BP). Various chemotherapies were tried and were found that there were no highly effective chemotherapies for CML BP.(3-11) Imatinib in patients with these advanced CML is also disappointing because of low response rates as well as short response duration, and sudden transformation to BC is found even in initial CML CP patients. (12-17). Recent studies showed that nilotinib or dasatinib is better than imatinib in terms of rapid response and higher molecular response in newly diagnosed CML patients.(18-21) More potent bcr-abl suppression of nilotinib is supposed to be more active than imatinib even in patients with advanced CML. However, nilotinib in patients with imatinib-resistant or -intolerant CML BP showed low hematologic response and major cytogenetic response.(22, 23)

Timeline

Start

2012-09

Primary completion

2019-09

Completion

2019-12

Publications

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• Background Dutcher JP, Lee S, Paietta E, Bennett JM, Stewart JA, Wiernik PH. Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992. Leukemia. 1998 Jul;12(7):1037-40. doi: 10.1038/sj.leu.2401056.
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• Background O'Brien S, Kantarjian H, Keating M, Beran M, Koller C, Robertson LE, Hester J, Rios MB, Andreeff M, Talpaz M. Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase. Blood. 1995 Nov 1;86(9):3322-6.
• Background Jabbour E, Kantarjian H, O'Brien S, Rios MB, Abruzzo L, Verstovsek S, Garcia-Manero G, Cortes J. Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate. Blood. 2006 Jan 15;107(2):480-2. doi: 10.1182/blood-2005-05-1816. Epub 2005 Sep 29.
• Background Kantarjian HM, Cortes J, O'Brien S, Giles FJ, Albitar M, Rios MB, Shan J, Faderl S, Garcia-Manero G, Thomas DA, Resta D, Talpaz M. Imatinib mesylate (STI571) therapy for Philadelphia chromosome-positive chronic myelogenous leukemia in blast phase. Blood. 2002 May 15;99(10):3547-53. doi: 10.1182/blood.v99.10.3547.
• Background Morimoto A, Ogami A, Chiyonobu T, Takanashi M, Sugimoto T, Imamura T, Ishida H, Yoshihara T, Imashuku S. Early blastic transformation following complete cytogenetic response in a pediatric chronic myeloid leukemia patient treated with imatinib mesylate. J Pediatr Hematol Oncol. 2004 May;26(5):320-2. doi: 10.1097/00043426-200405000-00013.
• Background Pavlu J, Czepulkowski B, Kaczmarski R, Jan-Mohamed R. Early blastic transformation with CNS infiltration in a patient with chronic myeloid leukaemia treated with imatinib. Lancet Oncol. 2005 Feb;6(2):128. doi: 10.1016/S1470-2045(05)01744-4. No abstract available.
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• Background Palandri F, Castagnetti F, Alimena G, Testoni N, Breccia M, Luatti S, Rege-Cambrin G, Stagno F, Specchia G, Martino B, Levato L, Merante S, Liberati AM, Pane F, Saglio G, Alberti D, Martinelli G, Baccarani M, Rosti G. The long-term durability of cytogenetic responses in patients with accelerated phase chronic myeloid leukemia treated with imatinib 600 mg: the GIMEMA CML Working Party experience after a 7-year follow-up. Haematologica. 2009 Feb;94(2):205-12. doi: 10.3324/haematol.13529. Epub 2009 Jan 14.
• Background Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. doi: 10.1056/NEJMoa0912614. Epub 2010 Jun 5.
• Background Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boque C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. doi: 10.1056/NEJMoa1002315. Epub 2010 Jun 5.
• Background Cortes JE, Jones D, O'Brien S, Jabbour E, Konopleva M, Ferrajoli A, Kadia T, Borthakur G, Stigliano D, Shan J, Kantarjian H. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010 Jan 20;28(3):392-7. doi: 10.1200/JCO.2009.25.4896. Epub 2009 Dec 14.
• Background Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M; GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009 Dec 3;114(24):4933-8. doi: 10.1182/blood-2009-07-232595. Epub 2009 Oct 12.
• Background Fava C, Kantarjian HM, Jabbour E, O'Brien S, Jain N, Rios MB, Garcia-Manero G, Ravandi F, Verstovsek S, Borthakur G, Shan J, Cortes J. Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood. 2009 May 21;113(21):5058-63. doi: 10.1182/blood-2008-10-184960. Epub 2009 Mar 12.
• Background Jabbour E, Cortes J, Kantarjian H. Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review. Core Evid. 2010 Jun 15;4:207-13. doi: 10.2147/ce.s6003.
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• Background Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. doi: 10.1182/blood-2003-08-2958. Epub 2003 Oct 9.
• Background Wassmann B, Pfeifer H, Goekbuget N, Beelen DW, Beck J, Stelljes M, Bornhauser M, Reichle A, Perz J, Haas R, Ganser A, Schmid M, Kanz L, Lenz G, Kaufmann M, Binckebanck A, Bruck P, Reutzel R, Gschaidmeier H, Schwartz S, Hoelzer D, Ottmann OG. Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2006 Sep 1;108(5):1469-77. doi: 10.1182/blood-2005-11-4386. Epub 2006 Apr 25.
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