Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

Gabriele Gugliotta, F. Castagnetti, M. Breccia, A. Gozzini, Emilio Usala, A.M. Carella, Giovanna Rege-Cambrin, B. Martino, Elisabetta Abruzzese, F. Albano, Fabio Stagno, L. Luciano, Mariella D'Adda, M. Bocchia, F. Cavazzini, M. Tiribelli, M. Lunghi, A. Pia Falcone, Caterina Musolino, G. L. LevatoC. Venturi, S. Soverini, Michele Cavo, G. Alimena, F. Pane, G. Martinelli, G. Saglio, G. Rosti, M. Baccarani

Research output: Contribution to journalArticle

Abstract

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. © 2016 Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)617-622
Number of pages6
JournalAmerican Journal of Hematology
Volume91
Issue number6
DOIs
Publication statusPublished - 2016

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Leukemia, Myeloid, Chronic Phase
Protein-Tyrosine Kinases
Therapeutics
Cytogenetics
Disease-Free Survival
Survival Rate
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
Safety
Survival

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Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia. / Gugliotta, Gabriele; Castagnetti, F.; Breccia, M.; Gozzini, A.; Usala, Emilio; Carella, A.M.; Rege-Cambrin, Giovanna; Martino, B.; Abruzzese, Elisabetta; Albano, F.; Stagno, Fabio; Luciano, L.; D'Adda, Mariella; Bocchia, M.; Cavazzini, F.; Tiribelli, M.; Lunghi, M.; Pia Falcone, A.; Musolino, Caterina; Levato, G. L.; Venturi, C.; Soverini, S.; Cavo, Michele; Alimena, G.; Pane, F.; Martinelli, G.; Saglio, G.; Rosti, G.; Baccarani, M.

In: American Journal of Hematology, Vol. 91, No. 6, 2016, p. 617-622.

Research output: Contribution to journalArticle

Gugliotta, G, Castagnetti, F, Breccia, M, Gozzini, A, Usala, E, Carella, AM, Rege-Cambrin, G, Martino, B, Abruzzese, E, Albano, F, Stagno, F, Luciano, L, D'Adda, M, Bocchia, M, Cavazzini, F, Tiribelli, M, Lunghi, M, Pia Falcone, A, Musolino, C, Levato, GL, Venturi, C, Soverini, S, Cavo, M, Alimena, G, Pane, F, Martinelli, G, Saglio, G, Rosti, G & Baccarani, M 2016, 'Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia', American Journal of Hematology, vol. 91, no. 6, pp. 617-622. https://doi.org/10.1002/ajh.24362
Gugliotta, Gabriele ; Castagnetti, F. ; Breccia, M. ; Gozzini, A. ; Usala, Emilio ; Carella, A.M. ; Rege-Cambrin, Giovanna ; Martino, B. ; Abruzzese, Elisabetta ; Albano, F. ; Stagno, Fabio ; Luciano, L. ; D'Adda, Mariella ; Bocchia, M. ; Cavazzini, F. ; Tiribelli, M. ; Lunghi, M. ; Pia Falcone, A. ; Musolino, Caterina ; Levato, G. L. ; Venturi, C. ; Soverini, S. ; Cavo, Michele ; Alimena, G. ; Pane, F. ; Martinelli, G. ; Saglio, G. ; Rosti, G. ; Baccarani, M. / Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia. In: American Journal of Hematology. 2016 ; Vol. 91, No. 6. pp. 617-622.
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title = "Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia",
abstract = "The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93{\%}, 87{\%}, and 61{\%}, respectively. The 5-year overall survival and progression-free survival were 89{\%}. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5{\%}). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. {\circledC} 2016 Wiley Periodicals, Inc.",
author = "Gabriele Gugliotta and F. Castagnetti and M. Breccia and A. Gozzini and Emilio Usala and A.M. Carella and Giovanna Rege-Cambrin and B. Martino and Elisabetta Abruzzese and F. Albano and Fabio Stagno and L. Luciano and Mariella D'Adda and M. Bocchia and F. Cavazzini and M. Tiribelli and M. Lunghi and {Pia Falcone}, A. and Caterina Musolino and Levato, {G. L.} and C. Venturi and S. Soverini and Michele Cavo and G. Alimena and F. Pane and G. Martinelli and G. Saglio and G. Rosti and M. Baccarani",
note = "Cited By :2 Export Date: 16 March 2017 CODEN: AJHED Correspondence Address: Gugliotta, G.; Institute of Hematology L. and A. Ser{\`a}gnoli, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of BolognaItaly; email: gabriele.gugliotta@unibo.it References: Kantarjian, H., O'Brien, S., Jabbour, E., Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: A single-institution historical experience (2012) Blood, 119, pp. 1981-1987; Baccarani, M., Deininger, M.W., Rosti, G., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013 (2013) Blood, 122, pp. 872-884; Hoglund, M., Sandin, F., Hellstrom, K., Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: Report from the population-based Swedish CML registry (2013) Blood, 122, pp. 1284-1292; O'Brien, S., Radich, J.P., Abboud, C.N., Chronic myelogenous leukemia, version 1.2015 (2014) J Natl Compr Canc Netw, 12, pp. 1590-1610; Apperley, J.F., Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia (2007) Lancet Oncol, 8, pp. 1018-1029; Bixby, D., Talpaz, M., Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia (2011) Leukemia, 25, pp. 7-22; Soverini, S., Hochhaus, A., Nicolini, F.E., BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Recommendations from an expert panel on behalf of European LeukemiaNet (2011) Blood, 118, pp. 1208-1215; Sokal, J.E., Cox, E.B., Baccarani, M., Prognostic discrimination in {"}good-risk{"} chronic granulocytic leukemia (1984) Blood, 63, pp. 789-799; Baccarani, M., Cortes, J., Pane, F., Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet (2009) J Clin Oncol, 27, pp. 6041-6051; Hughes, T., Deininger, M., Hochhaus, A., Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results (2006) Blood, 108, pp. 28-37; Cross, N.C., White, H.E., Colomer, D., Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia (2015) Leukemia, 29, pp. 999-1003; Soverini, S., Gnani, A., Colarossi, S., Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors (2009) Blood, 114, pp. 2168-2171; Kaplan, E.L., Meier, P., Nonparametric estimation from incomplete observations. J Am (1958) Stat Assoc, 53, pp. 457-481; Hoffmann, V.S., Baccarani, M., Hasford, J., The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries (2015) Leukemia, 29, pp. 1336-1343; Talpaz, M., Hehlmann, R., Quintas-Cardama, A., Mercer, J., Cortes, J., Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia (2013) Leukemia, 27, pp. 803-812; Ahmed, W., Van Etten, R.A., Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: Tyrosine-kinase inhibitor combinations and beyond (2013) Hematology Am Soc Hematol Educ Program, 2013, pp. 189-200; Jabbour, E., Kantarjian, H.M., O'Brien, S., Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: What is the optimal response? (2011) J Clin Oncol, 29, pp. 4260-4265; Marin, D., Ibrahim, A.R., Lucas, C., 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 (2012) J Clin Oncol, 30, pp. 232-238; Shami, P.J., Deininger, M., Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: The role of second-generation BCR-ABL inhibitors as first-line therapy (2012) Leukemia, 26, pp. 214-224; Hanfstein, B., Muller, M.C., Hehlmann, R., Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML) (2012) Leukemia, 26, pp. 2096-2102; Gurion, R., Gafter-Gvili, A., Vidal, L., Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis (2013) Haematologica, 98, pp. 95-102; Jain, P., Kantarjian, H., Nazha, A., Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: Results with four tyrosine kinase inhibitor modalities (2013) Blood, 121, pp. 4867-4874; Hughes, T., White, D., Which TKI? An embarrassment of riches for chronic myeloid leukemia patients (2013) Hematology Am Soc Hematol Educ Program, 2013, pp. 168-175; Jabbour, E., Kantarjian, H.M., Saglio, G., Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION) (2014) Blood, 123, pp. 494-500; Hughes, T.P., Saglio, G., Kantarjian, H.M., Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib (2014) Blood, 123, pp. 1353-1360; Experts in Chronic Myeloid, L., The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts (2013) Blood, 121, pp. 4439-4442; Aichberger, K.J., Herndlhofer, S., Schernthaner, G.H., Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML (2011) Am J Hematol, 86, pp. 533-539; Le Coutre, P., Rea, D., Abruzzese, E., Severe peripheral arterial disease during nilotinib therapy (2011) J Natl Cancer Inst, 103, pp. 1347-1348; Levato, L., Cantaffa, R., Kropp, M.G., Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: A single institution study (2013) Eur J Haematol, 90, pp. 531-532; Giles, F.J., Mauro, M.J., Hong, F., Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: A retrospective cohort analysis (2013) Leukemia, 27, pp. 1310-1315; Kim, T.D., Rea, D., Schwarz, M., Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib (2013) Leukemia, 27, pp. 1316-1321; Valent, P., Hadzijusufovic, E., Schernthaner, G.H., Wolf, D., Rea, D., le Coutre, P., Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors (2015) Blood, 125, pp. 901-906; Moslehi, J.J., Deininger, M., Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia (2015) J Clin Oncol, 33, pp. 4210-4218; Gugliotta, G., Castagnetti, F., Breccia, M., Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia (2015) Haematologica, 100, pp. 1146-1150; Saglio, G., Kim, D.W., Issaragrisil, S., Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia (2010) N Engl J Med, 362, pp. 2251-2259; Saglio, G., Hochhaus, A., Hughes, T.P., (2013), ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes. :ASH Meeting, Abstract 92Kantarjian, H.M., Hochhaus, A., Saglio, G., Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial (2011) Lancet Oncol, 12, pp. 841-851; Larson, R.A., Hochhaus, A., Hughes, T.P., Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up (2012) Leukemia, 26, pp. 2197-2203; Hochhaus, A., Saglio, G., Hughes, T.P., Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial (2016) Leukemia; Kantarjian, H., Shah, N.P., Hochhaus, A., Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia (2010) N Engl J Med, 362, pp. 2260-2270; Kantarjian, H.M., Shah, N.P., Cortes, J.E., Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION) (2012) Blood, 119, pp. 1123-1129; Cortes, J., Saglio, G., Baccarani, M., (2014), Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056). Blood. :ASH Meeting, Abstract 152Preudhomme, C., Guilhot, J., Nicolini, F.E., Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia (2010) N Engl J Med, 363, pp. 2511-2521; Guilhot, F., Rigal-Huguet, F., Guilhot, J., (2014), Long Term Outcome of Chronic Phase Chronic Myeloid Leukemia (CP CML) Patients (pts) from the French Spirit Study Comparing Imatinib (IM) 400 Mg to Higher Dose Imatinib or Combination with Peg-interferonα2a (PegIFN) or Cytarabine (Ara-C): A Trial of the FI LMC (France intergroupe de la leucemie my{\'e}lo{\"i}de chronique). Blood :ASH Meeting, Abstract 1793Wang, J., Shen, Z.X., Saglio, G., Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina (2015) Blood, 125, pp. 2771-2778; Hehlmann, R., Muller, M.C., Lauseker, M., Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: Results from the randomized CML-study IV (2014) J Clin Oncol, 32, pp. 415-423; Cervantes, F., Lopez-Garrido, P., Montero, M.I., Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: A study of the Spanish PETHEMA group (2010) Haematologica, 95, pp. 1317-1324; Cortes, J.E., Kantarjian, H.M., Goldberg, S.L., High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: High rates of rapid cytogenetic and molecular responses (2009) J Clin Oncol, 27, pp. 4754-4759; Hochhaus, A., Rosti, G., Cross, N.C., Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: Results from the European ENEST1st study (2016) Leukemia, 30, pp. 57-64; Gugliotta, G., Castagnetti, F., Apolinari, M., First-line treatment of newly diagnosed elderly patients with chronic myeloid leukemia: current and emerging strategies (2014) Drugs, 74, pp. 627-643",
year = "2016",
doi = "10.1002/ajh.24362",
language = "English",
volume = "91",
pages = "617--622",
journal = "American Journal of Hematology",
issn = "0361-8609",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

AU - Gugliotta, Gabriele

AU - Castagnetti, F.

AU - Breccia, M.

AU - Gozzini, A.

AU - Usala, Emilio

AU - Carella, A.M.

AU - Rege-Cambrin, Giovanna

AU - Martino, B.

AU - Abruzzese, Elisabetta

AU - Albano, F.

AU - Stagno, Fabio

AU - Luciano, L.

AU - D'Adda, Mariella

AU - Bocchia, M.

AU - Cavazzini, F.

AU - Tiribelli, M.

AU - Lunghi, M.

AU - Pia Falcone, A.

AU - Musolino, Caterina

AU - Levato, G. L.

AU - Venturi, C.

AU - Soverini, S.

AU - Cavo, Michele

AU - Alimena, G.

AU - Pane, F.

AU - Martinelli, G.

AU - Saglio, G.

AU - Rosti, G.

AU - Baccarani, M.

N1 - Cited By :2 Export Date: 16 March 2017 CODEN: AJHED Correspondence Address: Gugliotta, G.; Institute of Hematology L. and A. Seràgnoli, Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi Hospital, University of BolognaItaly; email: gabriele.gugliotta@unibo.it References: Kantarjian, H., O'Brien, S., Jabbour, E., Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: A single-institution historical experience (2012) Blood, 119, pp. 1981-1987; Baccarani, M., Deininger, M.W., Rosti, G., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013 (2013) Blood, 122, pp. 872-884; Hoglund, M., Sandin, F., Hellstrom, K., Tyrosine kinase inhibitor usage, treatment outcome, and prognostic scores in CML: Report from the population-based Swedish CML registry (2013) Blood, 122, pp. 1284-1292; O'Brien, S., Radich, J.P., Abboud, C.N., Chronic myelogenous leukemia, version 1.2015 (2014) J Natl Compr Canc Netw, 12, pp. 1590-1610; Apperley, J.F., Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia (2007) Lancet Oncol, 8, pp. 1018-1029; Bixby, D., Talpaz, M., Seeking the causes and solutions to imatinib-resistance in chronic myeloid leukemia (2011) Leukemia, 25, pp. 7-22; Soverini, S., Hochhaus, A., Nicolini, F.E., BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Recommendations from an expert panel on behalf of European LeukemiaNet (2011) Blood, 118, pp. 1208-1215; Sokal, J.E., Cox, E.B., Baccarani, M., Prognostic discrimination in "good-risk" chronic granulocytic leukemia (1984) Blood, 63, pp. 789-799; Baccarani, M., Cortes, J., Pane, F., Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet (2009) J Clin Oncol, 27, pp. 6041-6051; Hughes, T., Deininger, M., Hochhaus, A., Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: Review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results (2006) Blood, 108, pp. 28-37; Cross, N.C., White, H.E., Colomer, D., Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia (2015) Leukemia, 29, pp. 999-1003; Soverini, S., Gnani, A., Colarossi, S., Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors (2009) Blood, 114, pp. 2168-2171; Kaplan, E.L., Meier, P., Nonparametric estimation from incomplete observations. J Am (1958) Stat Assoc, 53, pp. 457-481; Hoffmann, V.S., Baccarani, M., Hasford, J., The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries (2015) Leukemia, 29, pp. 1336-1343; Talpaz, M., Hehlmann, R., Quintas-Cardama, A., Mercer, J., Cortes, J., Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia (2013) Leukemia, 27, pp. 803-812; Ahmed, W., Van Etten, R.A., Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: Tyrosine-kinase inhibitor combinations and beyond (2013) Hematology Am Soc Hematol Educ Program, 2013, pp. 189-200; Jabbour, E., Kantarjian, H.M., O'Brien, S., Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: What is the optimal response? (2011) J Clin Oncol, 29, pp. 4260-4265; Marin, D., Ibrahim, A.R., Lucas, C., 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 (2012) J Clin Oncol, 30, pp. 232-238; Shami, P.J., Deininger, M., Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: The role of second-generation BCR-ABL inhibitors as first-line therapy (2012) Leukemia, 26, pp. 214-224; Hanfstein, B., Muller, M.C., Hehlmann, R., Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML) (2012) Leukemia, 26, pp. 2096-2102; Gurion, R., Gafter-Gvili, A., Vidal, L., Has the time for first-line treatment with second generation tyrosine kinase inhibitors in patients with chronic myelogenous leukemia already come? Systematic review and meta-analysis (2013) Haematologica, 98, pp. 95-102; Jain, P., Kantarjian, H., Nazha, A., Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: Results with four tyrosine kinase inhibitor modalities (2013) Blood, 121, pp. 4867-4874; Hughes, T., White, D., Which TKI? An embarrassment of riches for chronic myeloid leukemia patients (2013) Hematology Am Soc Hematol Educ Program, 2013, pp. 168-175; Jabbour, E., Kantarjian, H.M., Saglio, G., Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION) (2014) Blood, 123, pp. 494-500; Hughes, T.P., Saglio, G., Kantarjian, H.M., Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib (2014) Blood, 123, pp. 1353-1360; Experts in Chronic Myeloid, L., The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts (2013) Blood, 121, pp. 4439-4442; Aichberger, K.J., Herndlhofer, S., Schernthaner, G.H., Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML (2011) Am J Hematol, 86, pp. 533-539; Le Coutre, P., Rea, D., Abruzzese, E., Severe peripheral arterial disease during nilotinib therapy (2011) J Natl Cancer Inst, 103, pp. 1347-1348; Levato, L., Cantaffa, R., Kropp, M.G., Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: A single institution study (2013) Eur J Haematol, 90, pp. 531-532; Giles, F.J., Mauro, M.J., Hong, F., Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: A retrospective cohort analysis (2013) Leukemia, 27, pp. 1310-1315; Kim, T.D., Rea, D., Schwarz, M., Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib (2013) Leukemia, 27, pp. 1316-1321; Valent, P., Hadzijusufovic, E., Schernthaner, G.H., Wolf, D., Rea, D., le Coutre, P., Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors (2015) Blood, 125, pp. 901-906; Moslehi, J.J., Deininger, M., Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia (2015) J Clin Oncol, 33, pp. 4210-4218; Gugliotta, G., Castagnetti, F., Breccia, M., Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia (2015) Haematologica, 100, pp. 1146-1150; Saglio, G., Kim, D.W., Issaragrisil, S., Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia (2010) N Engl J Med, 362, pp. 2251-2259; Saglio, G., Hochhaus, A., Hughes, T.P., (2013), ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes. :ASH Meeting, Abstract 92Kantarjian, H.M., Hochhaus, A., Saglio, G., Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial (2011) Lancet Oncol, 12, pp. 841-851; Larson, R.A., Hochhaus, A., Hughes, T.P., Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up (2012) Leukemia, 26, pp. 2197-2203; Hochhaus, A., Saglio, G., Hughes, T.P., Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial (2016) Leukemia; Kantarjian, H., Shah, N.P., Hochhaus, A., Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia (2010) N Engl J Med, 362, pp. 2260-2270; Kantarjian, H.M., Shah, N.P., Cortes, J.E., Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION) (2012) Blood, 119, pp. 1123-1129; Cortes, J., Saglio, G., Baccarani, M., (2014), Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056). Blood. :ASH Meeting, Abstract 152Preudhomme, C., Guilhot, J., Nicolini, F.E., Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia (2010) N Engl J Med, 363, pp. 2511-2521; Guilhot, F., Rigal-Huguet, F., Guilhot, J., (2014), Long Term Outcome of Chronic Phase Chronic Myeloid Leukemia (CP CML) Patients (pts) from the French Spirit Study Comparing Imatinib (IM) 400 Mg to Higher Dose Imatinib or Combination with Peg-interferonα2a (PegIFN) or Cytarabine (Ara-C): A Trial of the FI LMC (France intergroupe de la leucemie myéloïde chronique). 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PY - 2016

Y1 - 2016

N2 - The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. © 2016 Wiley Periodicals, Inc.

AB - The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. © 2016 Wiley Periodicals, Inc.

U2 - 10.1002/ajh.24362

DO - 10.1002/ajh.24362

M3 - Article

VL - 91

SP - 617

EP - 622

JO - American Journal of Hematology

JF - American Journal of Hematology

SN - 0361-8609

IS - 6

ER -