Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
2012; Elsevier BV; Volume: 23; Linguagem: Inglês
10.1093/annonc/mds228
ISSN1569-8041
AutoresMichele Baccarani, S. Pileri, J. L. Steegmann, Marc Müller, Simona Soverini, Martin Dreyling,
Tópico(s)Acute Lymphoblastic Leukemia research
ResumoThe incidence of chronic myeloid leukemia (CML) ranges between 10 and 15 cases/106/year (age adjusted) without any major geographic or ethnic differences [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet. Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar]. The median age at diagnosis ranges between 60 and 65 years in Europe, but is considerably lower in countries where the population is younger. The prevalence of CML is steadily rising due to the very substantial prolongation of survival that has been achieved with targeted therapy [2.Björkholm M. Ohm L. Eloranta S. et al.Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008.J Clin Oncol. 2011; 29: 2514-2520doi:10.1200/JCO.2011.34.7146Crossref PubMed Scopus (171) Google Scholar]. The translocation of the ABL gene from chromosome 9 to 22 t(9;22)(q3.4;q1.1) leads to the formation of a new, hybrid, fusion gene (BCR-ABL) that codes for an oncoprotein (P210, more rarely P190 or P230) that is located in the cytoplasm and has a strong, constitutively activated, tyrosine kinase activity, resulting in the activation of several downstream signals that transform hematopoietic stem cells [3.Quintás-Cardama A. Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia.Blood. 2009; 113: 1619-1630doi:10.1182/blood-2008-03-144790Crossref PubMed Scopus (519) Google Scholar]. BCR-ABL-positive cells are genetically unstable and are prone to develop multiple and heterogenous genomic abnormalities, resulting in the transformation of the leukemic phenotype from chronic to acute, hence leading to the progression from chronic (CP) to accelerated and blast phases (AP, BP) [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet. Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar]. One important event associated with progression is the development of point mutations in the kinase domain (KD) of the BCR-ABL gene, leading to resistance to the tyrosine kinase inhibitors (TKI) [4.Apperley J.F. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia.Lancet Oncol. 2007; 8: 1018-1029doi:10.1016/S1470-2045(07)70342-XAbstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 5.Apperley J.F. Part II: management of resistance to imatinib in chronic myeloid leukaemia.Lancet Oncol. 2007; 8: 1116-1128doi:10.1016/S1470-2045(07)70379-0Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar]. Bone marrow (BM) biopsies taken from untreated patients at diagnosis [6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar] show increased cellularity due to proliferation of the granulocytic series that turns in different stages of maturation, although myelocytes and segmented forms predominate. No substantial features of dysplasia are found. Eosinophils may be prominent. Blasts must account for 50% of patients. The hallmark of diagnosis is leukocytosis with basophilia and with immature granulocytes, mainly metamyelocytes, myelocytes and promyelocytes, and few or occasional myeloblasts. Severe anemia is rare. Thrombocytosis is frequent. Blood counts and differential are very important for the calculation of a prognostic risk (Table 1) [7.Sokal J.E. Cox E.B. Baccarani M. et al.Prognostic discrimination in 'good-risk' chronic granulocytic leukemia.Blood. 1984; 63: 789-799Crossref PubMed Google Scholar, 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: 850-858doi:10.1093/jnci/90.11.850Crossref PubMed Scopus (654) Google Scholar, 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: 686-692doi:10.1182/blood-2010-12-319038Crossref PubMed Scopus (333) Google Scholar] and for the distinction between chronic, accelerated and blast phases (Table 2) [6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar, 10.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: 1809-1820doi:10.1182/blood-2006-02-005686Crossref PubMed Scopus (1083) Google Scholar, 11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar].Table 1The relative risk of a patient with CML can be calculated using simple clinical and hematologic data provided that they are collected prior to any treatmentSokal et al. [7.Sokal J.E. Cox E.B. Baccarani M. et al.Prognostic discrimination in 'good-risk' chronic granulocytic leukemia.Blood. 1984; 63: 789-799Crossref PubMed Google Scholar]EURO [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: 850-858doi:10.1093/jnci/90.11.850Crossref PubMed Scopus (654) Google Scholar]EUTOS [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: 686-692doi:10.1182/blood-2010-12-319038Crossref PubMed Scopus (333) Google Scholar]Age (years)0.116 (age—43.4)0.666 when age >50NASpleen size (cm)0.345 × (spleen—7.51)0.042 × spleen4 × spleenPlatelet count (×109/l)0.188 × [(platelet/700)2- 0.563]1.0956 when platelet ≥1500NABlood blast cells (%)0.887 × (blast cells—2.10)0.0584 × blast cellsNABlood basophils (%)NA0.20399 when basophils >3%7 × basophilsBlood eosinophils (%)NA0.0413 × eosinophilsNARelative riskExponential of the totaltotal × 1000TotalLow 1.2>1480>87There are three systems: Sokal et al. [7.Sokal J.E. Cox E.B. Baccarani M. et al.Prognostic discrimination in 'good-risk' chronic granulocytic leukemia.Blood. 1984; 63: 789-799Crossref PubMed Google Scholar], that was developed in 1984, in the era of conventional chemotherapy; EURO [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: 850-858doi:10.1093/jnci/90.11.850Crossref PubMed Scopus (654) Google Scholar], that was derived in 1998 from IFNα-treated patients, and EUTOS [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: 686-692doi:10.1182/blood-2010-12-319038Crossref PubMed Scopus (333) Google Scholar], that has derived more recently (2011) from imatinib-treated patients. The EUTOS risk score is simpler, and in imatinib-treated patients have a prognostic value greater than Sokal and EURO.Spleen is measured by manual palpation and expressed as maximum distance below costal margin.NA: not applicable; CML: chronic myeloid leukemia; IFNα: interferon-α. Open table in a new tab Table 2Clinical and hematologic criteria for the definition of AP and BP according to WHO [6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar] and to ELN [11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar]Accelerated phaseBlast phaseWHO [6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar]ELN [11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar]WHO [6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar]ELN [11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar]SpleenPersisting or increasing splenomegaly unresponsive to therapy///WBCPersisting or increasing WBC (>10 × 109/l) unresponsive to therapy///Blast cellsaIn peripheral blood or in BM.10%–19%15%–29%≥20%≥30%BasophilsaIn peripheral blood or in BM.>20%>20%//Platelet count>1000 × 109/l uncontrolled by therapy///<100 × 109/l unrelated to therapyYes//CCA/Ph+PresentPresent//Extramedullary involvementbExcluding liver and spleen, including lymph nodes, skin, CNS, bone, and lung.//PresentPresentThe criteria of AP are different, reflecting the difficulty of making the diagnosis of this transitory phase. The criteria of BP differ only for the percent of blast cells. Only one of the listed criteria is sufficient for the diagnosis of AP or BP.CCA/Ph+ = clonal chromosome abnormalities in Ph+ cells.AP: accelerated phase; BP: blast phase; WHO: World Health Organization; ELN: European LeukemiaNet; BM: bone marrow.a In peripheral blood or in BM.b Excluding liver and spleen, including lymph nodes, skin, CNS, bone, and lung. Open table in a new tab There are three systems: Sokal et al. [7.Sokal J.E. Cox E.B. Baccarani M. et al.Prognostic discrimination in 'good-risk' chronic granulocytic leukemia.Blood. 1984; 63: 789-799Crossref PubMed Google Scholar], that was developed in 1984, in the era of conventional chemotherapy; EURO [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: 850-858doi:10.1093/jnci/90.11.850Crossref PubMed Scopus (654) Google Scholar], that was derived in 1998 from IFNα-treated patients, and EUTOS [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: 686-692doi:10.1182/blood-2010-12-319038Crossref PubMed Scopus (333) Google Scholar], that has derived more recently (2011) from imatinib-treated patients. The EUTOS risk score is simpler, and in imatinib-treated patients have a prognostic value greater than Sokal and EURO. Spleen is measured by manual palpation and expressed as maximum distance below costal margin. NA: not applicable; CML: chronic myeloid leukemia; IFNα: interferon-α. The criteria of AP are different, reflecting the difficulty of making the diagnosis of this transitory phase. The criteria of BP differ only for the percent of blast cells. Only one of the listed criteria is sufficient for the diagnosis of AP or BP. CCA/Ph+ = clonal chromosome abnormalities in Ph+ cells. AP: accelerated phase; BP: blast phase; WHO: World Health Organization; ELN: European LeukemiaNet; BM: bone marrow. The diagnosis must be confirmed by cytogenetics showing t(9; 22)(q3.4;q1.1), and by reverse transcriptase polymerase chain reaction (RT-PCR) showing BCR-ABL transcripts. Cytogenetics must be performed by chromosome banding analysis (CBA) of marrow cell metaphases [12.Hook E.B. Exclusion of chromosomal mosaicism: tables of 90%, 95% and 99% confidence limits and comments on use.Am J Hum Genet. 1977; 29: 94-97PubMed Google Scholar, 13.Shaffer L. Slovak M. Campbell L. ISCN 2009. An International System for Human Cytogenetic. Karger, Basel2009Google Scholar]. If marrow cells cannot be obtained, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of blood cells, using dual color dual fusion probes that allow the detection of BCR-ABL+ nuclei. CBA is required, because it is necessary to detect additional chromosome abnormalities. FISH is not required, but it may become necessary to detect some variant translocations [14.Testoni N. Marzocchi G. Luatti S. et al.Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP.Blood. 2009; 114: 4939-4943doi:10.1182/blood-2009-07-229864Crossref PubMed Scopus (63) Google Scholar]. Qualitative RT-PCR is performed on RNA extracted by freshly collected BM or blood cells. It identifies the transcript type, either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCR-ABL protein weight (P210, rarely P230 or P190). Real time, quantitative, PCR (RT-Q-PCR measuring BCR-ABL transcripts level as BCR-ABL % on the International Scale) is not required baseline. It will be necessary, later on, for monitoring the response to treatment [15.Hughes T. Deininger M. Hochhaus A. et al.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.Blood. 2006; 108: 28-37doi:10.1182/blood-2006-01-0092Crossref PubMed Scopus (1002) Google Scholar, 16.Branford S. Fletcher L. Cross N.C. et al.Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials.Blood. 2008; 112: 3330-3338doi:10.1182/blood-2008-04-150680Crossref PubMed Scopus (312) Google Scholar, 17.Müller M.C. Cross N.C. Erben P. et al.Harmonization of molecular monitoring of CML therapy in Europe.Leukemia. 2009; 23: 1957-1963doi:10.1038/leu.2009.168Crossref PubMed Scopus (180) Google Scholar]. These recommendations for the baseline diagnostic work-up are summarized in Table 3.Table 3Recommendations for the diagnostic workup and for assessing and monitoring the response to treatmentBaseline (diagnostic workup)To assess the responseTo monitor the response and the treatmentBlood counts and differentialYesEvery 15 days until a CHR has been achievedEvery 3 monthsBone marrow, cytologyYesNoNoBone marrow, Karyotype (CBA)YesAt 3 and 6 months, then every 6 months, until a CCgR has been achievedEvery 12 months, once a CCgR has been achieved, only if molecular response cannot be assuredBlood, I-FISHNoNoOnly if CBA of marrow cell metaphases cannot be performed, and molecular response cannot be assessedBlood, RT-PCR (qualitative)YesNoNoBlood, RT-Q-PCR (quantitative, BCR-ABL %)NoEvery 3 months until a major molecular response has been achievedEvery 6 months, once a MMR has been achievedMutational analysisOnly in AP or BPNoOnly in case of failure (see Table 6)There are no prospective studies providing evidence for these recommendations, but they are strongly supported by expert opinions and by the design of all main studies [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet. Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar, 10.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: 1809-1820doi:10.1182/blood-2006-02-005686Crossref PubMed Scopus (1083) Google Scholar, 11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar, 14.Testoni N. Marzocchi G. Luatti S. et al.Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP.Blood. 2009; 114: 4939-4943doi:10.1182/blood-2009-07-229864Crossref PubMed Scopus (63) Google Scholar, 15.Hughes T. Deininger M. Hochhaus A. et al.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.Blood. 2006; 108: 28-37doi:10.1182/blood-2006-01-0092Crossref PubMed Scopus (1002) Google Scholar, 16.Branford S. Fletcher L. 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De Souza C.A. et al.Bosutinib versus imatinib in newly diagnosed chronic phase chronic myeloid leukemia–BELA trial: 24-month follow-up.Blood (ASH Annual Meeting Abstracts). 2011; 118 (Abstract 455: 210)Google Scholar].CBA: chromosome banding analysis; I-FISH: interphase fluorescence in situ hybridization; CCgR: complete cytogenetic response; CHR: complete hematologic response; AP: accelerated phase; BP: blastic phase; RT-PCR: reverse transcriptase polymerase chain reaction; RT-Q-PCR: quantitative reverse transcriptase polymerase chain reaction; MMR: major molecular response. Open table in a new tab There are no prospective studies providing evidence for these recommendations, but they are strongly supported by expert opinions and by the design of all main studies [1.Hehlmann R. Hochhaus A. Baccarani M. European LeukemiaNet. Chronic myeloid leukaemia.Lancet. 2007; 370: 342-350Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 6.Vardiman J.W. Melo J.V. Baccarani M. Thiele J. Chronic myelogenous leukemia, BCR-ABL1 positive.in: Swerdlowsh WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. IARC, Lyon2008: 32-37Google Scholar, 10.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: 1809-1820doi:10.1182/blood-2006-02-005686Crossref PubMed Scopus (1083) Google Scholar, 11.Baccarani M. Cortes J. Pane F. et al.Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.J Clin Oncol. 2009; 27: 6041-6051doi:10.1200/JCO.2009.25.0779Crossref PubMed Scopus (1088) Google Scholar, 14.Testoni N. Marzocchi G. Luatti S. et al.Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response: a study of the GIMEMA CML WP.Blood. 2009; 114: 4939-4943doi:10.1182/blood-2009-07-229864Crossref PubMed Scopus (63) Google Scholar, 15.Hughes T. Deininger M. Hochhaus A. et al.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.Blood. 2006; 108: 28-37doi:10.1182/blood-2006-01-0092Crossref PubMed Scopus (1002) Google Scholar, 16.Branford S. Fletcher L. Cross N.C. et al.Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials.Blood. 2008; 112: 3330-3338doi:10.1182/blood-2008-04-150680Crossref PubMed Scopus (312) Google Scholar, 19.O'Brien S.G. Guilhot F. Larson R.A. et al.Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.N Engl J Med. 2003; 348: 994-1004doi:10.1056/NEJMoa022457Crossref PubMed Scopus (2983) Google Scholar, 20.Hughes T.P. 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: 1423-1432doi:10.1056/NEJMoa030513Crossref PubMed Scopus (1068) Google Scholar, 21.Druker B.J. Guilhot F. O'Brien S.G. et al.Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.N Engl J Med. 2006; 355: 2408-2417doi:10.1056/NEJMoa062867Crossref PubMed Scopus (2874) Google Scholar, 22.Hochhaus A. O'Brien S.G. Guilhot F. et al.Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.Leukemia. 2009; 23: 1054-1061doi:10.1038/leu.2009.38Crossref PubMed Scopus (729) Google Scholar, 23.Baccarani M. Rosti G. Castagnetti F. et al.Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study.Blood. 2009; 113: 4497-4504doi:10.1182/blood-2008-12-191254Crossref PubMed Scopus (167) Google Scholar, 24.Hehlmann R. Lauseker M. Jung-Munkwitz S. et al.Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia.J Clin Oncol. 2011; 29: 1634-1642doi:10.1200/JCO.2010.32.0598Crossref PubMed Scopus (269) Google Scholar, 25.Hochhaus A. Kantarjian H.M. Baccarani M. et al.Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy.Blood. 2007; 109: 2303-2309doi:10.1182/blood-2006-09-047266Crossref PubMed Scopus (544) Google Scholar, 26.Kantarjian H.M. Giles F.J. Bhalla K.N. 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: 1141-1145doi:10.1182/blood-2010-03-277152Crossref PubMed Scopus (299) Google Scholar, 27.Rosti G. Palandri F. Castagnetti F. et al.Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia.Blood. 2009; 114: 4933-4938doi:10.1182/blood-2009-07-232595Crossref PubMed Scopus (176) Google Scholar, 28.Saglio G. Kim D.W. Issaragrisil S. et al.Nilotinib versus
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