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matteo molica
elisabetta abruzzese
massimo breccia
(*) Corresponding Author:


Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene. In more than 95% of CML patients, the typical BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2), or the simultaneous expression of both. Other less frequent transcript subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3, and e14a3, have been sporadically reported. The main purpose of this review is to assess the possible impact of different transcripts on the response rate to tyrosine kinase inhibitors (TKIs), the achievement of stable deep molecular responses (s-DMR), the potential maintenance of treatment-free remission (TFR), and long-term outcome of CML patients treated with TKIs. According to the majority of published studies, patients with e13a2 transcript treated with imatinib have lower and slower cytogenetic and molecular responses than those with e14a2 transcript and should be considered a high-risk group who would mostly benefit from frontline treatment with second-generation TKIs (2GTIKIs). Although few studies have been published, similar significant differences in response rates to 2GTKIs have been not reported. The e14a2 transcript seems to be a favorable prognostic factor for obtaining s-DMR, irrespective of the TKI received, and is also associated with a very high rate of TFR maintenance. Indeed, patients with e13a2 transcript achieve a lower rate of s-DMR and experience a higher probability of TFR failure. According to most reported data in the literature, the type of transcript does not seem to affect long-term outcomes of CML patients treated with TKIs. In TFR, the e14a2 transcript appears to be related to favorable responses. 2GTKIs as frontline therapy might be a convenient approach in patients with e13a2 transcript to achieve optimal long-term outcomes.


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1. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol. 2018; 93(3):442-459.
2. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973; 243(5405):290–293.
3. Kurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med. 1988; 319(15):990-8.
4. Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med. 2003; 138(10):819-30.
5. Bennour A, Ouahchi I, Achour B, Zaier M, Youssef YB, Khelif A, Saad A, Sennana H. Analysis of the clinico-hematological relevance of the breakpoint location within M-BCR in chronic myeloid leukemia. Med Oncol. 2013; 30(1):348.
6. Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Batram CR, Grosveld G.. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984; 36:93–9.
7. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood. 2009; 113:1619–30.
8. Hai A, Kizilbash NA, Zaidi SH, Alruwaili J, Shahzad K. Differences in structural elements of Bcr-Abl oncoprotein isoforms in Chronic Myelogenous Leukemia. Bioinformation. 2014; 10(3): 108–114.
9. Verma D, Kantarjian HM, Jones D, Luthra R, Borthakur G, Verstovsek S, Rios MB, Cortes J. Chronic myeloid leukemia (CML) with P190BCR?ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009; 114:2232?2235.
10. Winter SS, Greene JM, McConnell TS, Willman CL. Pre-B acute lymphoblastic leukemia with b3a2 (p210) and e1a2 (p190) BCR-ABL fusion transcripts relapsing as chronic myelogenous leukemia with a less differentiated b3a2 (p210) clone. Leukemia. 1999; 13(12): 2007-11.
11. Jones D, Luthra R, Cortes J, Thomas D, O'Brien S, Bueso-Ramos C, Hai S, Ravandi F, de Lima M, Kantarjian H, Jorgensen JL. BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome–positive leukemias. Blood. 2008; 112(13):5190–5192.
12. Lichty BD, Keating A, Callum J, Yee K, Croxford R, Corpus G, Nwachukwu B, Kim P, Guo J, Kamel-Reid S. Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia. Br J Haematol. 1998; 103(3):711-5.
13. Gong Z, Medeiros JL, Cortes JE, et al. Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia. Blood Cancer J. 2017; 7(7): e583.
14. Verstovsek S, Lin H, Kantarjian H, Saglio G, De Micheli D, Pane F, Garcia-Manero G, Intrieri M, Rotoli B, Salvatore F, Guo JQ, Talpaz M, Specchia G, Pizzolo G, Liberati AM, Cortes J, Quackenbush RC, Arlinghaus RB. Neutrophilic-chronic myeloid leukemia: low levels of p230 BCR/ABL mRNA and undetectable BCR/ABL protein may predict an indolent course. Cancer 2002; 94:2416-2425.
15. Baccarani M, Castagnetti F, Gugliotta G, Rosti G, Soverini S, Albeer A, Pfirrmann M, the International BCR-ABLStudy Group. The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview. Leukemia. 2019.
16. Chasseriau J, Rivet J, Bilan F, Chomel JC, Guilhot F, Bourmeyster N, Kitzis A. Characterization of the Different BCR-ABL Transcripts with a Single Multiplex RT-PCR. J Mol Diagn. 2004; 6(4): 343–347.
17. Burmeister T, Reinhardt R. A multiplex PCR for improved detection of typical and atypical BCR-ABL fusion transcripts. Leuk Res. 2008; 32(4):579-85.
18. Limsuwanachot N, Siriboonpiputtana T, Karntisawiwat K, Chareonsirisuthigul T, Chuncharunee S, Rerkamnuaychoke B. Multiplex RT-PCR Assay for Detection of Common Fusion Transcripts in Acute Lymphoblastic Leukemia and Chronic Myeloid Leukemia Cases. Asian Pac J Cancer Prev. 2016; 17(2):677-84.
19. Mills KL, Mackenzie ED, Birnie GD. The site of the breakpoint within the bcr is a prognostic factor in Philadelphia chromosome?positive chronic myeloid leukemia. Blood. 1989; 72:1237–1241.
20. Schaefer-Rego K, Dudek H, Popenoe D, Z Arlin, Mears JG, Bank A, Leibowitz D. CML patients in blast crisis have breakpoints localized to a specific region of the BCR. Blood. 1987; 70(2):448-55.
21. Shepherd P, Suffolk R, Halsey J, Allan N. Analysis of molecular breakpoint and m?RNA transcripts in a prospective randomized trial of interferon in chronic myeloid leukaemia: no correlation with clinical features, cytogenetic response, duration of chronic phase, or survival. Br J Haematol. 1995; 89:546–554.
22. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Chronic myeloid leukemia, BCR/ABL transcript, response to interferon, and survival. Leukemia. 1995; 9:1648–1652.
23. 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, Hänel 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, Müller MC, SAKK and the German CML Study Group. Distinct characteristics of e13a2 versus e14a2 BCR?ABL1 driven chronic myeloid leukemia under first?line therapy with imatinib. Haematologica. 2014; 99:1441?1447.
24. 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, O'Brien S, Cortes J. Impact of BCR?ABL transcript type on outcome in patients with chronic?phase CML treated with tyrosine kinase inhibitors. Blood. 2016; 127:1269?1275.
25. Castagnetti F, Gugliotta G, Breccia M, Iurlo A, Levato L, Albano F, Vigneri P, Abruzzese E, Rossi G, Rupoli S, Cavazzini F, Martino M, Orlandi E, Pregno P, Annunziata M, Usala U, Tiribelli M, Sica S, Bonifacio M, Fava C, Gherlinzoni F, Bocchia M, Soverini S, Bochicchio MT, Cavo M , Martinelli G, Saglio G, Pane F, Baccarani M, Rosti G, GIMEMA CML Working Party. The BCR?ABL1 transcript type influences response and outcome in Philadelphia chromosome–positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol. 2017; 92:797?805.
26. Mir R, Ahmad I, Javid J, Zuberi M, Yadav P, Shazia R, Masroor M, Guru S, Ray PC, Gupta N, Saxena A. Simple multiplex RT?PCR for identifying common fusion BCR?ABL transcript types and evaluation of molecular response of the a2b2 and a2b3 transcripts to imatinib resistance in north Indian chronic myeloid leukemia patients. Indian J Cancer. 2015; 52:314?318.
27. Lin HX, Sjaarda J, Dyck J, Stringer R, Hillis C, Harvey M, Carter R, Ainsworth P, Leber B, Pare G, Sadikovic B. Gender and BCR?ABL transcript type are correlated with molecular response to imatinib treatment in patients with chronic myeloid leukemia. Eur J Haematol. 2016; 96:360?366.
28. Pagnano KBB, Miranda EC, Delamain MT, Oliveira Duarte G, de Paula EV, Lorand-Metze I, de Souza GA.Influence of BCR?ABL transcript type on outcome in patients with chronic?phase chronic myeloid leukemia treated with imatinib. Clin Lymphoma Myeloma Leuk. 2017; 17:728?733.
29. Sung-Eun L, Soo-Young C, Soo-Hyun K, Hye-Young S, Hae-Lyun Y, Mi-Young L, Hee-Jeong H, Ki-Hoon K, Kyung-Mi K, Eun-Jung J, Dong-Wook K. Baseline BCR?ABL1 transcript type of e13a2 and large spleen size are predictors of poor long?term outcomes in chronic phase chronic myeloid leukemia patients who failed to achieve an early molecular response after 3 months of imatinib therapy. Leuk Lymphoma. 2018; 59:105?113.
30. Vega?Ruiz A, Kantarjian H, Shan J, Wierda W, Burger J, Verstovsek S, Garcia-Manero G, Cortes J. Better molecular response to imatinib for patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) carrying the b3a2 transcript compared to b2a2 [abstract]. Blood. 2007; 110:1939.
31. Sharma P, Kumar L, Mohanty S, Kochupillai V. Response to imatinib mesylate in chronic myeloid leukemia patients with variant BCR?ABL fusion transcripts. Ann Hematol. 2010; 89:241?247.
32. Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, Chuah C, Pavlovsky C, Mayer J, Cortes J, Baccarani M, Kim DK, Bradley-Garelik MB, Mohamed H, Wildgust M, Hochhaus A.Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014; 123(4):494-500.
33. Jain P, Kantarjian H, Nazha A, O'Brien S, Jabbour E, Romo CG, Pierce S, Cardenas-Turanzas M, Verstovsek S, Borthakur G, Ravandi F, Quintás-Cardama A, Cortes J. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood 2013; 121(24):4867-4874.
34. Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, Flinn JW, Kurokawa M, Moiraghi B, Yu R, Blakesley RE, Gallagher NJ, Saglio G, Kantarjian H.. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia 2012; 26(10):2197-2203.
35. Catsagnetti F, Gugliotta G, Breccia M, Stagno F, D'Adda M, Levato L, Carella AM, Martino B, Tiribelli M, Fava C, Binotto G, Avanzini P, Bocchia M, Bergamaschi M, Russo Rossi A, Cavazzini F, Abruzzese E, Soverini S, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Baccarani M, Rosti G. Prognostic Value of BCR-ABL1 Transcript Type in Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib. Blood 2016; 128:3070.
36. Jain P, Kantarjian HM, Romo CG, et al. BCR?ABL fusion transcripts in patients with chronic myeloid leukemia in chronic phase (CML?CP): experience with ponatinib from MD Anderson Cancer Center [abstract]. Blood. 2013; 122:2727.
37. Bonifacio M, Scaffidi L, Binotto G, De Marchi F, Maino E, Calistri E, Bonalumi A,Frison L,Marin L, Medeot M, De Matteis G, Fanin R, Semenzato G, Ambrosetti A, Tiribelli M. Predictive Factors of Stable Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with Imatinib Standard Dose: A Study from the Gruppo Triveneto LMC. Blood 2015; 126:597.
38. Breccia M, Molica M, Colafigli G, Massaro F, Quattrocchi L, Latagliata R, M, Diverio D, Guarini A, Alimena G, Foà R. Prognostic factors associated with a stable MR4.5 achievement in chronic myeloid leukemia patients treated with imatinib. Oncotarget. 2017; 9(7):7534-7540.
39. Shanmuganathan N, Branford S, Yong ASM, Hiwase DK, Yeung DT, Ross DM, Hughes TP.
The e13a2 BCR-ABL1 Transcript Is Associated with Higher Rates of Molecular Recurrence after Treatment-Free Remission Attempts: Retrospective Analysis of the Adelaide Cohort. ASH 2018; Oral Poster 1731.
40. D’Adda M, Farina M, Cerqui E, Ruggeri G, Ferrari S, Chiara Bottelli C, Pagani C, Passi A, Rossi G. An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors. Blood 2017; 130:1589.
41. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P, Intergroupe Français des Leucémies Myéloïdes Chroniques Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010; 11(11):1029–1035.
42. Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini F, Varet B, Gardembas M, Etienne G, Réa D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014; 32(5):424–430.
43. Claudiani S, Apperley JF, Gale RP, Clark R, Szydlo R, Deplano S, Palanicawandar R, Khorashad J, Foroni L, Milojkovic D.E14a2 BCR?ABL1 transcript is associated with a higher rate of treatment?free remission in persons with chronic myeloid leukemia after stopping tyrosine kinase?inhibitor therapy. Haematologica. 2017; 102:e297?e299.
44. Pfirrmann M, Evtimova D, Saussele S, Castagnetti F, Cervantes F, Janssen J, Hoffmann VS, Gugliotta G, Hehlmann R, Hochhaus A, Hasford J, Baccarani M. No influence of BCR?ABL1 transcript types e13a2 and e14a2 on long?term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib. J Cancer Res Clin Oncol. 2017; 143:843?850.
45. Lucas CM, Harris RJ, Giannoudis A, Davies A, Knight K, Watmough SJ, Wang L, Clark RE. Chronic myeloid leukemia patients with the e13a2 BCR?ABL fusion transcript have inferior responses to imatinib compared to patients with the e14a2 transcript. Haematologica. 2009; 94:1362?1367.
46. Burmeister T, Reinhardt R. A multiplex PCR for improved detection of typical and atypical BCR–ABL fusion transcripts. Leuk Res 2008; 32: 579–585.
47. Verma D, Kantarjian H, Jones D, Luthra R, Borthakur G, Verstovsek S, Rios MB, Cortes J. Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance. Blood. 2009; 114(11): 2232–2235.
48. Gong Z, Medeiros LJ, Cortes JE, Zheng L, Khoury JD, Wang W, Tang G, Loghavi G, Luthra R, Yang W, Kantarjian H, Hu S. Clinical and prognostic significance of e1a2 BCR-ABL1 transcript subtype in chronic myeloid leukemia. Blood Cancer J. 2017; 7(7):e583.
49. Molica M, Zacheo I, Diverio D, Alimena G, Breccia M. Long-term outcome of chronic myeloid leukaemia patients with p210 and p190 co-expression at baseline. Br J Haematol. 2015; 169(1):148-50.
50. Pane F, Frigeri F, Sindona M, Luciano L, Ferrara F, Cimino R, Meloni G, Saglio G, Salvatore F, Rotoli B. Neutrophilic-chronic Myeloid Leukemia: A Distinct Disease With a Specific Molecular Marker (BCR/ABL With C3/A2 Junction). Blood. 1996; 88(7):2410-4.
51. Lee JJ, Kim HJ, Kim YJ, Lee S, Hwang JY, Kim YL, Kim DW. Imatinib induces a cytogenetic response in blast crisis or interferon failure chronic myeloid leukemia patients with e19a2 BCR-ABL transcripts. Leukemia 2004; 18,1539–1540.
52. Mondal BC, Majumdar S, Dasgupta UB, Chaudhuri U, Chakrabarti P, Bhattacharyya S. E19a2 BCR-ABL fusion transcript in typical chronic myeloid leukaemia: a report of two cases. J Clin Pathol 2006; 59:1102-1103.
53. Oshikawa G, Kurosu T, Arai A, Murakami N, Miura O. Clonal evolution with double Ph followed by tetraploidy in imatinib-treated chronic myeloid leukemia with e19a2 transcript in transformation. Cancer Genet Cytogenet 2010; 199:56- 61.
54. Martin SE, Sausen M, Joseph A, Kingham B. Chronic myeloid leukemia with e19a2 atypical transcript: early imatinib resistance and complete response to dasatinib. Cancer Genet Cytogenet 2010; 201:133-134.
55. Bennour A, Beaufils N, Sennana S, Saad A, Gabert J. E355G mutation appearing in a patient with e19a2 chronic myeloid leukaemia resistant to imatinib. J Clin Pathol 2010; 737- 740.
56. Langabeer SE, McCarron SL, Carroll P, Kelly J, O'Dwyer MJ, Conneally E. Molecular response to first line nilotinib in a patient with e19a2 BCR-ABL1 chronic myeloid leukemia. Leuk Res 2012; 35:e169- e170.
57. Al-Ali HK, Leiblein S, Kovacs I, Hennig E, Niederwieser D, Deininger MWN. CML with an e1a3 BCR-ABL fusion: rare, benign, and a potential diagnostic pitfall. Blood. 2002; 100(3):1092–1093.
58. Roman J, Jimenez A, Barrios M, J Castillejo A, Maldonado J, Torres A. E1A3 as a unique, naturally occurring BCR-ABL transcript in an indolent case of chronic myeloid leukaemia. Br J Haematol. 2001; 114(3):635–637.
59. Martinez-Serra J, del Campo R, Gutierrez A, Antich JL,Ginard M, Durán MA, Bento L, Ros T, Amat JC, Vidal C, Iglesias JF, Orlinska I, Besalduch J.Chronic myeloid leukemia with an e1a3 BCR-ABL fusion protein: transformation to lymphoid blast crisis. Biomark Res. 2014; 2: 14.
60. Schultheis B, Wang L, Clark RE, Melo J V. BCR-ABL with an e6a2 fusion in a CML patient diagnosed in blast crisis. Leukemia. 2003; 17(10):2054–2055.
61. Colla S, Sammarelli G, Voltolini S, Crugnola M, Sebastio P, Giuliani N. E6a2 BCR-ABL transcript in chronic myeloid leukemia: is it associated with aggressive disease? Haematologica. 2004; 89(5):611–613.
62. Beel KA, Lemmens J, Vranckx H, Maertens J, Vandenberghe P. CML with e6a2 BCR-ABL1 transcript: An aggressive entity? Annals of Hematology. 2011; 90(10):1241–1243.
63. Popovici C, Cailleres S, David M, Lafage-Pochitaloff M, Sainty D, Mozziconacci MJ. E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to imatinib. Leuk Lymph 2005; 46(9):1375–1377.
64. Breccia M, Cannella L, Diverio D, Streponi P, Nanni M, Stefanizzi C, Natalino F, Mecarocci S, Alimena G. Isolated thrombocytosis as first sign of chronic myeloid leukemia with e6a2 BCR/ABL fusion transcript, JAK2 negativity and complete response to imatinib. Leuk Res. 2008; 32(1):177–180.
65. Schnittger S, Bacher U, Kern W, Haferlach T, Hertenstein BM Haferlach C. A new case with rare e6a2 BCR-ABL fusion transcript developing two new resistance mutations during imatinib mesylate, which were replaced by T315I after subsequent dasatinib treatment. Leukemia. 2008; 22(4):856–858.
66. Vefring HK., Gruber FXE, Wee L, Kelleher E, O’Shea D, Conneally E, Langabeer SE. Chronic myelogenous leukemia with the e6a2 bcr-abl and lacking imatinib response: Presentation of two cases. Acta Haematologica. 2009; 122(1):11–16.
67. Mondal BC, Bandyopadhyay A, Majumdar S, Mukhopadhyay A, Chandra S, Chaudhuri U, Chakrabarti P, Bhattacharyya S, Dasgupta UB. Molecular profiling of chronic myeloid leukemia in eastern India. Am J Hematol. 2006; 81(11):845–849.
68. Lee M, Kantarjian H, Talpaz M. Association of the responsiveness to interferon therapy with the bcr/abl splicing pattern in Philadelphia chromosome positive chronic myelogenous leukemia. Blood. 1992; 80(suppl.I):210.
69. Polampalli S, Choughule A, Negi N, Shinde S, Baisane C, Amre P, Subramanian PG, Gujral S, Prabhash K, Parikh P. Analysis and comparison of clinicohematological parameters and molecular and cytogenetic response of two Bcr/Abl fusion transcripts. Genet Mol Res. 2008; 7:1138?1149.
70. Lee SE, Choi SY, Bang JH, Kim SH, Jang EJ, Byeun JY, Park JE, Jeon HR, Oh YJ, Kim HJ, Kim YK, Park JS, Jeong SH, Kim SH, Zang DY, Oh S, Koo DH, Kim H, Do YR, Kwak JY, Kim JA, Kim DY, Mun YC, Mauro MJ, Kim DW. Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib. Am J Hematol. 2013; 88:449?454.

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