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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2012, Vol. 6 Issue (2) : 204-211     DOI: 10.1007/s11684-012-0202-x
Prognostic analysis of chronic myeloid leukemia in Chinese population in an imatinib era
Haiyan He, Yang Shen, Yongmei Zhu, Saijuan Chen()
Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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We evaluated the outcomes of chronic myeloid leukemia (CML) patients in three clinical phases, namely, chronic (CP), accelerated (AP), and blast (BP) phases, receiving imatinib treatment. The single-institution treatment experiences of Chinese patients with CML were presented. A total of 275 CML patients (CP, 210; AP, 24; and BP, 41) who received imatinib between February 2001 and April 2008 were enrolled in this study. We evaluated the responses (hematologic, cytogenetic, and molecular), overall survival (OS), treatment event-free survival (EFS), and prognostic factors of outcome. At the cut-off point, the complete cytogenetic response (CCyR) and complete molecular response rates of patients in the CP were 84.7% and 61.9%, respectively, which were significantly higher than those of patients in the AP (50% and 29.1%, respectively, both P<0.001) and BP (24.3% and 9.7%, respectively, both P<0.001). The estimated five-year OS and five-year EFS rates were 93.2% and 86.4% for CP patients, as well as 64.5% and 50.9% for AP patients, which were significantly higher than those for BP patients (P<0.001). In CP patients, univariate analysis revealed that early treatment with imatinib, achieving CCyR within 12 months, additional cytogenetic abnormalities, and kinase domain mutations were associated with the treatment outcome. More patients are needed to carry out multivariate analysis.

Keywords imatinib      chronic myeloid leukemia      complete cytogenetic response     
Corresponding Authors: Chen Saijuan,   
Issue Date: 05 June 2012
URL:     OR
Gender, no. of patients (%)MaleFemale156 (56.7)119 (43.3)
Mean age, yearsRange41.5±16.916-80
Clinical phase, no. of patients (%)CPAPBP210 (76.4)24 (8.7)41 (14.9)
Time interval between diagnosis and imatinib initiation, monthsMedianRange60-144
Patients with ACAs*, only for CP patients, no. of patients (%)PretreatmentAcquired during treatment45 (21.4)20 (9.5)25 (11.9)
Tab.1  Demographic data of CML patients ( = 275)
CPAPBP2102441210 (100)23 (95.8)26 (63.4)188 (89.5)12 (50)11 (26.8)178 (84.7)12 (50)10 (24.3)130 (61.9)7 (29.1)4 (9.7)
P value&lt;0.001&lt;0.001&lt;0.001&lt;0.001
Tab.2  Cumulative incidence of treatment response of patients in the three phases
Fig.1  OS and EFS of patients in the three phases.
(A) For CP and AP patients, the 5-year OS rates were 93.2%±2.1% and 64.5%±10.2%, respectively. At 3 years, the probability of OS was 95.9%±1.4% for CP patients, 64.5%±10.2% for AP patients, and 23.7%±6.8% for BP patients. A significant difference was found among the three groups. (B) For CP and AP patients, the 5-year EFS rates were 86.4%±2.7% and 50.9%±10.9%, respectively. At 3 years, the probability of EFS was 91.6%±2.0% for CP patients, 62.2%±10.0% for AP patients, and 13.7%±5.7% for BP patients. A significant difference was found among the three groups.
Fig.2  Landmark analysis based on the cytogenetic response at 12 months.
(A) Patients who achieved CCyR had a better 5-year OS rate than those who did not (97.4% vs. 84.5%, <0.001). (B) Patients who achieved CCyR had a better 5-year EFS rate than those who did not (98% vs. 68.2%, = 0.005).
Fig.3  Landmark analysis according to molecular response at 12 months.
(A) The 5-year OS of patients who achieved MMoR at 12 months or did not were 99% and 94.3%, respectively. No statistical difference was observed in the OS rates ( = 0.252). (B) Patients who achieved MMoR at 12 months had a better 5-year EFS than those who did not (100% vs. 87.6%, = 0.001).
Fig.4  Treatment response of early and late imatinib therapy. Patients treated early with imatinib achieved better treatment response than patients treated late (McyR= 95.0% vs. 82.2%, CCyR= 93.3% vs. 73.3%, and CMoR= 70.0% vs. 51.1%, respectively; = 0.003, <0.001, and = 0.005, respectively).
ACAs acquired pretreatmentnACAs acquired during treatmentn
t(9; 11; 22), t(12;17)t(1; 9; 22)t(2; 9 ; 22)t(7; 9; 22)i(17q), +22, 2Ph1t(4; 16)t(1; 3) +8 +M9q+i(17q)22q+20q+1211111133221t(9; 16; 22)t(9; 20; 22)t(9; 17) +8, t(1;10) +M, 2Ph12Ph1 +8 +M-Y-21 +22 +8, i(17q)i(17q)9q+12p-der221111123521112111
Tab.3  Additional chromosomal abnormalities in CP patients
Fig.5  Effect of additional chromosomal abnormalities on OS. The estimated 5-year OS was 100% for patients who did not have ACAs, 98% for patients with pretreatment ACAs, and 75.9% for patients with during-treatment ACAs. A statistical difference was found in OS ( = 0.001).
PatientsPatient status whenmutations were detectedMonths afterimatinib initiationMutationsOutcome at the last follow-up
CP (1-12)123456789101112CHRCHRCHRCHRCHRCHRCHRPCyRLoss of CCyR-progress to BPProgress to APProgress to BPProgress to BP24181661218162418-25124812F359IM244VT315IG250EG250HG250ET315IG250EM244V/*F317L-*P441L/F317LT315IE255KE255KTherapy changeProgress to APNo CCyRTherapy changeDeathNo CCyRNo CCyRNo CCyRDeathDeathTherapy changeTherapy change
AP (13-15)131415CHRCHRProgress to BP afterachieving CCyR7126F359VE459KE459KTherapy changeTherapy changeDeath
BP (16-21)161718192021CHRCHRCHRCHRCHR-CHR-progress to BPProgress to BP afterachieving CCyR62236-18-2430E459KF359VL324QT315IT315I-F359I-Y253HL273MDeathDeathDeathDeathDeathDeath
Tab.4  Distribution of mutations
1 Kurzrock R, Gutterman JU, Talpaz M. The molecular genetics of Philadelphia chromosome-positive leukemias. N Engl J Med 1988; 319(15): 990-998
doi: 10.1056/NEJM198810133191506 pmid:3047582
2 Melo JV, Yan XH, Diamond J, Lin F, Cross NC, Goldman JM. Reverse transcription/polymerase chain reaction (RT/PCR) amplification of very small numbers of transcripts: the risk in misinterpreting negative results. Leukemia 1996; 10(7): 1217-1221
3 Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247(4944): 824-830
doi: 2406902" target="_blank">10.1126/science. pmid:2406902 pmid:2406902
4 McLaughlin J, Chianese E, Witte ON. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci USA 1987; 84(18): 6558-6562
doi: 10.1073/pnas.84.18.6558 pmid:3498165
5 Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA, O’Brien S, So C, Massimini G, Guilhot F. Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 2006; 108(5): 1478-1484
doi: 10.1182/blood-2006-02-001495 pmid:16627756
6 Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355(23): 2408-2417
doi: 10.1056/NEJMoa062867 pmid:17151364
7 Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99(6): 1928-1937
doi: 10.1182/blood.V99.6.1928 pmid:11877262
8 Sawyers CL, Hochhaus A, Feldman E, Goldman JM, Miller CB, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Deininger MW, Fischer T, O’Brien SG, Stone RM, Gambacorti-Passerini CB, Russell NH, Reiffers JJ, Shea TC, Chapuis B, Coutre S, Tura S, Morra E, Larson RA, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker BJ. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood 2002; 99(10): 3530-3539
doi: 10.1182/blood.V99.10.3530 pmid:11986204
9 Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100(7): 2292-2302
doi: 10.1182/blood-2002-04-1199 pmid:12239137
10 Trotti A, Byhardt R, Stetz J, Gwede C, Corn B, Fu K, Gunderson L, McCormick B, Morrisintegral M, Rich T, Shipley W, Curran W. Common toxicity criteria: version 2.0, an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000; 47(1): 13-47
doi: 10.1016/S0360-3016(99)00559-3 pmid:10758303
11 Matsuo E, Miyazaki Y, Tsutsumi C, Inoue Y, Yamasaki R, Hata T, Fukushima T, Tsushima H, Imanishi D, Imaizumi Y, Iwanaga M, Sakai M, Ando K, Sawayama Y, Ogawa D, Kawaguchi Y, Nagai K, Tsukasaki K, Ikeda S, Moriuchi Y, Yoshida S, Honda M, Taguchi J, Onimaru Y, Tsuchiya T, Tawara M, Atogami S, Yamamura M, Soda H, Yoshida Y, Matsuo Y, Nonaka H, Joh T, Takasaki Y, Kawasaki C, Momita S, Jinnai I, Kuriyama K, Tomonaga M. Imatinib provides durable molecular and cytogenetic responses in a practical setting for both newly diagnosed and previously treated chronic myelogenous leukemia: a study in nagasaki prefecture, Japan. Int J Hematol 2007; 85(2): 132-139
doi: 10.1532/IJH97.06157 pmid:17321991
12 Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, Hehlmann R. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108(6): 1809-1820
doi: 10.1182/blood-2006-02-005686 pmid:16709930
13 Marin D, Milojkovic D, Olavarria E, Khorashad JS, de Lavallade H, Reid AG, Foroni L, Rezvani K, Bua M, Dazzi F, Pavlu J, Klammer M, Kaeda JS, Goldman JM, Apperley JF. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008; 112(12): 4437-4444
doi: 10.1182/blood-2008-06-162388 pmid:18716134
14 O’Dwyer ME, Mauro MJ, Blasdel C, Farnsworth M, Kurilik G, Hsieh YC, Mori M, Druker BJ. Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate. Blood 2004; 103(2): 451-455
doi: 10.1182/blood-2003-02-0371 pmid:14512312
15 Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C, G?hring G, Schlegelberger B, Jotterand M, Reiter A, Jung-Munkwitz S, Proetel U, Schwaab J, Hofmann WK, Schubert J, Einsele H, Ho AD, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Lauseker M, Pfirrmann M, Hasford J, Saussele S, Hehlmann R. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 2011; 118(26): 6760-6768
doi: 10.1182/blood-2011-08-373902 pmid:22039253
16 Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2(2): 117-125
doi: 10.1016/S1535-6108(02)00096-X pmid:12204532
17 Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293(5531): 876-880
18 Nicolini FE, Corm S, Lê QH, Sorel N, Hayette S, Bories D, Leguay T, Roy L, Giraudier S, Tulliez M, Facon T, Mahon FX, Cayuela JM, Rousselot P, Michallet M, Preudhomme C, Guilhot F, Roche-Lestienne C. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(ф)-LMC GROUP). Leukemia 2006; 20(6): 1061-1066
doi: 10.1038/sj.leu.2404236 pmid:16642048
19 Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J, Taylor K, Herrmann R, Seymour JF, Arthur C, Joske D, Lynch K, Hughes T. Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood 2003; 102(1): 276-283
doi: 10.1182/blood-2002-09-2896 pmid:12623848
20 Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, Herrmann R, Lynch KP, Hughes TP. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood 2002; 99(9): 3472-3475
doi: 10.1182/blood.V99.9.3472 pmid:11964322
21 Cortes J, Jabbour E, Kantarjian H, Yin CC, Shan J, O’Brien S, Garcia-Manero G, Giles F, Breeden M, Reeves N, Wierda WG, Jones D. Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors. Blood 2007; 110(12): 4005-4011
doi: 10.1182/blood-2007-03-080838 pmid:17785585
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