Cancer Res Treat.  2010 Mar;42(1):37-41.

Coexisting with Clonal Evolution and BCR-ABL Mutant in CML Patients Treated with Second-generation Tyrosine Kinase Inhibitors Predict the Discrepancy of in vitro Drug Sensitivity

• Ahn JS
• Kim YK
• Lee SR
• Yu L
• Yang DH
• Cho SH
• Shim HJ
• Bae WK
• Lee JJ
• Chung IJ
• Shin MG
• Kim HJ

Abstract

PURPOSE
Second-generation tyrosine kinase inhibitors (second TKIs) such as nilotinib and dasatinib control the activity of most ABL kinase domain mutations observed in patients with imatinib resistance. Although in vitro data show that both agents can inhibit all mutations except T315I, some discrepancies have been observed in a small subset of mutation clones. Cytogenetic clonal evolution is the important resistance mechanism of chronic myeloid leukemia (CML). Accordingly, we observed the clinical significance of coexisting with clonal evolution and BCR-ABL mutant in CML patients treated with second TKIs. MATERIALS AND METHODS: We monitored BCR-ABL transcript kinetics, interrelationship of clones expressing non-mutated and mutant transcripts and clonal aberrations within Philadelphia (Ph) positive and negative clones, respectively, in eight patients with CML receiving dasatinib or nilotinib for 3~41 months. RESULTS: Clinical responses were correlated with in vitro sensitivity of the BCR-ABL mutants to the second TKIs in four patients. Four patients showed resistance to the second TKIs as compared to in vitro observations; three of them developed chromosomal abnormalities in the Ph chromosome positive or negative metaphases. Another patient lost the original mutation but acquired a more resistant new mutation and became resistant to the second TKI. CONCLUSION: Cytogenetic clonal evolution is an independent poor prognostic factor in CML, which could explain the onset of mechanisms for second TKIs resistance to ABL kinase domain mutations. The results indicate that an additional evaluation of chromosomal abnormalities is warranted when BCR-ABL mutants are more resistant than indicated by in vitro data.

Keyword

CML; Dasatinib; Nilotinib; Clonal evolution; BCR-ABL mutation

MeSH Terms

Benzamides
Chromosome Aberrations
Clonal Evolution
Clone Cells
Cytogenetics
Dasatinib
Humans
Hydrogen-Ion Concentration
Kinetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Metaphase
Philadelphia
Phosphotransferases
Piperazines
Protein-Tyrosine Kinases
Pyrimidines
Thiazoles
Tyrosine
Imatinib Mesylate
Benzamides
Phosphotransferases
Piperazines
Protein-Tyrosine Kinases
Pyrimidines
Thiazoles
Tyrosine

Figure

• 

  Fig. 1 Kinetics of all BCR-ABL transcripts and the percentage of mutant transcripts in representative patterns. Longitudinal line in graphes represent the time point of treatment with second TKIs and diamonds (◆) depict the quantitation of BCR-ABL transcripts by RQ-PCR expressed as BCR-ABL/ABL ratios on a log scale. Squares (□) and triangles (▲) represent the proportion of BCR-ABL mutated transcripts expressed in the percentage of total BCR-ABL transcripts. Round (●) symbols represent the percentage of chromosomal abnormalities in the Philadelphia chromosome. The arrow indicates the time point for a developed clonal evolution. The response of patient #2 (F359I) was correlated with in vitro sensitivity to dasatinib (A). Patient #5 (E255K) showed resistance to the second TKIs as compared to in vitro observation and developed clonal evolution during dasatinib treatment (B). Patient #8 (M351T → H396R) lost his original mutations but acquired a new mutation (H396R), which was the cause of the increase in BCR-ABL transcripts (C).

Reference

1. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999; 340:1330–1340. PMID: 10219069.

2. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002; 346:645–652. PMID: 11870241.

3. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004; 18:1321–1331. PMID: 15215876.

4. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. 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; 2:117–125. PMID: 12204532.

5. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16:2190–2196. PMID: 12399961.

6. Quintas-Cardama A, Kantarjian H, Jones D, Nicaise C, O'Brien S, Giles F, et al. Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. Blood. 2007; 109:497–499. PMID: 16990591.

7. Jarkowski A, Sweeney RP. Nilotinib: a new tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia. Pharmacotherapy. 2008; 28:1374–1382. PMID: 18956997.

8. Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009; 27:469–471. PMID: 19075254.

9. Khorashad JS, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006; 20:658–663. PMID: 16467863.

10. Nicolini FE, Chabane K, Tigaud I, Michallet M, Magaud JP, Hayette S. BCR-ABL mutant kinetics in CML patients treated with dasatinib. Leuk Res. 2007; 31:865–868. PMID: 17208297.

11. O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007; 110:2242–2249. PMID: 17496200.

12. Khorashad JS, Milojkovic D, Mehta P, Anand M, Ghorashian S, Reid AG, et al. In vivo kinetics of kinase domain mutations in CML patients treated with dasatinib after failing imatinib. Blood. 2008; 111:2378–2381. PMID: 17982022.

13. Verma D, Fava C, Kantarjian H, Cortes J. Complexity of BCR-ABL kinase domain mutations during the course of therapy with tyrosine kinase inhibitors in chronic myeloid leukemia. Am J Hematol. 2009; 84:256–257. PMID: 19260121.

14. Polakova KM, Zmekova V, Rulcova J, Klamova H, Zemanova Z, Moravcova J. BCR-ABL mutations in chronic myeloid leukemia - not only detection. Leuk Lymphoma. 2008; 49:1620–1622. PMID: 18452092.

15. Cortes JE, Talpaz M, Giles F, O'Brien S, Rios MB, Shan J, et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood. 2003; 101:3794–3800. PMID: 12560227.

16. Saglio G, Ulisciani S, Bosa M, Cilloni D, Rege-Cambrin G. New therapeutic approaches and prognostic factors in chronic myeloid leukemia. Leuk Lymphoma. 2008; 49:625–628. PMID: 18398722.

17. Fabarius A, Haferlach C, Muller MC, Erben P, Lahaye T, Giehl M, et al. Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure. Haematologica. 2007; 92:834–837. PMID: 17550857.

18. Jabbour E, Kantarjian HM, Abruzzo LV, O'Brien S, Garcia-Manero G, Verstovsek S, et al. Chromosomal abnormalities in Philadelphia chromosome negative metaphases appearing during imatinib mesylate therapy in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Blood. 2007; 110:2991–2995. PMID: 17625066.

19. Bacher U, Hochhaus A, Berger U, Hiddemann W, Hehlmann R, Haferlach T, et al. Clonal aberrations in Philadelphia chromosome negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha. Leukemia. 2005; 19:460–463. PMID: 15625554.

20. Terre C, Eclache V, Rousselot P, Imbert M, Charrin C, Gervais C, et al. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia. 2004; 18:1340–1346. PMID: 15190256.

21. Meeus P, Demuynck H, Martiat P, Michaux L, Wouters E, Hagemeijer A. Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib. Leukemia. 2003; 17:465–467. PMID: 12592350.