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Early molecular response in chronic myeloid leukemia patients predicts future response status

  • Research Article
  • Published:
Tumor Biology

Abstract

Imatinib is the frontline therapy for chronic myeloid leukemia (CML) management. Most of the CML patients achieve major responses, but a proportion (nearly 25–35 %) of them develop drug resistance. Molecular monitoring using quantitative real-time PCR at regular intervals according to European LeukemiaNet (ELN) helps in the assessment of long-term outcomes in imatinib-treated CML patients. Eighty-four CML patient samples (42 at diagnosis and 42 at 3-month intervals from the same patients) were analyzed for Bcr-Abl transcript levels. Quantification results revealed that the patients with <10 % Bcr-Abl levels at 3 months had higher rates of complete cytogenetic response (CCyR) and optimal responses compared to patients with >10 % Bcr-Abl levels (P < 0.0001). Patients with >10 % Bcr-Abl levels were found to have 25.0 % of suboptimal response and 3.57 % of failure to imatinib at standard dose. Hence, the present study confirms that early molecular monitoring at 3 months after imatinib initiation helps in predicting the concurrent cytogenetic response and treatment optimization in CML patients.

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References

  1. Hughes TP, Branford S, White DL, et al. Impact of early dose intensity on cytogenetic and molecular responses in chronic phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood. 2008;112(10):3965–73.

    Article  CAS  PubMed  Google Scholar 

  2. 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(35):6041–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. O’Brien S. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. Version 2. 2012. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#cml. Accessed 17 Oct 2011.

  4. Muller MC, Gattermann N, Lahaye T, Deininger MW, Berndt A, Fruehauf S, et al. Dynamics of BCR-ABL mRNA expression in first-line therapy of chronic myelogenous leukemia patients with imatinib or interferon alpha/ara-C. Leukemia. 2003;17(12):2392–400.

    Article  CAS  PubMed  Google Scholar 

  5. Programme NCR. Two year report of the population based cancer registries 1999–2000. Indian Council of Medical Research: New Delhi; 2005.

    Google Scholar 

  6. Kumar L. Chronic myelogenous leukemia (CML): an update. Natl Med J India. 2006;19:255–63.

    PubMed  Google Scholar 

  7. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  8. Arocho A, Chen B, Ladanyi M, Pan Q. Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. Diagn Mol Pathol. 2006;15:56–61.

    Article  CAS  PubMed  Google Scholar 

  9. Hongxin Fan and Ryan S Robertorye. Real-time quantitative reverse transcription polymerase chain reaction. Nicola King (ed.), RT-PCR protocols: second edition. Methods on molecular biology. 2010; 630: 199-213.

  10. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in good risk chronic granulocytic leukemia. Blood. 1984;63:789–99.

    CAS  PubMed  Google Scholar 

  11. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118:686–92.

    Article  CAS  PubMed  Google Scholar 

  12. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, 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;108:28–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Emig M, Saussele S, Wittor H, et al. Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leukemia. 1999;13:1825–32.

    Article  CAS  PubMed  Google Scholar 

  14. Branford S, Hughes TP, Rudzki Z. Monitoring chronic myeloid leukemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol. 1999;107:587–99.

    Article  CAS  PubMed  Google Scholar 

  15. Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res. 1996;6:986–94.

    Article  CAS  PubMed  Google Scholar 

  16. Hanfstein B, Muller MC, Erben P, et al. Molecular response after 3 months of 1st line imatinib therapy is predictive for treatment failure and disease progression with chronic phase chronic myeloid leukemia: a follow-up analysis of the German CML Study IV. Presented at 52nd ASH annual meeting and exposition, Orlando, December 4–7, 2010 (abstr 360).

  17. Hughes TP, Hochhaus A, Branford S, et al. Long term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from international randomized study of interferon and STI571 (IRIS). Blood. 2010;116:3758–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. 2008;26:3358–63.

    Article  PubMed  Google Scholar 

  19. Wang L, Pearson K, Ferguson JE, et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukemia. Br J Haematol. 2003;120:990–9.

    Article  CAS  PubMed  Google Scholar 

  20. Marin D, Milojkovic D, Olavarria E, Khorashad JS, de Lavallade H, Reid AG, et al. 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;112:4437–44.

    Article  CAS  PubMed  Google Scholar 

  21. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  PubMed  Google Scholar 

  22. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematological and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645–52.

    Article  CAS  PubMed  Google Scholar 

  23. Cortes J, Talpaz M, O’Brien S, et al. Molecular responses in patients which chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res. 2005;11:3425–32.

    Article  CAS  PubMed  Google Scholar 

  24. Hochhaus A, Druker B, Sawyers C, et al. Favourable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. 2008;111:1039–43.

    Article  CAS  PubMed  Google Scholar 

  25. Hochhaus A, Guilhot F, AL-Ali KH, et al. arly BCR-ABL transcript levels predict future molecular response and long-term outcomes in newly diagnosed patients with CML-CP: analysis of ENESTnd 3-year data. Hematol. 2012;97 Suppl 1:0584.

    Google Scholar 

  26. Jabbour E, Shah NA, Chuah C, et al. An exploratory analysis from 3 year DASISION follow-up examining the impact on patient outcomes of early complete cytogenetic responses at 3 months and major molecular responses at 12 months. Hematol. 2012;97 Suppl 1:1106.

    Google Scholar 

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Acknowledgments

The authors are thankful to the Department of Biotechnology (DBT), Government of India, for supporting this project.

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Authors and Affiliations

  1. Nizams Institute of Medical Sciences, Punjagutta, Hyderabad, 500082, Andhra Pradesh, India

    Sailaja Kagita, Sangeeta Jiwtani, Srihari Uppalapati, Vijay Gandhi Linga, Sadasivudu Gundeti & Raghunadharao Digumarti

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  1. Sailaja Kagita
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  2. Sangeeta Jiwtani
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  3. Srihari Uppalapati
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  4. Vijay Gandhi Linga
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  5. Sadasivudu Gundeti
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  6. Raghunadharao Digumarti
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Correspondence to Raghunadharao Digumarti.

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Kagita, S., Jiwtani, S., Uppalapati, S. et al. Early molecular response in chronic myeloid leukemia patients predicts future response status. Tumor Biol. 35, 4443–4446 (2014). https://doi.org/10.1007/s13277-013-1585-2

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  • DOI: https://doi.org/10.1007/s13277-013-1585-2

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