Skip to main content
Top
Published in: Current Hematologic Malignancy Reports 2/2017

Open Access 01-04-2017 | Chronic Myeloid Leukemias (J Pinilla-Ibarz, Section Editor)

The Role of Early Molecular Response in the Management of Chronic Phase CML

Authors: Patrick Harrington, Aytug Kizilors, Hugues de Lavallade

Published in: Current Hematologic Malignancy Reports | Issue 2/2017

Login to get access

Abstract

Purpose of Review

Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response.

Recent Findings

In the recent years, the achievement of an early molecular response (EMR, defined as 3-month BCR-ABL1 transcript <10% IS) has emerged as a useful tool to identify poor-risk patients. Although several groups have reported the importance of such milestone, clinical intervention based on it remains controversial partly due to its low specificity to predict progression, which may be partially improved by using the rate of decline in BCR-ABL1 transcript level (halving time or velocity of ratio reduction).

Summary

Standardization of halving time or velocity of ratio reduction will likely help establishing more stringent recommendation and modify current clinical practices.
Literature
2.
go back to reference Kantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, McCredie KB, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61(7):1441–6.CrossRefPubMed Kantarjian HM, Dixon D, Keating MJ, Talpaz M, Walters RS, McCredie KB, et al. Characteristics of accelerated disease in chronic myelogenous leukemia. Cancer. 1988;61(7):1441–6.CrossRefPubMed
5.
go back to reference Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(20):2333–40. doi:10.1200/jco.2015.64.8899.CrossRef Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(20):2333–40. doi:10.​1200/​jco.​2015.​64.​8899.CrossRef
6.
go back to reference Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17. doi:10.1056/NEJMoa062867.CrossRefPubMed Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17. doi:10.​1056/​NEJMoa062867.CrossRefPubMed
7.
go back to reference Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. doi:10.1038/leu.2016.5.CrossRefPubMedPubMedCentral Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. doi:10.​1038/​leu.​2016.​5.CrossRefPubMedPubMedCentral
9.
go back to reference 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(1):28–37. doi:10.1182/blood-2006-01-0092.CrossRefPubMedPubMedCentral 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(1):28–37. doi:10.​1182/​blood-2006-01-0092.CrossRefPubMedPubMedCentral
10.
go back to reference Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(35):6041–51. doi:10.1200/JCO.2009.25.0779.CrossRef Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(35):6041–51. doi:10.​1200/​JCO.​2009.​25.​0779.CrossRef
13.
go back to reference Mahon FX, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, Boiron JM, et al. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha. Blood. 1998;92(11):4059–65.PubMed Mahon FX, Faberes C, Pueyo S, Cony-Makhoul P, Salmi R, Boiron JM, et al. Response at three months is a good predictive factor for newly diagnosed chronic myeloid leukemia patients treated by recombinant interferon-alpha. Blood. 1998;92(11):4059–65.PubMed
14.
go back to reference Merx K, Muller MC, Kreil S, Lahaye T, Paschka P, Schoch C, et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia. 2002;16(9):1579–83. doi:10.1038/sj.leu.2402680.CrossRefPubMed Merx K, Muller MC, Kreil S, Lahaye T, Paschka P, Schoch C, et al. Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. Leukemia. 2002;16(9):1579–83. doi:10.​1038/​sj.​leu.​2402680.CrossRefPubMed
15.
go back to reference Wang L, Pearson K, Ferguson JE, Clark RE. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. 2003;120(6):990–9.CrossRefPubMed Wang L, Pearson K, Ferguson JE, Clark RE. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. 2003;120(6):990–9.CrossRefPubMed
16.
go back to reference de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(20):3358–63. doi:10.1200/JCO.2007.15.8154.CrossRef de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(20):3358–63. doi:10.​1200/​JCO.​2007.​15.​8154.CrossRef
17.
go back to reference Hughes TP, Hochhaus A, Branford S, Muller MC, Kaeda JS, Foroni L, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116(19):3758–65. doi:10.1182/blood-2010-03-273979.CrossRefPubMedPubMedCentral Hughes TP, Hochhaus A, Branford S, Muller MC, Kaeda JS, Foroni L, et al. Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood. 2010;116(19):3758–65. doi:10.​1182/​blood-2010-03-273979.CrossRefPubMedPubMedCentral
18.
go back to reference •• Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(3):232–8. doi:10.1200/JCO.2011.38.6565.CrossRef •• Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(3):232–8. doi:10.​1200/​JCO.​2011.​38.​6565.CrossRef
19.
go back to reference •• Hanfstein B, Muller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26(9):2096–102. doi:10.1038/leu.2012.85.CrossRefPubMed •• Hanfstein B, Muller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26(9):2096–102. doi:10.​1038/​leu.​2012.​85.CrossRefPubMed
20.
go back to reference • Marin D, Hedgley C, Clark RE, Apperley J, Foroni L, Milojkovic D, et al. Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood. 2012;120(2):291–4. doi:10.1182/blood-2012-01-407486.CrossRefPubMed • Marin D, Hedgley C, Clark RE, Apperley J, Foroni L, Milojkovic D, et al. Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib. Blood. 2012;120(2):291–4. doi:10.​1182/​blood-2012-01-407486.CrossRefPubMed
23.
go back to reference Hjorth-Hansen H, Stenke L, Soderlund S, Dreimane A, Ehrencrona H, Gedde-Dahl T, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006). Eur J Haematol. 2015;94(3):243–50. doi:10.1111/ejh.12423.CrossRefPubMed Hjorth-Hansen H, Stenke L, Soderlund S, Dreimane A, Ehrencrona H, Gedde-Dahl T, et al. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006). Eur J Haematol. 2015;94(3):243–50. doi:10.​1111/​ejh.​12423.CrossRefPubMed
24.
go back to reference • Neelakantan P, Gerrard G, Lucas C, Milojkovic D, May P, Wang L, et al. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood. 2013;121(14):2739–42. doi:10.1182/blood-2012-11-466037.CrossRefPubMed • Neelakantan P, Gerrard G, Lucas C, Milojkovic D, May P, Wang L, et al. Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies. Blood. 2013;121(14):2739–42. doi:10.​1182/​blood-2012-11-466037.CrossRefPubMed
25.
go back to reference Kim DD, Hamad N, Lee HG, Kamel-Reid S, Lipton JH. BCR/ABL level at 6 months identifies good risk CML subgroup after failing early molecular response at 3 months following imatinib therapy for CML in chronic phase. Am J Hematol. 2014;89(6):626–32. doi:10.1002/ajh.23707.CrossRefPubMed Kim DD, Hamad N, Lee HG, Kamel-Reid S, Lipton JH. BCR/ABL level at 6 months identifies good risk CML subgroup after failing early molecular response at 3 months following imatinib therapy for CML in chronic phase. Am J Hematol. 2014;89(6):626–32. doi:10.​1002/​ajh.​23707.CrossRefPubMed
26.
go back to reference •• Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C et al. Comparing the prognostic significance of early predictors of survival in chronic myeloid leukemia (CML) treated with imatinib—an analysis of the randomized CML-study IV. Blood. 2014; 124(21):156-. •• Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C et al. Comparing the prognostic significance of early predictors of survival in chronic myeloid leukemia (CML) treated with imatinib—an analysis of the randomized CML-study IV. Blood. 2014; 124(21):156-.
27.
go back to reference •• Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124(4):511–8. doi:10.1182/blood-2014-03-566323.CrossRefPubMed •• Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, et al. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014;124(4):511–8. doi:10.​1182/​blood-2014-03-566323.CrossRefPubMed
28.
go back to reference •• Hanfstein B, Shlyakhto V, Lauseker M, Hehlmann R, Saussele S, Dietz C, et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia. 2014;28(10):1988–92. doi:10.1038/leu.2014.153.CrossRefPubMed •• Hanfstein B, Shlyakhto V, Lauseker M, Hehlmann R, Saussele S, Dietz C, et al. Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia. 2014;28(10):1988–92. doi:10.​1038/​leu.​2014.​153.CrossRefPubMed
29.
go back to reference Iriyama N, Fujisawa S, Yoshida C, Wakita H, Chiba S, Okamoto S, et al. Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: results of the D-first study of Kanto CML study group. Am J Hematol. 2015;90(4):282–7. doi:10.1002/ajh.23923.CrossRefPubMed Iriyama N, Fujisawa S, Yoshida C, Wakita H, Chiba S, Okamoto S, et al. Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: results of the D-first study of Kanto CML study group. Am J Hematol. 2015;90(4):282–7. doi:10.​1002/​ajh.​23923.CrossRefPubMed
30.
go back to reference Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. 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):1029–35. doi:10.1016/S1470-2045(10)70233-3.CrossRefPubMed Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. 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):1029–35. doi:10.​1016/​S1470-2045(10)70233-3.CrossRefPubMed
31.
go back to reference Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22. doi:10.1182/blood-2013-02-483750.CrossRefPubMed Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22. doi:10.​1182/​blood-2013-02-483750.CrossRefPubMed
32.
go back to reference Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. 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 Off J Am Soc Clin Oncol. 2014;32(5):424–30. doi:10.1200/JCO.2012.48.5797.CrossRef Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. 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 Off J Am Soc Clin Oncol. 2014;32(5):424–30. doi:10.​1200/​JCO.​2012.​48.​5797.CrossRef
33.
go back to reference • Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818–24. doi:10.1182/blood-2012-10-462291.CrossRefPubMed • Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818–24. doi:10.​1182/​blood-2012-10-462291.CrossRefPubMed
35.
36.
go back to reference Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15. doi:10.1182/blood-2010-12-326405.CrossRefPubMed Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208–15. doi:10.​1182/​blood-2010-12-326405.CrossRefPubMed
37.
go back to reference Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(29):4806–13. doi:10.1200/JCO.2008.16.9953.CrossRef Khorashad JS, de Lavallade H, Apperley JF, Milojkovic D, Reid AG, Bua M, et al. Finding of kinase domain mutations in patients with chronic phase chronic myeloid leukemia responding to imatinib may identify those at high risk of disease progression. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(29):4806–13. doi:10.​1200/​JCO.​2008.​16.​9953.CrossRef
38.
go back to reference Kizilors A, Crisa E, Lea N, Best S, Syed M, Ireland RM, et al. Impact of finding of low level kinase domain mutations using ultra deep next generation sequencing in patients with chronic phase CML. Blood. 2015;126(23):347. Kizilors A, Crisa E, Lea N, Best S, Syed M, Ireland RM, et al. Impact of finding of low level kinase domain mutations using ultra deep next generation sequencing in patients with chronic phase CML. Blood. 2015;126(23):347.
Metadata
Title
The Role of Early Molecular Response in the Management of Chronic Phase CML
Authors
Patrick Harrington
Aytug Kizilors
Hugues de Lavallade
Publication date
01-04-2017
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 2/2017
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-017-0375-0

Other articles of this Issue 2/2017

Current Hematologic Malignancy Reports 2/2017 Go to the issue

Multiple Myeloma (P Kapoor, Section Editor)

POEMS Syndrome: an Enigma

Multiple Myeloma (P Kapoor, Section Editor)

CARs in the Lead Against Multiple Myeloma

Multiple Myeloma (P Kapoor, Section Editor)

Current Review on High-Risk Multiple Myeloma

Acute Lymphocytic Leukemias (K Ballen, Section Editor)

Who Should Receive a Transplant for Acute Lymphoblastic Leukaemia?