Abstract
The International Randomized Study of Interferon and STI571 (IRIS) demonstrated long-term cytogenetic responses in patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with the tyrosine kinase inhibitor (TKI) imatinib. However, deep molecular responses (MRs), as measured by reductions in BCR-ABL transcript levels below the threshold of major MR, were achieved only by a small proportion of patients. With the advent of the second-generation TKIs nilotinib and dasatinib for the treatment of patients with newly diagnosed CML-CP, the proportion of patients who achieve the deepest levels of MR is likely to increase significantly. With these changes, the potential for patient eligibility in TKI cessations studies is becoming a more widely discussed topic and area for research. These developments highlight the need for robust, standardized and workable definitions of deep MRs. Specifically, it is critical that the measurement of MR is standardized in a manner to withstand both intra- and inter-laboratory variability, as well as new methodological developments. This review summarizes the relevant clinical background and proposes a framework within which standardization of MR can be taken forward.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes TP et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 2009; 114: 462 (abstract 1126).
Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423–1432.
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.
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 2009; 27: 6041–6051.
Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G et al. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood 2009; 114: 4933–4938.
Cortes JE, Jones D, O’Brien S, Jabbour E, Konopleva M, Ferrajoli A et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010; 28: 392–397.
Cortes JE, Jones D, O'Brien S, Jabbour E, Ravandi F, Koller C et al. Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 2010; 28: 398–404.
Radich JP, Kopecky KJ, Kamel-Reid S, Stock W, Paietta E, Wadleigh M et al. A randomized phase II trial of dasatinib 100 mg vs imatinib 400 mg in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): the S0325 Intergroup trial. Blood 2010, 116 (abstract LBA-6).
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010; 362: 2251–2259.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260–2270.
Hughes TP, Hochhaus A, Saglio G, Kim DW, Jootar S, le Coutre PD et al. ENESTnd update: continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Blood 2010; 116: 94–95, (abstract 0207).
Hochhaus A, Lobo C, Pasquini R, Clark R, Kim DW, Issaragrisil S et al. Continued superiority of nilotinib vs imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond 1 year. Haematologica 2010; 95: 459 (abstract 1113).
Kantarjian HM, Hochhaus A, Saglio G, De Souza C, Flinn IW, Stenke L et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 2011; 12: 841–851.
Gugliotta G, Castagnetti F, Breccia M, Levato L, Capucci A, Tiribelli M et al. Early CP CML, Nilotinib 400 mg Twice Daily Frontline: Beyond 3 Years, Results Remain Excellent and Stable (A GIMEMA CML Working Party Trial). Blood 2011; 116, abstract 2756.
Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS et al. Dasatinib or imatinib in newly diagnosed chronic phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood 2012; 119: 1123–1129.
Kantarjian HM, Baccarani M, Jabbour E, Saglio G, Cortes JE . Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy. Clin Cancer Res 2011; 17: 1674–1683.
Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.
Cortes J, O’Brien S, Kantarjian H . Discontinuation of imatinib therapy after achieving a molecular response. Blood 2004; 104: 2204–2205.
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: 1029–1035.
Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Bartley PA et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 2010; 10: 1719–1724.
Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–2050.
Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J et al. Molecular heterogeneity in complete cytogenetic responders after interferon-alpha therapy for chronic myelogenous leukemia: low levels of minimal residual disease are associated with continuing remission. German CML Study Group and the UK MRC CML Study Group. Blood 2000; 95: 62–66.
Bonifazi F, de Vivo A, Rosti G, Guilhot F, Guilhot J, Trabacchi E et al. Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders. Blood 2001; 98: 3074–3081.
Kantarjian HM, O’Brien S, Cortes JE, Shan J, Giles FJ, Rios MB et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003; 97: 1033–1041.
Burchert A, Müller MC, Kostrewa P, Erben P, Bostel T, Liebler S et al. Sustained molecular response with interferon alfa maintenance after induction therapy with imatinib plus interferon alfa in patients with chronic myeloid leukemia. J Clin Oncol 2010; 28: 1429–1435.
Zhang B, Irvine D, Ho YW, Buonamici S, Manley P, Holyoake TL et al. Inhibition of chronic myeloid leukemia stem cells by the combination of the hedgehog pathway inhibitor LDE225 with nilotinib. Blood 2010; 116: 227 (abstract 514).
Nair RR, Tolentino JH, Argilagos RF, Zhang L, Pinilla-Ibarz J, Hazlehurst LA . Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML. Leuk Res 2012; 36: 756–763.
Packer LM, Rana S, Hayward R, O’Hare T, Eide CA, Rebocho A et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell 2011; 20: 715–727.
Kumari A, Brendel C, Hochhaus A, Neubauer A, Burchert A . Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood 2012; 119: 530–539.
Zhang JG, Lin F, Chase A, Goldman JM, Cross NC . Comparison of genomic DNA and cDNA for detection of residual disease after treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation. Blood 1996; 87: 2588–2593.
Sobrinho-Simoes M, Wilczek V, Score J, Cross NC, Apperley JF, Melo JV . In search of the original leukemic clone in chronic myeloid leukemia patients in complete molecular remission after stem cell transplantation or imatinib. Blood 2010; 116: 1329–1335.
Deininger M . Hematology: curing CML with imatinib—a dream come true? Nat Rev Clin Oncol 2011; 8: 127–128.
Hughes TP, Lipton JH, Leber B, Spector N, Cervantes F, Pasquini R et al. Complete molecular response (CMR) rate with nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) without CMR after ⩾2 years on imatinib: preliminary results from the randomized ENESTcmr trial of nilotinib 400 mg twice daily (BID) vs imatinib. Blood 2011; 118: 278 (abstract 606).
Branford S, Fletcher L, Cross NC, Müller MC, Hochhaus A, Kim DW et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008; 112: 3330–3338.
Müller MC, Cross NC, Erben P, Schenk T, Hanfstein B, Ernst T et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia 2009; 23: 1957–1963.
White HE, Matejtschuk P, Rigsby P, Gabert J, Lin F, Wang YL et al. Establishment of the 1st World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. Blood 2010; 116: e111–e117.
Beillard E, Pallisgaard N, van der Velden VH, Bi W, Dee R, van der Schoot E et al. Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)—a Europe against cancer program. Leukemia 2003; 17: 2474–2486.
Giles F, Rosti G, Ossenkoppele GJ, Tulliez M, Stentoft J, Giagounidis A et al. A Phase IIIb Multicentre Open-Label Study of Nilotinib in Adult Patients with Newly Diagnosed BCR-ABL Positive Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A European Clinical Initiative with EUTOS Collaboration for Standardisation of Molecular Remission. Blood 2011; 118: 1186–1187, (abstract 2759).
Acknowledgements
Financial support for editorial assistance in the production of part of this review was provided by Novartis. We thank Michael Mandola, PhD (Articulate Science) for editorial assistance. Research support was received by Novartis Pharma, Switzerland, and the European LeukemiaNet via the ‘European Treatment and Outcome Study’, EUTOS.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Cross, N., White, H., Müller, M. et al. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia 26, 2172–2175 (2012). https://doi.org/10.1038/leu.2012.104
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2012.104
Keywords
This article is cited by
-
The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib
Annals of Hematology (2024)
-
The importance of personalized medicine in chronic myeloid leukemia management: a narrative review
Egyptian Journal of Medical Human Genetics (2023)
-
Endothelial function measured by peripheral arterial tonometry in patients with chronic myeloid leukemia on tyrosine kinase inhibitor therapy: a pilot study
Cardio-Oncology (2023)
-
Survival with chronic myeloid leukaemia after failing milestones
Leukemia (2023)
-
Chronische myeloische Leukämie
Die Onkologie (2023)