CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2014; 35(01): 10-16
DOI: 10.4103/0971-5851.133704
REVIEW ARTICLE

Importance of early and deeper responses to long-term survival in CML patients: Implications of BCR-ABL testing in management of CML in Indian setting

Mohan B. Agarwal
Head, Department of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India
› Author Affiliations

Abstract

The prognosis of patients with chronic myeloid leukemia (CML) has changed radically since the advent of imatinib mesylate, a selective inhibitor of BCR-ABL tyrosine kinase. Shortly thereafter, more potent BCR-ABL inhibitors (dasatinib and nilotinib) were introduced for use in patients resistant to or intolerant of imatinib. All three drugs are now approved for initial therapy for chronic phase CML. Response to tyrosine kinase inhibitor (TKI) treatment is assessed with standardized quantitative reverse transcriptase polymerase chain reaction (Q-RTPCR) and/or cytogenetics at 3, 6 and 12 months. Clinical trials have clearly demonstrated that early and deeper cytogenetic and molecular response to TKI therapy is associated with lower rate of disease progression and improved long-term outcomes. In recent times, molecular response as determined by BCR-ABL transcript levels at defined time points is rapidly gaining popularity as a predictive marker for subsequent outcomes in CML. Optimal response is defined as BCR-ABL transcript levels of ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward while >10% at 6 months and >1% from 12 months onward define failure. Patients who do not achieve molecular milestones at 3 or 6 months with 3 months being highly predictive are less likely to achieve cytogenetic responses eventually; early identification of such patients who have a low probability of achieving an adequate response are thus candidates for alternative treatment. Review of literature by electronic search of MEDline, Google Scholar was done using keywords and data was identified and systematically evaluated.



Publication History

Article published online:
19 July 2021

© 2014. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

 
  • References

  • 1 Subramanian PG. Cytogenetic study in CML. Indian J Med Res 2012;135:12-3.
  • 2 O′Brien S, Abboud CN, Akhtari M, Altman JK, Berman E, Cohen AD, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version 4, 2013. Available at: JNCCN.org. Accessed June 11, 2013.
  • 3 Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al European LeukemiaNet recommendations for the management of chronic myeloid leukemia 2013. Blood 2013;122:872-84.
  • 4 Kantarjian HM, O′Brien S, Cortes JE, Shan J, Giles FJ, Rios MB, et al. Complete cytogenetic and molecular responses to interferon-α-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer 2003;97:1033-41.
  • 5 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;349:1423-32.
  • 6 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;355:2408-11.
  • 7 Deininger M, O′Brien GS, 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 [oral and poster abstract]. 51 st ASH Annual Meeting and Exposition 2009. Available from: http://ash.confex.com/ash/2009/webprogram/Paper23968.html. [Last updated on Dec 2009; Last accessed on Oct 2013]
  • 8 Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008;22:1200-6.
  • 9 Kantarjian H, Pasquini R, Le´vy V, Jootar S, Holowiecki J, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily. Cancer 2009; 115:4136-47.
  • 10 Jabbour E, Kantarjian H, Cortes J. Chronic myeloid leukemia and second-generation tyrosine kinase inhibitors: When, how, and which one? Semin Hematol 2010;47:344-53.
  • 11 Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica 2010;95:232-40.
  • 12 Neelakantan P, Gerrard G, Lucas C, Milojkovic D, May P, Wang L, et al. Combining BCR ABL transcript levels at 3 and 6 months in chronic myeloid leukemia: Implications for early intervention strategies. Blood 2013;121:2739-42.
  • 13 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 2012;30:232-8.
  • 14 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 treated with first-line dasatinib. Blood 2012;120:291-4.
  • 15 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: 2096-102.
  • 16 Jain P, Kantarjian H, Nazha A, O′Brien S, Jabbour E, Romo CG, et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: Results with four tyrosine kinase inhibitor modalities. Blood 2013;121:4867-74.
  • 17 Branford S, Kim DW, Soverini S, Haque A, Shou Y, Woodman RC, et al. Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib [abstract]. J Clin Oncol 2012;30:4323-9.
  • 18 Saglio G, Kantarjian HM, Shah N, Jabbour EJ, Quintas-Cardama A, Steegmann JL, et al. Early response (Molecular and Cytogenetic) and long-term outcomes in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Exploratory analysis of DASISION 3-Year Data [oral and poster abstract]. 54 th ASH Annual Meeting and Exposition 2012. Available from: http://ash.confex.com/ash/2012/webprogram/Paper47060.html [Last updated on Dec 2012; Last accessed on Oct 2013].
  • 19 White HE, Matejtschuk P, Rigsby P, Gabert J, Lin F, Wang LY, et al. Establishment of the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. Blood 2010; 116:e111-7.
  • 20 Balasubramanian P, Chendamarai E, Markose P, Fletcher L, Branford S, George B, et al. International reporting scale of BCR-ABL1 fusion transcript in chronic myeloid leukemia: First report from India. Acta Haematol 2012;127:135-42.
  • 21 Jabbour E, Kantarjian HM, O′Brien S, Shan J, Quintas-Cardama A, Faderl S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 2011;118:4541-6.
  • 22 Jabbour E, Saglio G, Hughes TP, Kantarjian H. Suboptimal responses in chronic myeloid leukemia. Cancer 2012; 118:1181-91.
  • 23 Marin D, Milojkovic D, Olavarria E, Khorashad JS, Lavallade H, Reid AG, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CMLin early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008;112:4437-44.
  • 24 Ohm L, Arvidsson I, Barbany G, Hast R, Stenke L. Early landmark analysis of imatinib treatment in CML chronic phase:Less than 10% BCR ABL by FISH at 3 months associated with improved long-term clinical outcome. Am J Hematol 2012;87:760-5.
  • 25 Hochhaus A, Saglio G, Chuah C, Pavlovsky C, Garelick BB, Lambert A, et al. Dasatinib and imatinib-induced reductions in BCR-ABL transcript levels below 10% at 3 months are associated with improved responses in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Analysis of molecular response kinetics in the DASISION Trial [abstract]. J Clin Oncol 2012;30:232-8.
  • 26 Deshmukh C, Saikia T, Bakshi A, Kadam PA, Baisane C, Parikh P. Imatinib mesylate in chronic myeloid leukemia: A prospective, single arm, non-randomized study. J Assoc Physicians India 2005;53:291-5.
  • 27 Gupta A, Prasad K. Hematological and molecular response evaluation of cml patients on imatinib. J Assoc Physicians India 2007;55:109-13.
  • 28 Jacob L, Bapsy P, Govind Babu K, Lokanatha D. Imatinib mesylate in newly diagnosed patients of chronic myeloid leukemia. Indian J Med Paediatr Oncol 2007;28:20-5.
  • 29 Rajappa S, Varadpande L, Paul T, Jacob R, Digumarti R. Imatinib mesylate in early chronic phase chronic myeloid leukemia: Experience from a developing country [abstract]. Leuk Lymphoma 2008;49:554-8.
  • 30 Medhi K, Raina V, Kumar L, Sharma A, Bakhshi S, Gupta R, et al. Response assessment of patients with chronic myeloid leukemia receiving imatinib mesylate (Glivec) therapy: Experience from a single center in a developing country [abstract]. Leuk Lymphoma 2010;51:1850-4.
  • 31 Ganesan P, Sagar TG, Dubashi B, Rajendranath R, Kannan K, Cyriac S, et al. Nonadherence to Imatinib adversely affects event free survival in chronic phase chronic myeloid leukemia. Am J Hematol 2011;86:471-4.
  • 32 Mukhopadhyay A, Dasgupta S, Mukhopadhyay S, Bose CK, Sarkar S, Gharami F. Imatinib mesylate therapy in patients of chronic myeloid leukemia with philadelphia chromosome positive: An experience from eastern India. Indian J Hematol Blood Transfus 2012;28:82-8.