Cancer Letters

Cancer Letters

Volume 352, Issue 1, 28 September 2014, Pages 21-27
Cancer Letters

Mini-review
Is cure of chronic myeloid leukemia in the third millennium a down to earth target (ed) or a castle in the air?

https://doi.org/10.1016/j.canlet.2014.01.003Get rights and content

Abstract

The therapeutic approach in chronic myeloid leukemia (CML) has undergone a revolutionary change during the last 2 decades with the introduction of the tyrosine kinase inhibitors. The use of these agents has changed overall survival as well as the quality of life of CML patients. Since the introduction of imatinib, newer agents have been developed and their role as first line treatment was examined. The use of genomics and proteomics as a means to tailor treatment of CML patients is underway. Meanwhile, clinical parameters as disease phase and response to treatment are used to guide a personalized approach.

In this review, we will discuss the various aspects of personalized medicine in CML, including the use of the different scoring systems to guide treatment, disease phase as a means to choose the proper approach and the value of early response evaluation in decision-making. The approach towards patients resistant to tyrosine kinase inhibitors (TKIs), individual strategies for discontinuation of TKIs and “operational” cure in CML will also be discussed and finally the personalized treatment for CML patients in the near future based on present outcomes.

Introduction

Personalized medicine means using the right drug for the right patient at the right time. Personalized cancer management includes testing for disease-causing mutations e.g. BRCA1 and BRCA2 genes for breast cancer, BCR-ABL1 gene for chronic myeloid leukemia (CML), c-KIT gene for gastrointestinal stromal tumors (GIST) and JAK2 for myeloproliferative disorders. Assaying for minimal residual disease and applying targeted therapy, namely medications designed to target aberrant molecular pathways in a subset of patients with a given cancer type.

Until the 1980s, most cancer therapy research did not concentrate on targeted treatments. Since then, increased knowledge of cancer pathogenesis and enhanced technical abilities for sequencing and proteomics led to accelerated identification of genetic and molecular targets and of relevant biomarkers in a patient’s cancer, assisting in selecting the appropriate targeted therapy.

The term biomarker implies that a molecular aberrancy has a predictive capacity for identifying increased risk for cancer or for identifying possible variations in response to a particular treatment. Biomarker identification through research on cancer specimens from patients allows for personalization of therapy for a particular patient and for identification of optimal targets for developmental therapeutics [1].

CML was the first leukemia to be described, simultaneously, by John Hughes Bennett from Glasgow and Rudolph Virchow from Berlin, in 1845. The next important step occurred in 1960 with the description of the Philadelphia (Ph) chromosome by Nowell and Hungerford. Rowley et al. determined that the Ph chromosome was the product of a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11) creating the chimeric BCR-ABL gene (later called BCR-ABL1) which encodes for the BCR-ABL chimeric tyrosine kinase. Studies conducted in the 1980s and 1990s established the role of this tyrosine kinase in the pathogenesis of CML. Treatment of CML has undergone many changes over the years with a dramatic progress in the last two decades with the introduction of tyrosine kinase inhibitors (TKIs).

Management of patients with CML has become sophisticated since there are a variety of treatment options available. The introduction of the TKI imatinib and later the second generation TKIs into the management of the patient with CML has made therapeutic decisions rather complex. At the end of the day, therapy decision must be shared between the patient and treating physician. Furthermore under the personalized medicine framework, decision-analytic models are likely to play an increasing role in shared decision making among payers, providers, and patients [2].

The ultimate challenge is to personalize treatment, i.e. choose the most appropriate treatment for an individual patient. Patient specific, tailored therapy for CML brings the hope of specific treatment, providing high efficacy for each patient with lower toxicity than conventional treatment.

In this review, we will discuss how personalized medicine can be used as a means to achieve cure or surrogates of cure in CML in the third millennium. To this end, the following topics will be discussed: the different scoring systems in CML, treatment of CML according to disease phase, personalized treatment with imatinib and upfront personalized first-line treatment in CML based on the available armamentarium. In addition the value of early molecular response evaluation at 3 months, the approach towards patients resistant to TKIs, personalized strategies for discontinuation of TKIs and “operational” cure in CML will be discussed and finally, future personalized treatment for CML will be presented.

Section snippets

Scoring systems in CML and their role in personalizing treatment – from Sokal to Eutos

Various staging systems have been advocated in an effort to predict the prognosis of individual patients and tailor therapy accordingly.

The first, developed by Sokal et al. in 1984, was based on sub-classifying chronic phase (CP) CML patients into prognostic groups for survival according to diagnostic features. Patients are classified into 3 distinct groups – good, intermediate and high risk, based on their age, spleen size, peripheral blood blast percentage and platelet count on diagnosis.

Personalized treatment of CML according to phase

Personalizing treatment for CML patients depends amongst others on the phase of their disease – i.e. chronic, accelerated, or blast phase. Theoretically, several options can be employed but it is of utmost importance to identify the patient’s status and personalize treatment accordingly.

According to the recently published ELN recommendations, outside of clinical trials, the first-line treatment of chronic phase (CP)-CML can be any of the three TKIs that have been approved for this indication,

Personalizing treatment of CML with imatinib – genomics and proteomics

The response of the majority of patients with CP-CML to imatinib is excellent. Indeed, until recently imatinib was the only first-line treatment approved for all patients with CP-CML [7], [8], [9], [10]. Despite these outstanding results, current estimates suggest that up to 35% of patients with CP-CML demonstrate either primary or secondary resistance to imatinib [11]. Thus, clinical as well as translational researches have made efforts to decipher the primary cause of suboptimal responses in

Personalizing first-line treatment in chronic phase CML – choosing the right drug

While a decade ago imatinib was the sole first-line treatment for all CP-CML patients, at present, 3 drugs can be prescribed for this purpose– imatinib, nilotinib and dasatinib, at a dose of – 400 mg daily for imatinib, 300 mg twice daily for nilotinib and 100 mg daily for dasatinib. All 3 have been shown to be effective in patients with CP-CML and all are recommended as first-line treatment by the recently published ELN recommendations as well as by the 2013 CML NCCN Clinical Practice Guidelines

Personalizing treatment in CML according to the 3 months’ checkpoint

Recently, it was suggested by several groups that measurement of BCR-ABL1 level at 3 months during standard dose imatinib treatment strongly correlates with subsequent achievement of CCyR and molecular response as well as with overall survival and progression free survival. These data are used to personalize treatment in CML patients according to transcript level at 3 months. In a seminal paper, Marin et al. from Hammersmith analyzed 282 patients with CP-CML who received imatinib 400 mg daily as

The approach towards patients resistant to tyrosine kinase inhibitors

Resistance to TKI therapy is rarely primary. Point mutations in the ABL tyrosine kinase domain are the most common causes of acquired TKI resistance. More than 80-point mutations are associated with imatinib exposure. Subsequent TKI generations are associated with fewer mutations. Before changing therapy for treatment failure, it is prudent to check for the relevant mutations in order to guide the choice of a second- or third-line treatment. For example, in patients treated with imatinib,

Personalized strategies for discontinuation of TKIs and “operational” cure

Cure means disappearance of the disease or disappearance of all signs of the disease and return to a “normal” healthy state. Yet, we may never know whether all leukemic cells have been completely eradicated.

The concept that a patient is considered cured when every leukemia cell has been eradicated is probably an over-simplification. Furthermore, a DNA-based PCR might reveal BCR-ABL1 positive cells that were not detected by RNA-based real-time quantitative PCR and ultrasensitive PCR techniques

Personalized treatment for CML in the near future (see Fig. 1)

Can this information be integrated and translated into a personalized approach for newly diagnosed CML patients it in the near future?

The following is our personal view, based on recent information, of personalizing treatment for the newly diagnosed CML patient.

When a newly diagnosed CML patient is first seen, disease stage should be defined. This has always been a cornerstone in the approach to CML patients and remains so also in the era of the novel TKIs. Patients with chronic phase CML

Conclusions

Predicting patient’s response to therapy and consequently individualizing the treatment to increase efficacy and to reduce toxicity has been a longstanding clinical goal in tumor therapy in general and in CML in particular. The mapping of the human genome and technological developments in next-generation sequencing, gene expression profiling and proteomics have assisted in implementing genotype–phenotype data into the clinical decision process and are likely to become commonplace in CML

Conflict of Interest

Pia Raanani has received research funding from Novartis and has been a member of advisory boards for Novartis and BMS.

References (64)

  • K.M. Call et al.

    Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 wilms’ tumor locus

    Cell

    (1990)
  • O.A. Elisseeva et al.

    Humoral immune responses against wilms tumor gene wt1 product in patients with hematopoietic malignancies

    Blood

    (2002)
  • D. Cilloni et al.

    Usefulness of quantitative assessment of wilms tumor suppressor gene expression in chronic myeloid leukemia patients undergoing imatinib therapy

    Seminars Hematol.

    (2003)
  • T. Yamagami et al.

    Growth inhibition of human leukemic cells by wt1 (wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of wt1 in leukemogenesis

    Blood

    (1996)
  • H.M. Kantarjian 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)
  • F. Bonifazi et al.

    Chronic myeloid leukemia and interferon-alpha: a study of complete cytogenetic responders

    Blood

    (2001)
  • D. Milojkovic et al.

    Responses to second-line tyrosine kinase inhibitors are durable: an intention-to-treat analysis in chronic myeloid leukemia patients

    Blood

    (2012)
  • E. Jabbour 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)
  • M. Breccia et al.

    The role of comorbidities in chronic myeloid leukemia

    Leukemia Res.

    (2013)
  • M. Breccia et al.

    To switch or not to switch: That is the question – more than 10% of ratio @ 3 months: how to treat chronic myeloid leukemia patients with this response?

    Leukemia Res.

    (2013)
  • P. Jain et al.

    Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities

    Blood

    (2013)
  • D. Marin et al.

    Predictive value of early molecular response in patients with chronic myeloid leukemia treated with first-line dasatinib

    Blood

    (2012)
  • C. Biernaux et al.

    Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals

    Blood

    (1995)
  • S. Bose et al.

    The presence of typical and atypical bcr-abl fusion genes in leukocytes of normal individuals: biologic significance and implications for the assessment of minimal residual disease

    Blood

    (1998)
  • F.X. Mahon et al.

    Intergroupe Francais des Leucemies Myeloides C: 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)
  • D.M. Ross et al.

    Safety and efficacy of imatinib cessation for cml patients with stable undetectable minimal residual disease: results from the twister study

    Blood

    (2013)
  • H.Y. Yhim et al.

    Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response

    Leukemia Res.

    (2012)
  • L. Noens et al.

    Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the adagio study

    Blood

    (2009)
  • A.R. Ibrahim et al.

    Poor adherence is the main reason for loss of ccyr and imatinib failure for chronic myeloid leukemia patients on long-term therapy

    Blood

    (2011)
  • J. Mendelsohn

    Personalizing oncology: perspectives and prospects

    J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol.

    (2013)
  • K.R. Saverno et al.

    Application of decision-analytic models in personalized medicine for cml treatment decisions made by payers, providers, and patients

    J. Manage. Care Pharm.: JMCP

    (2012)
  • J. Hasford et al.

    A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa Writing committee for the collaborative cml prognostic factors project group

    J. Nat. Cancer Inst.

    (1998)
  • Cited by (0)

    View full text