Elsevier

Seminars in Oncology

Volume 39, Issue 1, February 2012, Pages 58-66
Seminars in Oncology

Molecular pathogenesis of hematologic malignancies
Chronic Myeloid Leukemia: Clinical Impact of BCR-ABL1 Mutations and Other Lesions Associated With Disease Progression

https://doi.org/10.1053/j.seminoncol.2011.11.002Get rights and content

The introduction of the tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib has dramatically improved the treatment of chronic myeloid leukemia (CML). However, a minority of CML patients in chronic phase (CP) and a substantial proportion of patients in advanced phase are either initially refractory to TKIs or eventually develop resistance. Rates of resistance and relapse directly correlate with disease progression. The most frequently identified mechanism of acquired TKI resistance is BCR-ABL1 kinase domain (KD) mutations that impair TKI binding by disrupting the drug contact sites or causing conformational changes that make the contact sites inaccessible. The underlying mechanisms of disease progression are heterogeneous and only poorly understood. So far the most frequent and best characterized include genomic instability, loss of tumor-suppressor functions, and differentiation arrest. Clinical data indicate that both development of a BCR-ABL1 KD mutation during TKI treatment and/or disease progression are associated with a poorer outcome. Thus, therapeutic strategies are needed for the treatment or prevention of resistance and disease progression. They include, for example, TKI dose escalation, treatment interruption to stop selection of resistant cells, and allogeneic stem cell transplantation in eligible patients, as well as the use of novel TKIs with activity against resistant mutations and/or inhibition of alternative pathways.

Section snippets

Definition of Imatinib Resistance

Imatinib resistance can be classified as primary (failure to achieve an initial response) or acquired (loss of response).5 Criteria for hematologic, cytogenetic, and molecular responses are provided in Table 1. Based on current treatment recommendations from the European LeukemiaNet (ELN), primary imatinib resistance is defined as a failure to achieve any of the following: a complete hematologic response (CHR) by 3 months, any cytogenetic response (CyR) by 6 months, a partial CyR (PCyR) by 12

Definition of CML Phases

Classically, CML is characterized by a triphasic course.12, 13 The precise definitions of these three phases have much been debated in recent years. The chronic phase (CP) is the initial stage of CML in which most patients are diagnosed. It usually has an insidious onset, and the main clinical findings include enlarged spleen, fatigue, and weight loss. It is characterized by a hypercellular marrow with high peripheral white blood cells counts (∼150 × 109/L). Blasts usually represent less than

Imatinib Resistance is Associated with Disease Progression

After phase I and II studies established the safety of imatinib and demonstrated its ability to induce high hematologic response and cytogenetic response rates in patients with CML, the International Randomized Study of Interferon and STI571 (IRIS) investigated imatinib efficacy in 553 patients with newly diagnosed CP-CML.15 At 6 years, the cumulative best CCyR rate was 82%. The estimated rate of event-free survival was 83% and the estimated rate of freedom from progression to AP or BC was 93%.

Mechanisms of Imatinib Resistance

Resistance to imatinib therapy is a multifactorial process. Mechanisms of resistance include, for example, oral biovailability, changes in plasma–protein binding or intracellular availability of imatinib, overexpression of the multidrug-resistant P-glycoprotein (MDR1), amplification and/or overexpression of BCR-ABL1, clonal cytogenetic evolution, BCR-ABL1 KD mutations, and activation of alternative signaling pathways.6, 20 An area of intense research is primary resistance of quiescent leukemic

Location of BCR-ABL1 KD Mutations

To date, more than 100 different BCR-ABL1 KD mutations, encoding for more than 50 different amino acid substitutions, have been described in imatinib-resistant CML patients.20 Mutations may be categorized into four groups, based on the crystallographic structure of ABL1: (1) those within the phosphate-binding (P)-loop (residues 248–255), (2) those within the drug contact site (T315/F317) that directly impair imatinib binding to the catalytic domain of the oncogenic protein, (3) those within the

Biology of BCR-ABL1 KD Mutations

Various BCR-ABL1 KD mutations show different biochemical and clinical properties. The biochemical and cellular impact of different mutations is heterogeneous, ranging from a minor increase of the median inhibitory concentrations of imatinib to a virtual insensitivity of imatinib.23 Different amino acid substitutions occur at the same residue, for example, F317C, F317L, and F317V, and confer different imatinib sensitivities. Recently published review articles have summarized the distribution and

Frequency of BCR-ABL1 KD Mutations

BCR-ABL1 KD mutations are responsible for a substantial proportion of imatinib resistance. In patients with CP-CML, developing a BCR-ABL1 KD mutation on imatinib is associated with a greater likelihood of progression to advanced CML and shorter survival.26, 30 In analyses of patients with any phase of CML, mutations were detected in 35%–45% of patients with imatinib resistance,25, 31, 32 and in a study of imatinib-treated patients at a single institution, 89% of patients (24/27) with a

Dynamics of BCR-ABL1 KD Mutations

Mutations can be detected before patients develop clinical resistance. In an analysis of serial blood samples from 53 imatinib-treated patients who had a BCR-ABL1 KD mutation detected at relapse, clones harboring mutations were detectable using sensitive methods several months before relapse in most cases. In 19% of patients, mutations were detectable prior to imatinib therapy. The interval between mutation detection and relapse appeared to correlate with the location of the mutation within the

Screening and Monitoring for BCR-ABL1 KD Mutations

There is currently no accepted consensus when patients should be screened for BCR-ABL1 KD mutations. Expert recommendations suggest that mutations should be identified as early as possible because they may indicate the need to reconsider the therapeutic strategy.46 A more than twofold increase of BCR-ABL1 transcripts was suggested to be an indicator for predicting mutations,47 but other investigators found that this was only a poor predictor.48 In a recent study of 150 CML patients, of whom 53

Methods for BCR-ABL1 KD Mutation Detection

Various techniques have been employed to detect BCR-ABL1 KD mutations, resulting in different reported frequencies of mutations and the finding of a heterogeneous pattern of individual mutations. There is currently no consensus concerning the technique that should be used for routine monitoring of CML patients and there are still difficulties in clinical interpretation of specific mutations. One particularly reliable and sensitive approach is the selection and expansion of specific clones

ABL Single-Nucleotide Polymorphisms

Single-nucleotide polymorphisms (SNPs) are inherited changes occurring in a single nucleotide of a gene on one of a pair of alleles/chromosomes that cause amino acid changes similar to those caused by point mutations. In a study of 911 patients with CML who either failed to respond or had a suboptimal response to imatinib, BCR-ABL1 KD sequencing found three SNPs that caused amino acid changes (K247R, F311V, and Y320C) and three silent SNPs (within amino acids T240, T315, and E499).64 Although

Mechanisms of Disease Progression

The mechanisms of transformation to advanced-phase CML are heterogeneous and poorly understood. Disease progression seems to be a multistep and time-dependent process initiated by both BCR-ABL1–dependent and –independent processes. BCR-ABL1 KD mutations in late CP are associated with greater likelihood of progression to BC, confirming the significance of BCR-ABL1 for the development of disease progression.26 On the other hand, a key feature of CML progression is the genetic instability with

Loss of Tumor-Suppressor Gene Function

The most common mutation in myeloid BC occur at the loci of the tumor-suppressor gene p53 (in about 25% of cases)66, 67 and the Runt-related transcription factor gene RUNX1 (in about 40% of cases).68 In lymphoid BC the most common mutation was reported in the cyclin-dependent kinase inhibitor CDKN2A (in about 50% of cases).69 This deletion eliminates both p16 and p19, two proteins that normally check G1/S cell cycle progression and upregulate p53. Recently, frequent mutations of the Ikaros

Differentiation Arrest

A block in myeloid differentiation occurs in progression, contributing to the accumulation of immature blasts. The transcription factor CCAAT/enhancer binding protein alpha (CEBPA) is essential to the control of granulocytic differentiation. In BC-CML, high levels of BCR-ABL1 induce the mitogen-activated protein kinase (MAPK) phosphorylation of heterogeneous nuclear ribonucleoprotein (hnRNP) E2, which then causes the translation block of CEBPA mRNA.76, 77 However, complete loss of CEBPA,

Therapeutic Recommendations

Recent ELN recommendations specify dasatinib or nilotinib as second-line treatment options for patients with CML following failure, suboptimal response, or intolerance to imatinib.9 The detection of BCR-ABL1 KD mutations may help to decide between dasatinib and nilotinib. Because of their higher potency against BCR-ABL1, first-line treatment with dasatinib or nilotinib may have the potential to reduce the occurrence of mutations or disease progression, although additional clinical data from

Conclusions

Clinical data indicate that both development of a BCR-ABL1 KD mutation during TKI treatment and/or disease progression is associated with a poorer outcome. Monitoring for BCR-ABL1 KD mutations is thus recommended in any patient with failure or suboptimal response to imatinib and prior to changing to other TKIs. With the advent of the newer BCR-ABL1 inhibitors dasatinib and nilotinib, effective second-line agents that can overcome almost all imatinib-resistant BCR-ABL mutants are available.

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    Disclosures: A.H. has received research support and honoraria from Novartis and Bristol-Myers Squibb. T.E. has no conflicts of interest to disclose.

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