Molecular pathogenesis of hematologic malignanciesChronic Myeloid Leukemia: Clinical Impact of BCR-ABL1 Mutations and Other Lesions Associated With Disease Progression
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.
References (83)
- et al.
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia
Blood
(2007) - 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) - et al.
European LeukemiaNetChronic myeloid leukaemia
Lancet
(2007) - et al.
Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet
Blood
(2006) Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia
Lancet Oncol
(2007)- et al.
Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro
Blood
(2002) - et al.
BCR-ABL SH3-SH2 domain mutations in chronic myeloid leukemia patients on imatinib
Blood
(2010) - et al.
Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib
Blood
(2003) - et al.
Detection of BCR-ABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis
Blood
(2003) - et al.
High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy
Blood
(2005)
Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment
Blood
Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment
Blood
Punish the parent not the progeny
Blood
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors
Blood
Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to second- or third-line tyrosine kinase inhibitors
Blood
Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations
Blood
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
Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations
Blood
Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib
Blood
Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
Cancer Cell
High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance
Blood
High-resolution melt curve analysis: initial screening for mutations in BCR-ABL kinase domain
Leuk Res
The biology of CML blast crisis
Blood
RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance
Blood
Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia
Blood
The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein
Cancer Cell
Absence of the human retinoblastoma gene product in the megakaryoblastic crisis of chronic myelogenous leukemia
Blood
Abnormalities of the retinoblastoma gene in the pathogenesis of acute leukemia
Blood
High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBPalpha-driven myeloid differentiation
Blood
Analysis of total phosphotyrosine levels in CD34+ cells from CML patients to predict the response to imatinib mesylate treatment
Blood
Reduction of BCR-ABL1 mutant clones after discontinuation of TKI therapy
Leuk Res
Chronic myeloid leukemia—advances in biology and new approaches to treatment
N Engl J Med
Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells
Nat Med
Tyrosine kinase activity and transformation potency of bcr-abl oncogene products
Science
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia
N Engl J Med
Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance
Leukemia
Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias
N Engl J Med
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL
N Engl J Med
Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet
J Clin Oncol
Harmonization of molecular monitoring of CML therapy in Europe
Leukemia
Chronic myeloid leukaemia as a model of disease evolution in human cancer
Nat Rev Cancer
Cited by (46)
Association of T315I mutation with resistance to tyrosine kinase inhibitor therapy in patients with CML attended the Oncology-Hematology center in Al-Najaf city of Iraq
2017, Karbala International Journal of Modern ScienceCitation Excerpt :Four different classes of BCR-ABL kinase domain mutations have been distinguished and comprise those that influence the catalytic loop (C-loop), the activation-loop (A-loop), the phosphate binding-loop (P-loop) and the direct binding site [8]. The majority of the mutations do not happen with a high level of incidence in CML patients, but 15 mutations constitute about 85% of all ones noticed [11]. Authors observed that amino acid exchange at 7 residues (G250E, M244V, E255K/V, F359V, Y253F/H, M351T and T315I) comprised 85% of all mutations related to resistance [12].
Ovarian minimal residual disease in chronic myeloid leukaemia
2014, Reproductive BioMedicine OnlineCitation Excerpt :This includes elevated white blood cells specifically immature cells (blasts) as well as abnormal cells of the myeloid megakaryocyte cell lineages. Molecular studies have reported a reciprocal chromosomal translocation between chromosomes 9q34 and 22p11 in haematopoietic cells in at least 95% of the patients with CML yielding the Philadelphia chromomsome (Ph; Cotta and Bueso-Ramos, 2007; Ernst and Hochhaus, 2012; Ernst et al., 2011; Kishore and Marin, 2011; Sudoyo and Hardi, 2011). Ph harbours the Breakpoint Cluster Region (BCR)–ABL1 (c-ABL oncogene) fusion gene which encodes a tyrosine kinase (TK) oncogenic protein.
The impact of molecular biology techniques on the management of newly diagnosed chronic myeloid leukemia patients in chronic phase. A review
2013, Transfusion and Apheresis ScienceCitation Excerpt :This is represented in Fig. 1. The mutational analysis of the KD domain is now well established and mutations causing resistance to one of the TKIs well known [21]. It is worth noting that these mutations cannot be responsible for all cases of resistance.
Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: A clinical perspective and emerging treatment options
2013, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :Recent analyses of patients resistant to imatinib therapy have identified more than 100 distinct point mutations in BCR-ABL.1 Most of the mutations do not occur with a high level of frequency in patients with CML, but 15 mutations comprise approximately 85% of all those detected.59,60 Table 2 shows the relative frequency of the most common mutations as a proportion of all mutations detected in a range of studies in patients receiving imatinib.58-68
Disclosures: A.H. has received research support and honoraria from Novartis and Bristol-Myers Squibb. T.E. has no conflicts of interest to disclose.