Prognostic and Predictive Molecular Biomarkers in Chronic Lymphocytic Leukemia
2020; Elsevier BV; Volume: 22; Issue: 9 Linguagem: Inglês
10.1016/j.jmoldx.2020.06.004
ISSN1943-7811
Autores Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoChronic lymphocytic leukemia (CLL) is a malignancy of B cells with a variable clinical course. Prognostication is important to place patients into different risk categories for guiding decisions on clinical management, to treat or not to treat. Although several clinical, cytogenetic, and molecular parameters have been established, in the past decade, a tremendous understanding of molecular lesions has been obtained with the advent of high-throughput sequencing. Meanwhile, rapid advances in the understanding of the CLL oncogenic pathways have led to the development of small-molecule targeting signal transducers, Bruton tyrosine kinase and phosphatidylinositol 3-kinase, as well as anti-apoptotic protein BCL2 apoptosis regulator. After an initial response to these targeted therapies, some patients develop resistance and experience disease progression. Novel gene mutations have been identified that account for some of the drug resistance mechanisms. This article focuses on the prognostic and predictive molecular biomarkers in CLL relevant to the molecular pathology practice, beginning with a review of well-established prognostic markers that have already been incorporated into major clinical guidelines, which will be followed by a discussion of emerging biomarkers that are expected to impact clinical practice soon in the future. Special emphasis will be put on predictive biomarkers related to newer targeted therapies in hopes that this review will serve as a useful reference for molecular diagnostic professionals, clinicians, as well as laboratory investigators and trainees. Chronic lymphocytic leukemia (CLL) is a malignancy of B cells with a variable clinical course. Prognostication is important to place patients into different risk categories for guiding decisions on clinical management, to treat or not to treat. Although several clinical, cytogenetic, and molecular parameters have been established, in the past decade, a tremendous understanding of molecular lesions has been obtained with the advent of high-throughput sequencing. Meanwhile, rapid advances in the understanding of the CLL oncogenic pathways have led to the development of small-molecule targeting signal transducers, Bruton tyrosine kinase and phosphatidylinositol 3-kinase, as well as anti-apoptotic protein BCL2 apoptosis regulator. After an initial response to these targeted therapies, some patients develop resistance and experience disease progression. Novel gene mutations have been identified that account for some of the drug resistance mechanisms. This article focuses on the prognostic and predictive molecular biomarkers in CLL relevant to the molecular pathology practice, beginning with a review of well-established prognostic markers that have already been incorporated into major clinical guidelines, which will be followed by a discussion of emerging biomarkers that are expected to impact clinical practice soon in the future. Special emphasis will be put on predictive biomarkers related to newer targeted therapies in hopes that this review will serve as a useful reference for molecular diagnostic professionals, clinicians, as well as laboratory investigators and trainees. Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western countries, with a mean diagnosis age of 72 years and a 2:1 male/female incidence ratio.1Jemal A. Siegel R. Ward E. Murray T. Xu J. Thun M.J. Cancer statistics, 2007.CA Cancer J Clin. 2007; 57: 43-66Crossref PubMed Scopus (7452) Google Scholar It is a hematological malignancy defined by the presence of ≥5 × 109/L (or 5000/μL) B lymphocytes in the peripheral blood for >3 months.2Hallek M. Cheson B.D. Catovsky D. Caligaris-Cappio F. Dighiero G. Dohner H. Hillmen P. Keating M. Montserrat E. Chiorazzi N. Stilgenbauer S. Rai K.R. Byrd J.C. Eichhorst B. O'Brien S. Robak T. Seymour J.F. Kipps T.J. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.Blood. 2018; 131: 2745-2760Crossref PubMed Scopus (725) Google Scholar The tumor cells are mature CD19+ B cells with a typical immunophenotype of CD5 and CD23. Although the leukemia is generally considered an indolent disease, its disease course is highly variable among patients. Approximately one-third of patients have an indolent disease that may not need any treatment, another approximately one-third may progress in several years after diagnosis, and the last one-third require immediate treatment. Thus, prognostication is important to place patients into risk categories to help guide clinical follow-up options, either to treat or to wait and watch. To stratify patients for prognostication, Rai and Binet staging systems were developed in the late 1970s to early 1980s, which separated patients into different stages on the basis of clinical characteristics and hematology laboratory findings. In the past decade, the rapid development of genomics technique greatly expanded understanding of CLL at the molecular level. This, in turn, translated into many newer prognostic markers based on chromosomal aberrations or gene mutations. Advances in the understanding of CLL pathogenesis, in the meantime, have led to the development of several highly effective targeted therapies, including Bruton tyrosine kinase (BTK)–, phosphatidylinositol 3-kinase–, and BCL2 apoptosis regulator (BCL2)–directed inhibitors. There are several excellent reviews that cover the clinical, therapeutic, or pathogenic aspects of CLL,3Nabhan C. Rosen S.T. Chronic lymphocytic leukemia: a clinical review.JAMA. 2014; 312: 2265-2276Crossref PubMed Scopus (102) Google Scholar, 4Zhang S. Kipps T.J. The pathogenesis of chronic lymphocytic leukemia.Annu Rev Pathol. 2014; 9: 103-118Crossref PubMed Scopus (74) Google Scholar, 5Nabhan C. Raca G. Wang Y.L. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era.JAMA Oncol. 2015; 1: 965-974Crossref PubMed Scopus (37) Google Scholar, 6Rai K.R. Jain P. Chronic lymphocytic leukemia (CLL)-then and now.Am J Hematol. 2016; 91: 330-340Crossref PubMed Scopus (83) Google Scholar, 7Tees M.T. 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An updated perspective on current prognostic and predictive biomarkers in chronic lymphocytic leukemia in the context of chemoimmunotherapy and novel targeted therapy.Cancers (Basel). 2020; 12: 894Crossref Scopus (13) Google Scholar This article aims to provide a concise summary of the molecular and genomic biomarkers most relevant to the current molecular diagnostic practice. Well-established markers that have already been incorporated into major clinical guidelines are discussed first. Next, emerging biomarkers that are expected to impact clinical practice soon in the future are discussed. Special emphasis is placed on predictive biomarkers related to newer therapies, and some of the key information is organized in tables and graphs. The hope for this review is to serve as a useful reference for molecular pathology professionals, clinicians, as well as laboratory researchers and trainees. First, it is important to explain the distinction between markers of prognostic and predictive values. Prognostic markers refer to biomarkers that can provide information regarding the patient's outcome regardless of treatment. These markers are normally intrinsic characteristics of the patients or characteristics of the patients' tumors. They are often assessed upfront before treatment to help guide decisions on to treat or not to treat. Markers associated with overall survival (OS) or time to first treatment (TTFT) represent such examples. On the other hand, predictive markers are biomarkers that are related to extrinsic factors, such as therapeutic interventions. Examples include markers predicting treatment response to a drug. These markers are normally assessed when patients receive the particular therapy. Some markers can be both prognostic and predictive. Such cases are identified in the relevant context. The presence of a clonal population of B cells (>5000/μL) with surface CD5 and CD23 expression assessed by flow cytometry is diagnostic in most cases of CLL. Molecular and cytogenetic testing play a role only in differential diagnosis, to help exclude other entities, such as mantle cell lymphoma or lymphoplasmacytic lymphoma, in cases where the presentation is atypical and overlaps with CLL. On the other hand, several genomic and molecular markers have been established in assessing CLL prognosis. Specifically, the National Comprehensive Cancer Network guideline recommends using TP53 genetic alterations, IGHV mutation status, and several well-established cytogenetic markers for CLL prognostication (https://www.nccn.org/professionals/physician_gls/default.aspx, last accessed September 20, 2019, registration required). Of these, TP53 mutations, IGHV unmutated status, del(17p), and del(11q), as well as complex karyotype (the presence of three or more unrelated clonal chromosomal abnormalities in a sample), are associated with poor prognosis.2Hallek M. Cheson B.D. Catovsky D. Caligaris-Cappio F. Dighiero G. Dohner H. Hillmen P. Keating M. Montserrat E. Chiorazzi N. Stilgenbauer S. Rai K.R. Byrd J.C. Eichhorst B. O'Brien S. Robak T. Seymour J.F. Kipps T.J. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.Blood. 2018; 131: 2745-2760Crossref PubMed Scopus (725) Google Scholar Normal karyotype and trisomy 12 are considered as intermediate prognostic factors, whereas del(13q) is associated with a favorable prognosis (Table 1).Table 1Established Biomarkers and Their Prognostic ValuePrognosisCytogenetic markersEstablished molecular markersEmerging molecular markersFavorabledel(13q) aloneMutated IGHVIntermediateTrisomy 12Normal karyotypeUnfavorabledel(17p)TP53NOTCH1del(11q)Unmutated IGHVSF3B1Complex karyotypeBIRC3ATM Open table in a new tab The frequency of the molecular markers in CLL varies in relation to disease status. Genetic alterations associated with poor prognosis are often more enriched in patients at advanced stages or after treatment. For example, in the European Research Initiative on CLL data set, the frequency of TP53 mutations is 3.8% in untreated patients versus 13% in treated patients. Similarly, del(17p) is 3% versus 10%, and IGHV unmutated status is 22% versus 66%. In contrast, the good prognosis marker del(13q) is 48% in untreated patients versus a lower frequency of 33% in patients who received therapies.16Baliakas P. Hadzidimitriou A. Sutton L.A. Rossi D. Minga E. Villamor N. Larrayoz M. Kminkova J. Agathangelidis A. Davis Z. Tausch E. Stalika E. Kantorova B. Mansouri L. Scarfo L. Cortese D. Navrkalova V. Rose-Zerilli M.J. Smedby K.E. Juliusson G. Anagnostopoulos A. Makris A.M. Navarro A. Delgado J. Oscier D. Belessi C. Stilgenbauer S. Ghia P. Pospisilova S. Gaidano G. Campo E. Strefford J.C. Stamatopoulos K. Rosenquist R. 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Each abnormality is discussed in the following sections.Table 2Frequency of Prognostic BiomarkersReferenceUntreated patientsTreated/relapsed/refractory patients192016212223242526RangeMean∗The mean values are derived from averaging the frequency reported in each study without weighting and are rounded up to the one's position.162127282425RangeMean∗The mean values are derived from averaging the frequency reported in each study without weighting and are rounded up to the one's position.Patients, N5066358572283472116030640020616146016311449280IGHV-U256322386038323622–63406660806360–8067Del(17p)4834710†Frequency of del(17p) and TP53 patients is combined in this particular study and is not included in the calculation for ranges and means.83–861018.52335†Frequency of del(17p) and TP53 patients is combined in this particular study and is not included in the calculation for ranges and means.248.5–2416Del(13q)503748553560.1523635–6046335029572121–5738Trisomy 12141213141215191512–19141781729128–2917Del(11q)25591711.56125–251221202025262020–2622TP53511.54104710†Frequency of del(17p) and TP53 patients is combined in this particular study and is not included in the calculation for ranges and means.124–12813102335†Frequency of del(17p) and TP53 patients is combined in this particular study and is not included in the calculation for ranges and means.3710–3721NOTCH113103.55812111653.5–22111216152417.512–2417SF3B1913415941483–1581612282423.512–2821BIRC391470.50.5–9459524.595–24.511ATM111511–1512261717–2622∗ The mean values are derived from averaging the frequency reported in each study without weighting and are rounded up to the one's position.† Frequency of del(17p) and TP53 patients is combined in this particular study and is not included in the calculation for ranges and means. Open table in a new tab Del(17p) and TP53 mutations are observed in approximately 6% and approximately 8% of untreated CLL patients, respectively, and approximately 16% and approximately 21% in the treated CLL population, respectively (Table 2). Deletion 17p invariably involves the TP53 gene at 17p13 locus, and commonly co-occurs with TP53 mutation on the other allele.29Rossi D. Cerri M. Deambrogi C. Sozzi E. Cresta S. Rasi S. De Paoli L. Spina V. Gattei V. Capello D. Forconi F. Lauria F. Gaidano G. The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness.Clin Cancer Res. 2009; 15: 995-1004Crossref PubMed Scopus (249) Google Scholar TP53 mutations can be missense, frame-shift, or splicing mutations, and usually involve the DNA binding domain encoded between exon 4 and exon 8 (Figure 1).30Cerami E. Gao J.J. Dogrusoz U. Gross B.E. Sumer S.O. Aksoy B.A. Jacobsen A. Byrne C.J. Heuer M.L. Larsson E. Antipin Y. Reva B. Goldberg A.P. Sander C. Schultz N. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.Cancer Discov. 2012; 2: 401-404Crossref PubMed Scopus (9399) Google Scholar,31Quesada V. Conde L. Villamor N. Ordonez G.R. Jares P. Bassaganyas L. et al.Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia.Nat Genet. 2011; 44: 47-52Crossref PubMed Scopus (783) Google Scholar Most of these mutations abolish the function of TP53 as a tumor suppressor. Although inactivation of a single TP53 allele is associated with poor survival, bi-allelic TP53 inactivation confers a worse OS in all populations, in both treated and untreated patients.32Malcikova J. Smardova J. Rocnova L. Tichy B. Kuglik P. Vranova V. Cejkova S. Svitakova M. Skuhrova Francova H. Brychtova Y. Doubek M. Brejcha M. Klabusay M. Mayer J. Pospisilova S. Trbusek M. 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Valetto A. Allen S.L. Buchbinder A. Budman D. Dittmar K. Kolitz J. Lichtman S.M. Schulman P. Vinciguerra V.P. Rai K.R. Ferrarini M. Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.Blood. 1999; 94: 1840-1847Crossref PubMed Google Scholar,35Hamblin T.J. Davis Z. Gardiner A. Oscier D.G. Stevenson F.K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia.Blood. 1999; 94: 1848-1854Crossref PubMed Google Scholar Unmutated IGHV is present in approximately 40% of untreated cases (Table 2). The unmutated status not only informs a bad prognosis but also predicts a worse response to chemoimmunotherapy regimen, fludarabine-cyclophosphamide-rituximab.36Rossi D. Terzi-di-Bergamo L. De Paoli L. Cerri M. Ghilardi G. Chiarenza A. Bulian P. Visco C. Mauro F.R. Morabito F. Cortelezzi A. Zaja F. Forconi F. Laurenti L. Del Giudice I. Gentile M. Vincelli I. Motta M. Coscia M. Rigolin G.M. 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Kipps T.J. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.Blood. 2018; 131: 2745-2760Crossref PubMed Scopus (725) Google Scholar The mechanism for how IGHV status impacts CLL prognosis remains unclear. CLL cases with unmutated IGHV are thought to have increased B-cell receptor (BCR) signaling and increased malignant cell proliferation.37Guo A. Lu P. Galanina N. Nabhan C. Smith S.M. Coleman M. Wang Y.L. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib.Oncotarget. 2016; 7: 4598-4610Crossref PubMed Scopus (38) Google Scholar,38Rozovski U. Keating M.J. Estrov Z. Why is the immunoglobulin heavy chain gene mutation status a prognostic indicator in chronic lymphocytic leukemia?.Acta Haematol. 2018; 140: 51-54Crossref PubMed Scopus (11) Google Scholar Laboratory determination of IGHV mutation status involves mainly sequencing of the variable region of the Ig heavy chain and aligning the resulting sequences with the germ-line sequences, where ≥98% homology or ≤2% mutation to the germ-line IGV sequence is interpreted as unmutated and >2% mutation and <98% homology is considered mutated. A new category of borderline cases is recently defined as having 97.0% to 97.9% homology.39Rosenquist R. Ghia P. Hadzidimitriou A. Sutton L.A. Agathangelidis A. Baliakas P. Darzentas N. Giudicelli V. Lefranc M.P. Langerak A.W. Belessi C. Davi F. Stamatopoulos K. Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: updated ERIC recommendations.Leukemia. 2017; 31: 1477-1481Crossref PubMed Scopus (88) Google Scholar The clinical implication of the borderline finding is unclear at present and remains to be elucidated. Stereotypes of the IGHV also matter. In particular, the National Comprehensive Cancer Network guideline notes that IGHV stereotype VH3-21 carries a poor prognosis, even in the IGHV mutated background. Interested readers are referred to a recent review by Ten Hacken et al10Ten Hacken E. Gounari M. Ghia P. Burger J.A. The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia.Leukemia. 2019; 33: 287-298Crossref PubMed Scopus (31) Google Scholar for details. Del(13q), the most common genetic aberration, is found in close to half of CLL patients40Dohner H. Stilgenbauer S. Benner A. Leupolt E. Krober A. Bullinger L. Dohner K. Bentz M. Lichter P. 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