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Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era

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Clinical Review & Education Review in the Contemporary Era Chadi Nabhan, MD; Gordana Raca, MD, PhD; Y. Lynn Wang, MD, PhD IMPORTANCE Next-generation sequencing has identified new genetic markers that have
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Clinical Review & Education Review in the Contemporary Era Chadi Nabhan, MD; Gordana Raca, MD, PhD; Y. Lynn Wang, MD, PhD IMPORTANCE Next-generation sequencing has identified new genetic markers that have altered prognosis for patients with chronic lymphocytic leukemia (CLL) at diagnosis. Understanding the significance of these prognostic indicators and recognizing their potential impact on treatment selection and patients outcomes is critical for clinicians and investigators. OBJECTIVE To review novel prognostic factors at CLL diagnosis that have shown an impact on the prognosis and outcomes of this disease. EVIDENCE REVIEW Literature from January 2004 through December 2014 was searched in PubMed, Cochrane Central Register of Controlled Trials, and Scopus to identify English-language, peer-reviewed articles on clinical and prognostic factors for CLL (TP53, ATM, NOTCH1, SF3B1, BIRC3, and MYD88). Reference lists were subsequently reviewed for additional articles. A total of 450 articles was identified, and 48 articles meeting inclusion criteria were reviewed. FINDINGS Among prognostic markers reviewed, chromosomal aberrations have been validated and are currently used clinically to predict prognosis. Patients with 17p13.1 deletion have poor response to chemoimmunotherapy and are treated differently, with some undergoing allogeneic transplantation in first remission. CD38 and ZAP-70 status of malignant cells and unmutated immunoglobulin variable heavy chain gene have similarly been validated to predict adverse prognosis, but their implications on treatment selection have not been proven. The presence of TP53 and ATM mutations predicts worse prognosis, which has been corroborated in various studies. Patients with TP53 mutations have lower responses to chemoimmunotherapy. Furthermore, patients with TP53 and ATM mutations have inferior progression-free survival and overall survival, independent of other factors. Patients carrying the NOTCH1 and SF3B1 mutations have worse prognosis; patients with the NOTCH1 mutation have lower response rates to standard chemoimmunotherapy. The impact of BIRC3 on prognosis and survival requires further confirmation. CONCLUSIONS AND RELEVANCE The heterogeneous clinical course of CLL is likely explained by underlying molecular prognostic factors. Moving forward, analyzing these factors at diagnosis is recommended for better prognostication. JAMA Oncol. doi: /jamaoncol Published online May 7, Author Affiliations: Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois (Nabhan, Raca); Section of Hematology/ Oncology, Cancer Cytogenetics Laboratory, University of Chicago, Chicago, Illinois (Raca); Division of Genomic and Molecular Pathology, Department of Pathology, University of Chicago, Chicago, Illinois (Wang). Corresponding Author: Chadi Nabhan, MD, Section of Hematology/ Oncology, Department of Medicine, Outpatient Cancer Center, The University of Chicago Medicine, 5841 S Maryland Ave, MC2115, Chicago, IL (Reprinted) E1 Clinical Review & Education Review Chronic lymphocytic leukemia (CLL) is diagnosed in more than cases annually, contributing to 5000 deaths yearly. 1 NotableadvancesinmolecularunderstandingofCLL have led to better prognostic risk stratification and have largely explained the heterogeneous clinical course of this disease. 2 In this review, we discuss the various prognostic parameters in CLL, focusing on cytogenetics, cellular-based factors, and gene mutations. We comprehensively analyze these factors in light of the historical as well as modern approach to CLL therapy. Furthermore, we provide a framework for the future of CLL therapeutic investigations, especially as the newly approved B-cell receptor (BCR) pathwaytargeted agents have become widely used. At a Glance Prognosis at diagnosis in chronic lymphocytic leukemia (CLL) is dictated by clinical and molecular prognostic factors that separate the disease into high- and low-risk categories. 17p Deletion and/or TP53 mutations remain the most important adverse prognostic features predicting inferior responses and survival in CLL. NOTCH1 and SF3B1 mutations seem to be mutually exclusive and are both associated with adverse prognosis. CLL patients with a NOTCH1 mutation might not respond well to anti-cd20 based therapies. Newer agents targeting the B-cell receptor pathway have shown significant activity in high-risk CLL patients who carry the 17p deletion. Data Sources and Literature Review PubMed, Cochrane Central Register of Controlled Trials, and Scopus were searched to find literature on clinical and prognostic factors for chronic lymphocytic leukemia (Table). Searches were limited to literature published from January 2004 through December English language limits were applied. The search used subject heading and keyword variations based on the following concepts: CLL, chronic lymphocytic leukemia AND NOTCH1, SF3B1, ATM, TP53, BIRC3, MYD88 AND progression-free survival, disease-free survival, and survival. Additional references were identified by searching relevant articles reference lists. The results of the searches were combined, then deduplicated, and the final number of articles that met the selection criteria was 48 out of 450 identified articles. Historical Background Despite recent advances in treating CLL, watchful waiting remains the recommended approach for asymptomatic patients. 3 When treatment is indicated and initiated, chemoimmunotherapy combinations are the preferred front-line treatment. 4 The activity noted with the fludarabine, cyclophosphamide, and rituximab (FCR) regimen led to the conduct of a prospective phase 3 randomized clinical trial comparing FCR to fludarabine and cyclophosphamide (FC) and demonstrating that FCR had better responses and superior survival. 5 Another phase 3 study, designed for frail patients with comorbidities, randomized 781 patients to chlorambucil alone or chlorambucil plus either rituximab or obinutuzumab, a glycoengineered type 2 anti-cd20 antibody. 6 The combination of chlorambucil with eitherantibodyimprovedresponseratesandprolongedprogressionfree survival (PFS). Furthermore, the combination of chlorambucil and obinutuzumab improved overall survival (OS) compared with chlorambucil alone (hazard ratio [HR], 0.41; P .001). These studies, as well as a recent evidence-based comprehensive review and systematic analysis, provided additional evidence that chemoimmunotherapy is the logical front-line therapy for patients with CLL (CLL patients). 7 Risk Stratification Overtheyears, clinicianshaveusedtraditionalprognosticfactorsthat are easily obtained using staging, serum testing, and other accessible parameters to predict progression risk of CLL and diseaserelated mortality. 8 As newer prognostic factors became available, better ability to predict responses to therapy, duration of responses, time to first treatment, OS, and selections of therapy ensued. Understanding these prognostic indicators allows for better design of future clinical trials that are tailored to the basic mechanism of the disease. Chromosomal Aberrations In addition to normal cytogenetics, recurrent chromosomal abnormalities in CLL include 17p deletion, 11q deletion, trisomy 12, and 13q deletion (Figure 1). Over a decade ago, Döhner et al 9 reported a pivotal work showing that 82% of CLL patients carry at least 1 genomic abnormality when fluorescence in situ hybridization (FISH) testingwasused. Furthermore, theydemonstratedthatpatientswith the 17p13.1 or 11q22.3 deletions have the worst prognosis, with a median survival of 32 and 79 months, respectively, whereas patients with a normal cytogenetic status and those who carry the 13q deletion have a median survival of 111 and 133 months, respectively. This investigation and others led to the development of the FISH-based hierarchical prognostic model based on the presence of 17p deletion,11qdeletion,trisomy12,normalcytogenetics,and13qdeletion. 10 The prognostic significance in the 17p13.1 deletion is related to the TP53 gene that is mapped to this chromosomal location. The 17p13.1 deletion can occur with or without TP53 mutations on the second allele and TP53 mutations can also be present without deletions. 11 Both deletions and mutations lead to impaired TP53 functions. In patients with 17p deletion and TP53 mutations of the second allele, p53 function is completely lost. 11 In addition to atypical immunophenotypes (where some patients have brighter expression of CD20 and surface immunoglobulin 12 ) that have been occasionally observed in these patients, other adverse prognostic factors, such as high expressions of CD38, unmutated immunoglobulin heavy chain gene (IGHV), and zeta-associated protein-70 (ZAP-70) expression have been seen in higher frequency in patients with 17p deletions. 13,14 It is important to note that 17p13.1 occurs in less than 10% of CLL patients but carries the worst prognosis as it has been observed in 30% to 50% of patients who develop resistance and refractoriness to chemotherapy. 15 Patients who carry this deletion have historically had inferior response rates, PFS, and OS 5 However, in later investigations, Tam et al 16 showed that there is a clinical heterogeneity in patients with 17p deletions in which those who acquire the E2 JAMA Oncology Published online May 7, 2015 (Reprinted) jamaoncology.com Review Clinical Review & Education Table. Prognostic Factors at the Time of Diagnosis in Patients With CLL Category Select clinical and laboratory parameters Prognostic Factor Description Biologic Function Prognostic Significance Rai stage 73b Uses the presence or absence of lymphadenopathy, organomegaly (spleen and liver), and cytopenias Lymphocyte doubling time 24 Measures the number of months it takes the absolute lymphocyte count to double β-2 microglobulin and LDH 24 Separates patients into groups with different anticipated survival times based on disease burden Inclusion in Guidelines Recommendations a Higher Rai stage predicts shorter survival Yes (NCCN, IWCLL, ESMO) Estimates the pace of disease Short doubling time ( 12 mo) predicts higher risk Yes (NCCN, IWCLL, ESMO) Measures serum β-2 microglobulin and LDH Estimates tumor burden Increasing levels indicate a poorer prognosis Yes (NCCN, ESMO) Strong Evidence for Prognostic Value Strong Strong Immunoglobulin heavy chain gene mutational status Flow cytometry markers FISH abnormalities Gene mutations Other IGHV 27,28 Mutation status of the immunoglobulin gene variable region Determines the origin from a pregerminal (unmutated IGHV) or postgerminal (mutated IGHV) center B-cell Unmutated IGHV indicates shorter survival and a higher risk of relapse CD38 30,31 Transmembrane glycoprotein Possible role in apoptosis CD38 expression ( 30%) predicts inferior survival ZAP-70 14,32,33 Zeta chain associated protein 70 A tyrosine kinase expressed by NK and T cells and not expressed by B cells 17p- 16,52,74 Deletion of the p13 region of the short arm of chromosome 17 11q- 9,75 Deletion of the q22 region of the long arm of chromosome 11 20% ZAP70-positive cells indicate higher risk of progression, short time from diagnosis to treatment, and poorer survival Results in a loss of 1 copy of the TP53 gene Associated with inferior response, shorter time to progression, and worse survival when chemotherapy is used Yes (NCCN, IWCLL, Strong ESMO) c Yes (NCCN, IWCLL, Strong ESMO) c Yes (NCCN, IWCLL, Strong ESMO) c Yes (NCCN, IWCLL, ESMO) Results in a loss of 1 copy of the ATM gene Indicates high risk Yes (NCCN, IWCLL, ESMO) Trisomy Gain of chromosome 12 Molecular consequences of trisomy 12 unknown Indicates intermediate risk unless NOTCH1 mutation is present 13q- 12,21 Deletion of the q14 region of the long arm of chromosome 13 and loss of chromosome 13 6q- 76 Deletion of the q23 region of the long arm of chromosome 6 Results in a loss of mir-15a/16-1 micro RNA cluster. mir-15a and mir-16-1 regulate cell cycle genes and control cell proliferation Molecular consequences of the 6q deletion are unknown TP53 11,35,74 Tumor protein p53 Tumor suppressor protein, mediates cell cycle arrest, apoptosis, senescence and DNA repair ATM 41,42 Ataxia telangiectasia mutated Member of the PI3/PI4-kinase family, important cell cycle checkpoint kinase BIRC3 43,58,77 Baculoviral IAP repeat containing 3 A member of the IAP family of proteins that inhibits apoptosis. NOTCH1 47,58,78 Notch homologue 1, translocation associated (Drosophila) A ligand-activated transmembrane protein that regulates downstream pathways important for cell growth Strong Strong Yes (NCCN, IWCLL) Strong Indicates low risk Yes (NCCN, IWCLL) Strong Indicates intermediate risk IWCLL only Weak TP53 mutations are independent predictors of poor survival when standard therapy is used ATM mutations indicate high risk for progression, in particular when associated with 11q loss Yes (NCCN, ESMO) Strong No Intermediate BIRC3 disruption indicates poor outcome No Weak NOTCH1 mutations are associated with adverse prognosis SF3B1 58,79 Splicing factor 3b, subunit 1 Role in mrna splicing SF3B1 mutations are associated with adverse prognosis MYD88 80 Myeloid differentiation primary response 88 Cytosolic adapter protein with a role in the innate and adaptive immune response XPO1 10 Exportin 1 Implicated in nuclear export signal-dependent protein transport Genetic Multiple chromosomal complexity 81 karyotyping or array analysis, or subclonal driver mutations by molecular testing MYD88 mutations are associated with favorable outcome XPO1 mutations may be associated with high risk of progression No Strong No Strong No Intermediate No Weak Indicators of genomic instability and clonal evolution Associated with adverse prognosis No Intermediate Abbreviations: CLL, chronic lymphocytic leukemia; ESMO, European Society of Clinical Oncology; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy chain gene; IWCLL, international workshop on chronic lymphocytic leukemia; LDH, lactate dehydrogenase; mrna, messenger RNA; NCCN, National Comprehensive Cancer Network Version ; NK, natural killer; TP53, tumor protein p53; ZAP-70, zeta-associated protein-70. a Summary of recommendations by the National Comprehensive Cancer Network, version , 4 International Workshop on Chronic Lymphocytic Leukemia, 3 and European Society of Clinical Oncology. 56,82 b Binet staging system is used in Europe. c Recommended only in the context of well-designed clinical trials but not in general practice. jamaoncology.com (Reprinted) JAMA Oncology Published online May 7, 2015 E3 Clinical Review & Education Review Figure 1. Array Findings in a Case of High-Risk Chronic Lymphocytic Leukemia (CLL) A B Copy number state (segments) Mosaic copy number state (segments) Weighted Log2 Ratio Allele peaks Smooth signal kb kb kb kb kb kb kb C Copy number state (segments) Mosaic copy number state (segments) Genes Weighted Log2 Ratio Allele peaks Smooth signal 7571 kb 7572 kb 7573 kb 7574 kb 7575 kb 7576 kb 7577 kb 7578 kb 7579 kb A, Screenshot from the array analysis software, summarizing all detected abnormalities. Blue bars indicate copy number gains (duplications), and red bars indicate copy number losses (deletions). Duplications were detected on chromosomes 4, 7, and 9, and deletions were detected on chromosomes 7 and 17. None of the abnormalities were detected by karyotyping owing to low propensity of CLL cells to grow in culture, or by the fluorescence in situ hybridization (FISH) panel owing to localization of the abnormalities outside of the regions targeted by the FISH probes. B, The complexity of the copy number abnormalities detected on chromosome 7. The copy number state (segments) plot depicts chromosomal segments with a copy number gain (blue) and copy number loss (red). The weighted Log2 ratio plot represents per marker log2 ratio of normalized signal intensity for the leukemia sample with respect to a reference. The allele peaks plot represents allelic ratio values for individual single nucleotide polymorphism (SNP)-genotyping markers, allowing to depict genotypes (AA, AB or BB) for SNP sites along the length of the chromosome. The smooth signal plot depicts calibrated copy number estimate for different regions of the chromosome. C, Enlarged view of the deletion (red bar) on chromosome 17, which involves the 5 region of thetp53 gene resulting in its disruption. The deletion was not detected by the TP53 FISH probe because it only partially overlaps with the probe target region. E4 JAMA Oncology Published online May 7, 2015 (Reprinted) jamaoncology.com Review Clinical Review & Education 17p deletion as part of their clonal evolution during therapy fare an inferior survival when compared with those who carry a 17p deletion at the time of diagnosis. The other adverse genomic aberration involves deletions in the long arm of chromosome 11, which occur in up to 20% of CLL patients at diagnosis. 9 These patients often present with bulky nodes and demonstrate other poor prognostic features. 17 The prognostic significance of this deletion stems mainly from mutations in the ATM gene, located on the long arm of chromosome While original studies suggested short time to first treatment, shorter remission duration, and poorer survival in these patients, recent chemoimmunotherapy programs have proven to overcome these adverse features. 18 Contrary to 17p and 11q deletions, the presence of trisomy 12 in CLL at initial diagnosis has traditionally carried intermediate prognostic significance. 9 Landau et al 19 proposed that trisomy 12 occurs early in the course of CLL, facilitating subsequent chromosomal aberrations. Further studies demonstrated that patients with trisomy 12 can acquire trisomy 19 and that these patients carry other adverse prognostic features. 20 Similarly, but to a better extent, the presence of 13q deletion carries a favorable prognosis and is the most common genomic abnormality detected in CLL, seen in 50% of cases. 9 Biallelic loss in 13q has been observed in 30% of CLL patients with 13q deletion, and this finding has been of controversial significance. 21 Because micrornas mir-15a and mir-16-1 are located within the commonly deleted region on chromosome 13, their deletions contribute to the pathogenesis of this subtype of CLL. Both of these micrornas have been shown to accelerate the proliferation of human and mouse B cells by modulating the expression of genes controlling cell-cycle progression; their deletion might partially explain the good prognosis associated with 13q deletion. 22 Moreover, investigations have demonstrated that mir-15a and mir expression is inversely correlated with BCL-2 expression in CLL and that both micrornas negatively regulate BCL-2 at a posttranscriptional level. 23 The clinical significance of this observation remains uncertain. While it is often reported as part of the FISH-CLL panel when this test is ordered, the impact of treatment selection when detecting trisomy 12 or 13q deletion abnormalities in CLL patients is uncertain. Mutational Status of the IGHV Gene AsaB-cellmalignantneoplasm, CLLcanevolveeitherfrompregerminal or postgerminal B cells. 24 This divides CLL into 2 subsets: a disease whose cells have successfully passed through the germinal center, resulting in a mutated phenotype, and another subset that originates from B cells with the unmutated or germline sequence. Ghia et al 25 reported on guidelines to analyze the IGHV rearrangement citing that sequences that are more than 2% nonhomologous to germline are considered to have undergone somatic hypermutation. While the molecular basis for this differential outcome in CLL based on IGHV mutational status remains debatable, investigators have recently proposed that the unmutated CLL overexpresses proteins associated with transcriptional and translational activity. 26 Furthermore, when unmutated, CLL cells tend to be more adhesive and less migratory, wh
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