Chronic lymphocytic leukaemia/small lymphocytic lymphoma

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Jaime Nagy, PhD, University of Iowa

Renee Eigsti, MD, Pathology Services of Kalamazoo

Honey Reddi, PhD, Belay Diagnostics

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Mature B-cell neoplasms
Type Pre-neoplastic and neoplastic small lymphocytic proliferations
Subtype(s) Chronic lymphocytic leukaemia/small lymphocytic lymphoma

Definition / Description of Disease

This is a distinct entity in the 5th edition World Health Organization (WHO) classification system. It was also a distinct entity in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition[1]. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. CLL is defined by the presence of >5x109/L monoclonal B-cells in the peripheral blood. Cells are small, mature appearing lymphocytes with light chain restriction by flow cytometry. The term small lymphocytic lymphoma (SLL) is used for cases with <5x109/L circulating monoclonal B-cells and documented nodal, splenic, or other extramedullary involvement[2].

Synonyms / Terminology

Chronic lymphocytic leukemia, B-cell type; chronic lymphoid leukemia; chronic lymphatic leukemia

Epidemiology / Prevalence

CLL is the most common leukemia in the Western world with an annual incidence of approximately 5/100,000, comprising 25% to 30% of all leukemias in the United States. The incidence increases with age with a median age at diagnosis of 70 years. CLL can also present in younger individuals with approximately 10% of cases diagnosed in individuals less than 55 years of age[3]. CLL occurrence is more prevalent in anglo americans and much lower in asian populations[4].

Clinical Features

Most (90%) patients with CLL are asymptomatic and are diagnosed based on routine blood tests[1]. Only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue[4].

Signs and Symptoms Asymptomatic (incidental finding on complete blood counts)

Weight loss, fever, night sweats

Fatigue

Lymphadenopathy, splenomegaly (less common)

Laboratory Findings absolute lymphocytosis

anemia

thrombocytopenia

paraprotein, usually IgM type (~10% of patients) hypogammaglobulinemia (~30% of patients at diagnosis)

Sites of Involvement

CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement (e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases[5].

Morphologic Features

Lymph Nodes: Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)[6]. The predominant cell in the diffuse areas is a typical CLL cell (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.

Bone Marrow: Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease[7]. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present[8]. Most cases have > 30% CLL cells in the bone marrow aspirate[2].

Peripheral Blood: Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.

Immunophenotype

CLL cells express CD19, CD20, CD5, CD23, CD43, CD200, and LEF1[9][10]. The levels of surface CD20, surface immunoglobulin and CD79b is low compared to normal B-cells[11]. Cells have kappa or lambda restricted Ig light chain expression.

Finding Marker
Positive (universal) CD5, CD43 and strongly positive

for CD23 and CD200

Negative (universal) CD10 is negative

FMC7 is usually negative or

only weakly expressed.

Subset CD5― or CD23―, FMC7+,

strong surface immunoglobulin, or

CD79b+[12]

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T

Approximately 32-42% of CLL patients are found to have a translocation noted on conventional G-banding cytogenetics[13][14][15]. Balanced translocations involving IGH are uncommon (4-9% of patients)[16].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(14;19) IGH::BCL3 No Yes No Inferior prognosis
t(14;18) IGH::BCL2 No No No No negative effect on outcome observed[17]
t(8;14) IGH::MYC <1% No Yes No Prolymphocytes are detected in most of these cases. MYC translocations are associated with an inferior prognosis[18][19].

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

  • Approximately 80% of CLL patients have a cytogenetic abnormality detectable by fluorescence in situ hybridization (FISH)
  • Deletion of chromosome 13q14 detected by FISH is the most common cytogenetic abnormality in CLL. The deleted region includes two microRNAs, miR15A and miR16-1[20]. These microRNAs inhibit the expression of genes involved in apoptosis and cell cycle regulation. Deletion of miR15A and miR16-1 leads to upregulation of BCL2[21]. Deletion of 13q14 as the sole cytogenetic abnormality is associated with a favorable prognosis. Deletions may be heterozygous or homozygous with a similar prognosis. Individuals with a high percentage of nuclei with 13q deletion (>65%) may have a less favorable prognosis[22]
  • Deletion of 17p, which includes TP53, is associated with poor prognosis and resistance to standard chemotherapy regimens[23].

CLL Tables - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [[24]] with permission from Cancer Genetics. See CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH.

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
13 Loss 13q14 No Yes No Most common cytogenetic abnormality. Isolated 13q deletion is associated with favorable prognosis[20].
11 Loss 11q22.3 No Yes No Deletion of ATM. Associated with a poor prognosis.
17 Loss 17p13.1 No Yes Yes Deletion of TP53. Patients with 17p deletion show resistance to genotoxic chemotherapies. TP53 deletion is associated with a poor prognosis[23].

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T

Common cytogenetic abnormalities include deletions of 13q, 11q, 6q, and 17p, and trisomy 12. Complex karyotypes (three or more chromosomal abnormalities) are detected in approximately 16% of patients[13][25].

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
13q14 deletion No Yes No Can also be detected in the homozygous state. Biallelic deletions are often cryptic and not cytogenetically visible[26]. 13q deletion as the sole abnormality is typically associated with a good prognosis, however, CLL with a high percentage of nuclei with 13q deletion may have a more aggressive clinical course[27]
11q22.3 deletion No Yes No 11q deletions are most often seen in patients with advanced CLL and are associated with more rapid disease progression[28][23]
Trisomy 12 No Unknown No Conflicting evidence on prognostic significance. As a sole abnormality may be associated with low risk. Associated with intermediate risk if NOTCH1 mutation is present[29]
6q21 deletion No Yes No Intermediate risk[30]
17p13 deletion No Yes Yes poor prognosis[23]
Complex karyotype No Yes No Patients with a complex karyotype have a shortened overall survival and are associated with 11q and/or 17p deletions[25][31].

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

  • IGHV genes are mutated in 50-70% of cases and unmutated in 30-50%.
  • Unmutated IGHV genes have been shown to have a poorer prognosis, along with TP53, BIRC3, NOTCH1, and SF3B1 mutations.
Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
IGHV mutations Other (IGVH unmutated B lymphocytes are naïve cells. IGHV mutated B lymphocytes are previously-triggered, postgerminal center “memory" cells) 50-70% No Yes Yes Unmutated IGHV genes have a poor prognosis and respond poorly to continuous multiregimen chemotherapy[32][33]


NOTCH1; frameshift, nonsense, and missense mutations Other (may be important for follicular differentiation and possible cell fate selection within the follicle) 5-12.3% FBXW7 mutation and trisomy 12 SF3B1 mutation No Yes No intermediate risk[34][29]
SF3B1; missense (most) Other (part of the spliceosome machinery) 9-10% Del(11q) NOTCH1 and FBXW7 mutations No Yes No intermediate risk[34][29]
TP53; missense (most) Tumor suppressor gene 7.1% No Yes No High risk[34][29]
BIRC3; frameshift and nonsense Tumor suppressor gene 7.2% No Yes Yes High risk and subject to failure of FCR chemoimmunotherapy[29][35][36]

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Whole genome methylation studies have identified three epigenetic subgroups of CLL[37]. These subgroups are related to different stages of B-cell maturation and include naïve B-cell like, intermediate, and memory B-cell like CLL. Naïve B-cell like epigenetic subgroup mainly has unmutated IGHV, whereas the memory B-like subgroup mainly have mutated IGHV genes. The intermediate epigenetic subgroup was also found to have mainly mutated IGHV, however, is associated with a worse prognosis than the memory B-like subgroup. The epigenetic classification was found to be an independent prognostic factor for time to first treatment[37][38].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
NOTCH1; PEST domain truncation Notch signaling Abnormally stabilized Notch signaling[39]
TP53; deletion and mutations DNA damage response Cell proliferation and reduced response to cytotoxic chemotherapy[40]
BIRC3; mutations NF-kB signaling Activation of non-canonical NF-kB signaling[35]

Genetic Diagnostic Testing Methods

Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray)

Immunoglobulin Heavy Chain Variable Region Gene (IGHV) mutation status

Familial Forms

Familial predisposition is found in 5-10% of patients with CLL[41]. The overall risk of developing CLL is 2-7 times higher in first-degree relatives of individuals with CLL.

Additional Information

Not Applicable

Links

Not Applicable

References

  1. ↑ Jump up to: 1.0 1.1 Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.
  2. ↑ Jump up to: 2.0 2.1 Hallek, Michael; et al. (2008-06-15). "Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines". Blood. 111 (12): 5446–5456. doi:10.1182/blood-2007-06-093906. ISSN 1528-0020. PMC 2972576. PMID 18216293.
  3. ↑ Parikh, Sameer A.; et al. (2014-01). "Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes". Haematologica. 99 (1): 140–147. doi:10.3324/haematol.2013.086066. ISSN 1592-8721. PMC 4007929. PMID 23911703. Check date values in: |date= (help)
  4. ↑ Jump up to: 4.0 4.1 Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL) SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK470433/.
  5. ↑ M, Ratterman; et al. (2014). "Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012". PMID 24064196.
  6. ↑ Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.
  7. ↑ E, Montserrat; et al. (1996). "Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients". PMID 8611442.
  8. ↑ M, Chilosi; et al. (1985). "Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia". PMID 3891066.
  9. ↑ Dorfman, David M.; et al. (2010-11). "CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms". American Journal of Clinical Pathology. 134 (5): 726–733. doi:10.1309/AJCP38XRRUGSQOVC. ISSN 1943-7722. PMID 20959655. Check date values in: |date= (help)
  10. ↑ Matutes, E.; et al. (1994-10). "The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL". Leukemia. 8 (10): 1640–1645. ISSN 0887-6924. PMID 7523797. Check date values in: |date= (help)
  11. ↑ Moreau, E. J.; et al. (1997-10). "Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b)". American Journal of Clinical Pathology. 108 (4): 378–382. doi:10.1093/ajcp/108.4.378. ISSN 0002-9173. PMID 9322589. Check date values in: |date= (help)
  12. ↑ A, Criel; et al. (1999). "The concept of typical and atypical chronic lymphocytic leukaemia". PMID 10194119.
  13. ↑ Jump up to: 13.0 13.1 Baliakas, Panagiotis; et al. (2014-03). "Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data". American Journal of Hematology. 89 (3): 249–255. doi:10.1002/ajh.23618. ISSN 1096-8652. PMID 24166834. Check date values in: |date= (help)
  14. ↑ Van Den Neste, E.; et al. (2007-08). "Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine". Leukemia. 21 (8): 1715–1722. doi:10.1038/sj.leu.2404764. ISSN 0887-6924. PMID 17541398. Check date values in: |date= (help)
  15. ↑ Mayr, Christine; et al. (2006-01-15). "Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia". Blood. 107 (2): 742–751. doi:10.1182/blood-2005-05-2093. ISSN 0006-4971. PMID 16179374.
  16. ↑ Cavazzini, Francesco; et al. (2008-08). "Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis". British Journal of Haematology. 142 (4): 529–537. doi:10.1111/j.1365-2141.2008.07227.x. ISSN 1365-2141. PMID 18547320. Check date values in: |date= (help)
  17. ↑ Put, N.; et al. (2009-06). "Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia". Leukemia. 23 (6): 1201–1204. doi:10.1038/leu.2009.44. ISSN 1476-5551. PMID 19295547. Check date values in: |date= (help)
  18. ↑ Put, Natalie; et al. (2012-06). "Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course". Annals of Hematology. 91 (6): 863–873. doi:10.1007/s00277-011-1393-y. ISSN 1432-0584. PMID 22205151. Check date values in: |date= (help)
  19. ↑ Huh, Yang O.; et al. (2008-07). "MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis". British Journal of Haematology. 142 (1): 36–44. doi:10.1111/j.1365-2141.2008.07152.x. ISSN 1365-2141. PMID 18477041. Check date values in: |date= (help)
  20. ↑ Jump up to: 20.0 20.1 Liew, Danny; et al. (2002-10). "The role of aldosterone receptor blockade in the management of cardiovascular disease". Current Opinion in Investigational Drugs (London, England: 2000). 3 (10): 1468–1473. ISSN 1472-4472. PMID 12431020. Check date values in: |date= (help)
  21. ↑ Cimmino, Amelia; et al. (2005-09-27). "miR-15 and miR-16 induce apoptosis by targeting BCL2". Proceedings of the National Academy of Sciences of the United States of America. 102 (39): 13944–13949. doi:10.1073/pnas.0506654102. ISSN 0027-8424. PMC 1236577. PMID 16166262.
  22. ↑ Van Dyke, Daniel L.; et al. (2010-02). "A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia". British Journal of Haematology. 148 (4): 544–550. doi:10.1111/j.1365-2141.2009.07982.x. ISSN 1365-2141. PMC 2866061. PMID 19895615. Check date values in: |date= (help)
  23. ↑ Jump up to: 23.0 23.1 23.2 23.3 Döhner, H.; et al. (2000-12-28). "Genomic aberrations and survival in chronic lymphocytic leukemia". The New England Journal of Medicine. 343 (26): 1910–1916. doi:10.1056/NEJM200012283432602. ISSN 0028-4793. PMID 11136261.
  24. ↑ K, Chun; et al. (2018). "Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia". PMID 30554732.
  25. ↑ Jump up to: 25.0 25.1 Haferlach, C.; et al. (2007-12). "Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping". Leukemia. 21 (12): 2442–2451. doi:10.1038/sj.leu.2404935. ISSN 1476-5551. PMID 17805327. Check date values in: |date= (help)
  26. ↑ Migliazza, A.; et al. (2001-04-01). "Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia". Blood. 97 (7): 2098–2104. doi:10.1182/blood.v97.7.2098. ISSN 0006-4971. PMID 11264177.
  27. ↑ Dal Bo, Michele; et al. (2011-08). "13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia". Genes, Chromosomes & Cancer. 50 (8): 633–643. doi:10.1002/gcc.20885. ISSN 1098-2264. PMID 21563234. Check date values in: |date= (help)
  28. ↑ Döhner, H.; et al. (1997-04-01). "11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis". Blood. 89 (7): 2516–2522. ISSN 0006-4971. PMID 9116297.
  29. ↑ Jump up to: 29.0 29.1 29.2 29.3 29.4 Rossi, Davide; et al. (2013-02-21). "Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia". Blood. 121 (8): 1403–1412. doi:10.1182/blood-2012-09-458265. ISSN 1528-0020. PMC 3578955. PMID 23243274.
  30. ↑ Cuneo, A.; et al. (2004-03). "Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis". Leukemia. 18 (3): 476–483. doi:10.1038/sj.leu.2403242. ISSN 0887-6924. PMID 14712287. Check date values in: |date= (help)
  31. ↑ Jaglowski, Samantha M.; et al. (2012-10). "Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia". British Journal of Haematology. 159 (1): 82–87. doi:10.1111/j.1365-2141.2012.09239.x. ISSN 1365-2141. PMC 3719859. PMID 22831395. Check date values in: |date= (help)
  32. ↑ Damle, R. N.; et al. (1999-09-15). "Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia". Blood. 94 (6): 1840–1847. ISSN 0006-4971. PMID 10477712.
  33. ↑ Hamblin, T. J.; et al. (1999-09-15). "Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia". Blood. 94 (6): 1848–1854. ISSN 0006-4971. PMID 10477713.
  34. ↑ Jump up to: 34.0 34.1 34.2 Jeromin, S.; et al. (2014-01). "SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients". Leukemia. 28 (1): 108–117. doi:10.1038/leu.2013.263. ISSN 1476-5551. PMID 24113472. Check date values in: |date= (help)
  35. ↑ Jump up to: 35.0 35.1 Diop, Fary; et al. (2020). "Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia". Haematologica. 105 (2): 448–456. doi:10.3324/haematol.2019.219550. ISSN 1592-8721. PMC 7012473 Check |pmc= value (help). PMID 31371416.
  36. ↑ Blakemore, Stuart J.; et al. (2020-07). "Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial". Leukemia. 34 (7): 1760–1774. doi:10.1038/s41375-020-0723-2. ISSN 1476-5551. PMC 7326706 Check |pmc= value (help). PMID 32015491 Check |pmid= value (help). Check date values in: |date= (help)
  37. ↑ Jump up to: 37.0 37.1 Queirós, A. C.; et al. (2015-03). "A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact". Leukemia. 29 (3): 598–605. doi:10.1038/leu.2014.252. ISSN 1476-5551. PMID 25151957. Check date values in: |date= (help)
  38. ↑ Oakes, Christopher C.; et al. (2016-03). "DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia". Nature Genetics. 48 (3): 253–264. doi:10.1038/ng.3488. ISSN 1546-1718. PMC 4963005. PMID 26780610. Check date values in: |date= (help)
  39. ↑ Mesini, Nicolò; et al. (2022). "Role of Notch2 pathway in mature B cell malignancies". Frontiers in Oncology. 12: 1073672. doi:10.3389/fonc.2022.1073672. ISSN 2234-943X. PMC 9846264 Check |pmc= value (help). PMID 36686759 Check |pmid= value (help).
  40. ↑ Aitken, Marisa J. L.; et al. (2019). "Emerging treatment options for patients with p53-pathway-deficient CLL". Therapeutic Advances in Hematology. 10: 2040620719891356. doi:10.1177/2040620719891356. ISSN 2040-6207. PMC 6896129. PMID 31839919.
  41. ↑ Goldin, Lynn R.; et al. (2004-09-15). "Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database". Blood. 104 (6): 1850–1854. doi:10.1182/blood-2004-01-0341. ISSN 0006-4971. PMID 15161669.

Notes

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