Chronic lymphocytic leukaemia/small lymphocytic lymphoma

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Haematolymphoid Tumours (5th ed.)

Primary Author(s)*

Jaime Nagy, PhD, University of Iowa

Renee Eigsti, MD, Pathology Services of Kalamazoo

Honey Reddi, PhD, Belay Diagnostics

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Chronic lymphocytic leukemia/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]

Chromosomal Rearrangements (Gene Fusions)

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

  • 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 Patterns

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)

  • 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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.

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