chronic lymphocytic leukemia

Digital cases

 HPC:278 : CD5+ small cell lymphoma in bone marrow. Nodular aspect of a chronic lymphocytic keukemia.
 HPC:287 : Chronic lymphocytic leukemia in lymph node
 HPC:343 : Richter syndrome. Progression of a chronic lymphocytic leukemia (CLL)
 HPC:346 : Pseudonodular lymphocytic lymphoma (chronic lymphocytic leukemia)
 HPC:348 : Pseudonodular lymphocytic lymphoma (chronic lymphocytic leukemia)
 UI:493 - Blood in Chronic lymphocytic leukemia

See also

 chronic lymphocytic leukemia

Definition: Chronic lymphoproliferation of B-cells. The existence of rare cases of T-CLL has been debated.

Epidemiology

Annual incidence 30/106; represents 70% of lymphoid leukaemias, 1/4 of all leukaemias; median age: 60-80 yrs, 2M/1F.

Clinics

Diagnosis is often delayed, due to the lack of symptoms (therefore, median survival from the begining of the disease may be much more than median survival from diagnosis). The patient may present with enlarged lymph nodes, splenomegaly, lymphocytosis > 4 5 X 109/l; hypogammaglobulinemia in 60%.

Cytology

Typically, proliferation of mature small lymphocytes of normal morphology; lymphocytes with more abundant cytoplasm may be present. When prolymphocytes are 10% or greater they are classified as ’chronic lymphocytic leukaemia-prolymphocytic leukaemia’.

Immunophenotype

The predominant population shares B-cell markers CD19, CD20, and CD23 with the CD5 antigen, in the absence of other pan-T-cell markers.

The B-cell is monoclonal with regard to expression of either kappa or lambda; and surface immunoglobulin (slg) is of low density.

Not only are these characteristics generally adequate for a precise diagnosis, but, importantly, they distinguish CLL from uncommon disorders such as PLL, hairy-cell leukemia, mantle-cell lymphoma, and other lymphomas.

Further, the Matutes score based on the most common marker profile in CLL, CD5+, CD23+, FMC7- and weak expression (+/-) of surface immunoglobulin (SIg) and CD22, can distinguish between typical and atypical CLL by assigning scores that range from 5 (typical of CLL) to 0 (atypical for CLL).

Types

 B-cell chronic lymphocytic leukemia (B-CLL)
 T-cell chronic lymphocytic leukemia (T-CLL) (rare)

Cytogenetics

 11q23 deletion
 del(13)(q14.3)
 trisomy 8
 trisomy 12
 translocations

• t(X;11)(q13;q23) (ARHGAP20 and BRWD3 genes disruption)

Clonal anomaly is found in about 50% of cases by chromosome analysis and in about 80% of CLL cases by fluorescence in situ hybridization (FISH) of interphase cell nuclei with a disease-specific comprehensive probe set.

The disease progression as assessed by the treatment-free interval for 17p deletion (n=23), 11q deletion (n=56), 12q trisomy (n=47), normal (n=57) and 13q deletion (single abnormality: n=117) were 9, 13, 33, 49, and 92 months respectively; and the survival probabilities were 32, 79, 114, 111 and 133 months respectively.

Complex karyotypes are found in 10%; unrelated clones demonstrating the existence of cells subpopulations are frequent findings in this disease.

Trisomy12, found in 15-20% [cytogenetics] or 16-25 % [FISH] of CLL cases has an unresolved pathogenic impact, and intermediate outcome. In other studies, trisomy 12 is an adverse prognostic factor (median survival: 5 yrs); found either as the sole anomaly, as an anomaly accompanied by others, or even as an accompanying (secondary) anomaly; present only in a subset of the malignant cell population; Trisomy 12 is found frequently in atypical lymphocyte morphology and CD5- cases, often with an increased number of prolymphocytes.

The most common deletion, del(13)(q14.3) found in 10-20% [cytogenetics] or 36-64% [FISH] CLL cases includes a nontranscribed gene and two micro-RNA genes. As the sole abnormality, has good prognosis. The disease free interval and overall survival is better than cases with normal karyotype because of slow disease progression.

Deletion 11q22-q23, involving ATM gene, is marked by lymphadenopathy and poor survival and is detected in 11-18% [FISH] of CLL cases.
Deletion 17p13 (p53) occurs in 7-8% [FISH] of CLL cases that are resistant to chemotherapy and have a short survival.

Although, 14q32 involvement was frequent in early CLL studies, currently, t(11;14)(q13;q32) with BCL1 / IgH rearrangement, is considered to be a hallmark of mantle cell lymphoma, similarly other rare 14q32 rearrangements such as CLL; t(14;19)(q32;q13), are associated with leukemic lymphoma. Therefore, translocations involving 14q32 IgH locus are probably diseases other than CLL. Eliminating t(11;14) and t(14;18), 14q32 rearrangements are found in about 4% of cases studied by FISH.

IgH deletion may be hetero- or homozygous. A 14q32 involvement is considered a good prognostic feature (median survival > 15 yrs) in CLL.

As in other B-cell chronic leukaemias or lymphomas; t(11;14)(q13;q32), typical of mantle cell lymphoma with BCL1 / IgH rearrangement, t(14;19)(q32;q13) with BCL3/IgH rearrangement, may be associated with short survival, t(2;14)(p13;q32), exceptional; and other t(14;var) may occasionally be found in CLL.
Other recurring anomalies are del(6q) [0-6% by FISH], +8q24 [5% by FISH], +3, and +18. Deletion 6q21 has a poor prognosis.

Immunochemistry

 CD20+ , CD5+ , CD23+

 Nota bene : Cyclin D1 / CCND1 can be expressed in CLL proliferation centers

• https://twitter.com/Gleason4plus5/status/740977055395893250

Molecular biology

ATM and P53 are deleted in 11q and 17p deletions, respectively.

Predisposition loci

Associations

 peripheral T-cell lymphoma (PTCL) (15223953)

Treatment

Binet staging is used for therapeutic intervention. The treatments options are: watchful waiting for symptoms, radiation therapy, chemotherapy, surgery such as splenectomy. Those being tested in clinical trails are monoclonal antibodies, chemotherapy with stem cell transplant.

Prognosis

Evolution: unrelated causes and disease-related infections are the 2 major causes of death ; others: autoimmune hemolytic anaemia and thrombocytopenia; transformation into Richter’s disease or into prolymphocytic leukaemia (in 10%).

Some patients with CLL survive for many years without therapy with minimal signs and symptoms, during the entire disease course and have a survival time similar to age-matched controls, whereas others have a rapidly deteriorating blood counts and organomegaly. Rai et al and Binet et al devised staging: less than 3 lymph nodes, HGB @<@10 g/dL, platelets 100 K/mm3): survival not reduced compared to age matched population; B (3 or more lymph nodes; HGB and platelets maintained): median survival of 5 yrs; C (Hb @<@ 10g/dL and/or platelets @<@100 K/mm3): median survival of 2 yrs; for assessing the extent of the disease to determine medical follow-up and treatment, but failed to predict the course of the disease in patients in whom CLL is diagnosed at an early stage.

Since more than 80% CLL are diagnosed at early disease stages, many prognostic markers have been identified. One of the most important molecular genetic markers defining pathogenic and prognostic subgroups of CLL is the mutation status of VH gene.

Surrogate markers for VH status are CD38 and ZAP-70 and their validity has yielded controversial results. Patients with few or no VH mutations or many CD38+ or ZAP-70+ B cells have an aggressive usually fatal course, whereas patients with mutated clones or few CD38+ or ZAP-70+ B cells have an indolent course.

Genomic aberrations are the other genetic parameter shown to be of prognostic relevance in CLL.

Gene mutations

 recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. (22158541)

Links

 AGCOH

Reviews

 Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005 Feb 24;352(8):804-15. PMID: 15728813

Links

 Mossafa H, Huret JL . Chronic lymphocytic leukaemia (CLL). Atlas Genet Cytogenet Oncol Haematol. August 1997 . URL : http://AtlasGeneticsOncology.org/Anomalies/CLL.html

 Reddy KS . Chronic lymphocytic leukaemia (CLL). Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Anomalies/CLL.html

References

 Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Quesada V, Conde L, Villamor N, Ordóñez GR, Jares P, Bassaganyas L, Ramsay AJ, Beà S, Pinyol M, Martínez-Trillos A, López-Guerra M, Colomer D, Navarro A, Baumann T, Aymerich M, Rozman M, Delgado J, Giné E, Hernández JM, González-Díaz M, Puente DA, Velasco G, Freije JM, Tubío JM, Royo R, Gelpí JL, Orozco M, Pisano DG, Zamora J, Vázquez M, Valencia A, Himmelbauer H, Bayés M, Heath S, Gut M, Gut I, Estivill X, López-Guillermo A, Puente XS, Campo E, López-Otín C. Nat Genet. 2011 Dec 11;44(1):47-52. PMID: 22158541

 Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, Escaramis G, Jares P, Beà S, González-Díaz M, Bassaganyas L, Baumann T, Juan M, López-Guerra M, Colomer D, Tubío JM, López C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernández JM, Puente DA, Freije JM, Velasco G, Gutiérrez-Fernández A, Costa D, Carrió A, Guijarro S, Enjuanes A, Hernández L, Yagüe J, Nicolás P, Romeo-Casabona CM, Himmelbauer H, Castillo E, Dohm JC, de Sanjosé S, Piris MA, de Alava E, San Miguel J, Royo R, Gelpí JL, Torrents D, Orozco M, Pisano DG, Valencia A, Guigó R, Bayés M, Heath S, Gut M, Klatt P, Marshall J, Raine K, Stebbings LA, Futreal PA, Stratton MR, Campbell PJ, Gut I, López-Guillermo A, Estivill X, Montserrat E, López-Otín C, Campo E. Nature. 2011 Jun 5;475(7354):101-5. PMID: 21642962

 Prognostic and therapeutic advances in CLL management: the experience of the French Cooperative Group. French Cooperative Group on Chronic Lymphocytic Leukemia. Seminars in hematology. 1987 ; 24 (4) : 275-290. PMID 3317854

 Karyotypes of 33 patients with clonal aberrations in chronic lymphocytic leukaemia. Review of 216 abnormal karyotypes in chronic lymphocytic leukaemia. Huret JL, Mossafa H, Brizard A, Dreyfus B, Guilhot F, Xue XQ, Babin P, Tanzer J. Annales de genetique. 1989 ; 32 (3) : 155-159. PMID 2817776

 Fluorescent in situ hybridization and cytogenetic studies of trisomy 12 in chronic lymphocytic leukemia. Escudier SM, Pereira-Leahy JM, Drach JW, Weier HU, Goodacre AM, Cork MA, Trujillo JM, Keating MJ, Andreeff M Blood. 1993 ; 81 (10) : 2702-2707. PMID 7683927

 Trisomy 12 in chronic lymphocytic leukemia detected by fluorescence in situ hybridization: analysis by stage, immunophenotype, and morphology. Que TH, Marco JG, Ellis J, Matutes E, Babapulle VB, Boyle S, Catovsky D. Blood. 1993 ; 82 (2) : 571-575. PMID 7687164

 Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias.
Criel A, Wlodarska I, Meeus P, Stul M, Louwagie A, Van Hoof A, Hidajat M, Mecucci C, Van den Berghe H. British journal of haematology. 1994 ; 87 (3) : 523-528. PMID 7993792

 The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH, Catovsky D. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1994 ; 8 (10) : 1640-1645. PMID 7523797

 National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O’Brien S, Rai KR. Blood. 1996 ; 87 (12) : 4990-4997. PMID 8652811

 Trisomy 12 in chronic lymphocytic leukaemia. Matutes E. Leukemia research. 1996 ; 20 (5) : 375-377. PMID 8683975

 Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Matutes E, Oscier D, Garcia-Marco J, Ellis J, Copplestone A, Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D. British journal of haematology. 1996 ; 92 (2) : 382-388. PMID 8603004

 Trisomy 12 is a rare cytogenetic finding in typical chronic lymphocytic leukemia.
Woessner S, Solˆ© F, Pˆ©rez-Losada A, Florensa L, Vilˆ° RM. Leukemia research. 1996 ; 20 (5) : 369-374. PMID 8683974

 Genes and chromosomes in chronic B-cell leukemia. Crossen PE. Cancer genetics and cytogenetics. 1997 ; 94 (1) : 44-51. PMID 9078290

 Genetic abnormalities in chronic lymphocytic leukemia and their clinical and prognostic implications. Dierlamm J, Michaux L, Criel A, Wlodarska I, Van den Berghe H, Hossfeld DK. Cancer genetics and cytogenetics. 1997 ; 94 (1) : 27-35. PMID 9078288

 Interphase cytogenetics in chronic lymphocytic leukemia. Garcia-Marco JA, Price CM, Catovsky D. Cancer genetics and cytogenetics. 1997 ; 94 (1) : 52-58. PMID 9078291

 Chromosome aberrations in B-cell chronic lymphocytic leukemia: reassessment based on molecular cytogenetic analysis. Dˆ hner H, Stilgenbauer S, Dˆ hner K, Bentz M, Lichter P. Journal of molecular medicine (Berlin, Germany). 1999 ; 77 (2) : 266-281. PMID 10023780

 Genomic aberrations and survival in chronic lymphocytic leukemia. Dˆ hner H, Stilgenbauer S, Benner A, Leupolt E, Krˆ ber A, Bullinger L, Dˆ hner K, Bentz M, Lichter P The New England journal of medicine. 2000 ; 343 (26) : 1910-1916. PMID 11136261

 Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia. Dewald GW, Brockman SR, Paternoster SF, Bone ND, O’Fallon JR, Allmer C, James CD, Jelinek DF, Tschumper RC, Hanson CA, Pruthi RK, Witzig TE, Call TG, Kay NE. British journal of haematology. 2003 ; 121 (2) : 287-295. PMID 12694251

 Chronic lymphocytic leukemia. Byrd JC, Stilgenbauer S, Flinn IWHematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2004 : 163-183. PMID 15561682

 Molecular genetics and its clinical relevance. Stilgenbauer S, Dˆ hner H. Hematology/oncology clinics of North America. 2004 ; 18 (4) : 827-848. PMID 15325701

 Chronic lymphocytic leukemia. Chiorazzi N, Rai KR, Ferrarini M The New England journal of medicine. 2005 ; 352 (8) : 804-815. PMID 15728813