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B-cell Prolymphocytic Leukemia

Written2021-02Elise Chapiro, Florence Nguyen-Khac
Cytogénétique Hématologique, Service d'Hématologie Biologique, Hpital Pitié-Salpêtrière, APHP,.Sorbonne Université. Centre de Recherche des Cordeliers, INSERM UMRS_1138, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, Paris, France elise.chapiro@aphp.fr; florence.nguyen-khac@psl.aphp.fr

Abstract B-cell prolymphocytic leukemia (B-PLL) is a very rare mature B-cell leukemia occurring in elderly people diagnosed when prolymphocytes comprise more than 55% of the lymphoid cells in peripheral blood. A complex karyotype, MYC gene abnormalities (translocation or more rarely gain/amplification) and 17p deletion including TP53 are frequent. The prognosis is poor.

Keywords B-cell prolymphocytic leukemia, B prolymphocytes, complex karyotype, MYC, 17p deletion, TP53

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9833/3 B-cell prolymphocytic leukaemia
Atlas_Id 2033
Note This paper is an update of B-cell prolymphocytic leukemia (B-PLL) (published in 1998)

Clinics and Pathology

Phenotype / cell stem origin There is no specific immunologic marker. The B-PLL cells strongly express surface IgM/lgD, CD19, CD20, CD22, CD79a, CD79b, and FMC7. CD5 is expressed in more than half of cases, CD23 in 20-30%, and CD200 is weakly positive or negative.
Epidemiology Very rare. Accounting for <1% of lymphocytic leukemias. The median age at diagnosis is 65-72 years, the M:F ratio is equal. The majority of cases occurs de novo, but B-PLL secondary to chronic lymphocytic leukemia (CLL) or more rarely marginal zone lymphoma exist.
Clinics B symptoms, marked splenomegaly, no or minimal lymphadenopathy, rapidly increasing lymphocyte count, usually >100x109/L.
Cytology Prolymphocytes must represent more than 55% of lymphoid cells in peripheral blood. Prolymphocytes are medium-sized lymphoid cells with a round nucleus, moderately condensed nuclear chromatin, a prominent central nucleolus, and basophilic cytoplasm.
 
Figure 1. Courtesy F. Nguyen-Khac
Treatment No consensus of treatment. Like in CLL, first-line treatment was classically based on the presence of a TP53 aberration. Chemo-immunotherapy can be proposed in patients devoid of TP53 abnormality. In patients harboring a TP53 aberration, alemtuzumab has been used. Now, targeted therapies such as BCR pathway inhibitors (such as ibrutinib) or BCL2 inhibitors (like venetoclax) are interesting options that need evaluation. Allogeneic transplant should be considered in the rare younger patients.
Evolution Variable clinical course. A median OS of 3 years was reported; however this was prior to the advent of immunotherapy and targeted therapies. A more recent study of 34 B-PLL reported a median overall survival of 125 months.
Prognosis The prognosis of B-PLL is poor. Three distinct cytogenetic risk groups are described: low-risk (no MYC aberration), intermediate-risk (MYC aberration but no del17p), and high-risk (MYC aberration and del17p).

Genetics

 
Figure 2. R-banded complex karyotype: t(8;22)(q24;q11) juxtaposing MYC and IGL genes loci, trisomy 12 and trisomy 18 (Courtesy F. Nguyen-Khac and E. Chapiro)
 
Figure 3. FISH analysis with a IGL(green)/MYC(red) probe (CYTOTEST) showing a t(8;22)(q24;q11) with IGL/MYC juxtaposition. (Courtesy F. Nguyen-Khac and E. Chapiro)
 
Figure 4. FISH analyses with a MYC break-apart probe. A and B. Gain of two copies of MYC resulting from multiple unbalanced translocation. C . Interphasic FISH: gain of one copy of MYC. (Courtesy F. Nguyen-Khac and E. Chapiro)

Cytogenetics

Cytogenetics Morphological There is no specific chromosomal abnormality. The karyotype is complex (≥3 abnormalities) in 3/4 of the patients and highly complex (>5 abnormalities) in almost half of cases. The most frequent chromosomal aberration is a translocation involving MYC (62%) and one of the immunoglobulin genes loci ( IGH, IGK or IGL). MYC gain or amplification is observed in 15% of cases. MYC gain/amplification is mainly subclonal and/or overlooked as part of a complex karyotype. Overall, 3/4 of cases have a MYC abnormality, MYC translocation and MYC gain being mutually exclusive. The other recurrent abnormalities are deletion ( del(17p)) involving the TP53 gene (38%), trisomy 18 (30%), del(13q) (29%), trisomy 3 (24%), trisomy 12 (24%), and del(8p) (23%).
Note: Cases of lymphoid proliferations with relatively similar morphology but with a t(11;14)(q13;q32) (IGH/ CCND1) translocation (or rare translocations involving CCND2 (12p13) and CCND3 (6p21) are leukemic forms of mantle cell lymphoma.

Genes involved and Proteins

Note Next generation sequencing
The most frequently mutated genes by whole exome sequencing in a series of 16 patients were: TP53 (38%, associated with del17p), MYD88 (25%), BCOR (25%), MYC (19%), SF3B1 (19%), SETD2 (12%), CHD2 (12%), CXCR4 (12%), and BCLAF1 (12%).
Mutations
IGHV analysis: the majority of B-PLL uses the IGHV3 or IGHV4 subgroups and displayed significantly mutated IGHV genes.

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Citation

This paper should be referenced as such :
Chapiro E, Nguyen-Khac F
B-cell Prolymphocytic Leukemia;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/BPLLID2033.html



Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

Genes CCND1 IGH ABCC1



External links

arrayMap (UZH-SIB Zurich)Morph ( 9833/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
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