B-cell prolymphocytic leukemia (B-PLL) is a disorder characterized by proliferation of neoplastic B prolymphocytes in the peripheral blood, bone marrow and spleen (Campo E et al, 2008) which represent, by definition, more than 55% of lymphoid cells. B-PLL is not the transformation of chronic lymphocytic leukemia, as previously thought, and it represents a distinct biological entity as shown by the analysis of gene expression profiles, which show an overexpression of genes related to cell cycle, cell metabolism and adhesion (Del Giudice I et al, 2009)PubMed .

 

Epidemiology

B-PLL represents less than 1% of mature leukemic disorders and is therefore a very rare entity. The median age of onset is 65-69 years, with an equal distribution between males and females (Dungarwalla M et al, 2008)PubMed.

 

Clinical and laboratory characteristics

Typically, B-PLL patients complain of B systemic symptoms (fever, night sweats and weight loss), with important splenomegaly and no significant adenopathy. The leukocyte count generally exceeds 100 x 10^9/l with a majority (more than 55% but often over 90%) of prolymphocytes. In 50% of cases anemia and thrombocytopenia secondary to bone marrow infiltration are present. A monoclonal serum component is frequently observed (Campo E et al, 2008; Del Giudice I et al, 2009PubMed; Dungarwalla M et al, 2008PubMed).

 

Cell morphology, immunophenotype and genetic of prolymphocytes

In the peripheral blood prolymphocytes appear as large cells (Figure I) with round nucleus with moderately condensed chromatin and a prominent nucleolus in a central position and with a nucleus-cytoplasmic ratio lower than that of CLL and T-cell prolymphocytic leukemia cells. The cytoplasm is relatively abundant and weakly basophilic (Dungarwalla M et al, 2008PubMed).

 

CUNEO_B-CELL_PROLYMPHOCYTIC_LEUKEMIA_FIGURE_

Figure I: Prolymphocyte (to the right)

 

In the bone marrow a nodular or interstitial infiltration of lymphoid cells with an intertrabecular distribution is present (Campo E et al, 2008). The spleen is characterized by an expansion of the white and red pulp while lymph nodes have a vaguely nodular aspect without proliferation centers that however are present in CLL.
Immunophenotypically, prolymphocytes express bright surface immunoglobulin (IgM +/- IgD) and B cell antigens (CD19, CD20, CD22, CD79a/b and FMC7). CD5 and CD23 are present in 30% of cases and 20% of patients, respectively. In those cases with CD5/CD323 negativity the differential diagnosis between B-PLL and mantle cell lymphoma in the leukemic phase may be difficult. ZAP70 and CD38 are expressed in about half the cases, but their expression does not correlate with the mutational status of the immunoglobulin genes. The immunoglobulin genes are clonally rearranged with a non-mutated configuration of the IGHV genes in about half the cases. B-PLL mostly uses the VH3 (68%) and VH4 (32%) members of gene families with genes V3-23, V4-59 and V4-34 represented in more than 50% of cases regardless of the mutational status (Del Giudice I et al, 2006)PubMed.

 

Cytogenetics

The cases with t(11;14) which in the past represented up to 20% of B-PLL must be considered variants of mantle cell lymphoma (Ruchlemer R et al, 2004)PubMed . In most B-PLL patients the karyotype is complex and involves in about half the cases del(17p) and TP53 mutations. Del13q is identified by FISH in 27% of patients, while trisomy of chromosome 12 is rare (Lens D et al, 1999PubMed ; Solé F et al, 1998PubMed ).

 

Therapy, prognosis, predictive factors

As for CLL, treatment is not indicated in the rare asymptomatic patients. In most patients, however, the disease is rapidly progressive. The most used therapy schemes are: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) (Shvidel L et al, 1999)PubMed, purine analogs (fludarabine, pentostatin, cladribine) (Kantarjian HM et al, 1991PubMed ; Döhner H et al, 1993PubMed ; Saven A et al, 1997PubMed ; Herold M et al, 2003), bendamustine-mitoxantrone-rituximab (Weide R et al, 2004)PubMed, alemtuzumab (Bowen AL et al, 1997)PubMed.
Response to treatment is generally poor and the median survival is 30-50 months. ZAP70, CD38, del17p and mutational status, unlike for CLL, do not represent prognostic factors that correlate with survival (Del Giudice I et al, 2009)PubMed.

 

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