B cell prolymphocytic leukemia

INTRODUCTION — B cell prolymphocytic leukemia (B-PLL) is a very rare B cell neoplasm comprised of so-called prolymphocytes, typically with involvement of the peripheral blood, bone marrow, and spleen. The name "prolymphocyte" is actually a misnomer, as the tumor cells in this disease are mature activated B cells. By definition, these prolymphocytes comprise greater than 55 percent of the cells in the blood and bone marrow.

The epidemiology, clinical presentation, pathology, diagnosis, and treatment of B-PLL are discussed here.

EPIDEMIOLOGY — B-PLL is an extremely rare disease, comprising far less than 1 percent of B cell leukemias [1]. Its rarity has become increasingly apparent as advances in diagnostic criteria have refined the diagnosis of B-PLL and excluded cases of mantle cell lymphoma, atypical chronic lymphocytic leukemia (CLL), and CLL with prolymphocytic progression (defined as greater than 15 percent prolymphocytes) [2,3].

B-PLL mainly affects older adults with a mean age at presentation of between 65 and 70 years [4]. Males and females appear to be equally affected [1]. The vast majority of patients are White individuals.

CLINICAL FEATURES — Patients typically present with a rapidly rising white blood cell count, often >100,000/microL, and massive splenomegaly; anemia and thrombocytopenia are present in approximately 65 and 35 percent of cases, respectively [2,5]. Systemic B symptoms (ie, fevers, night sweats, weight loss) are common. If present, peripheral lymphadenopathy is not prominent. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

PATHOLOGY

Morphology

Peripheral blood and bone marrow — By definition, more than 55 percent of the circulating cells in the peripheral blood are prolymphocytes; more typically, the percentage of prolymphocytes is greater than 90 percent. Peripheral blood prolymphocytes are medium-sized cells (approximately twice the size of a small lymphocyte), with moderately condensed chromatin and a single, prominent vesicular nucleolus (picture 1). The nucleus is typically round or oval, and the cytoplasm is usually moderately abundant and slightly basophilic [6,7]. The bone marrow is infiltrated in an interstitial or nodular pattern by similar cells (picture 2).

Other tissues — B-PLL is only rarely diagnosed in tissues other than the blood and bone marrow [2].

●The spleen shows extensive white and red pulp infiltration by prolymphocytes [4,8-10] morphologically similar to those seen in the blood and bone marrow (picture 3).

●Involved lymph nodes may show vague nodularity, but the proliferation centers (pseudofollicles) seen in CLL are absent [4,8-10].

Immunophenotype — B-PLL is a tumor of monoclonal B cells that typically express bright surface IgM +/- IgD, bright surface Ig kappa or lambda light chain, bright CD20, and CD19, CD22, CD79a, and FMC7 (table 1). This is in contrast to chronic lymphocytic leukemia (CLL), which generally has dim expression of surface Ig and CD20. ZAP-70 and CD38 are expressed in about 50 percent of cases, while CD5 and CD23 are expressed in about one-third of cases.

CD38 and ZAP-70 do not have prognostic significance [11]. Helping to distinguish B-PLL from lymphoproliferative disorders other than CLL/small lymphocytic leukemia (SLL) is the absence of expression of CD11c, CD103, CD10, CD25, and cyclin D1 [5].

Genetic features — Genetic changes are common in B-PLL, but none are specific. Most cases have a complex karyotype (≥3 abnormalities) [12].

Abnormalities of MYC (rearrangements or increased copy number) are seen in approximately 60 percent of cases and are associated with a more aggressive clinical behavior [12].

Deletions of 17p (the chromosomal arm that carries the TP53 gene) and TP53 mutations are found in approximately 40 percent [12,13].

Other abnormalities include trisomy 18 and del13q (approximately 30 percent each), and trisomy 3 and deletion 8p (approximately 25 percent each) [12,14,15].

Mutations have also been found in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1.

The leukemic variant of mantle cell lymphoma can be confused morphologically with B-PLL but is readily distinguished by the presence of t(11;14)(q13;q32) involving the cyclin D1 gene [16]. As such, it is important to exclude this translocation, either by cytogenetic testing or by immunohistochemical staining for cyclin D1, in cases of suspected B-PLL. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Immunoglobulin genes are clonally rearranged, and in approximately half of cases demonstrate somatic hypermutation [2]. Although not used in routine practice, the gene expression profile of B-PLL is different from that of CLL and displays over-expression of MYC and AKT [17].

DIAGNOSIS — The diagnosis of B-PLL is usually made based on the results of immunophenotypic and genetic analysis of the peripheral blood. Results of bone marrow biopsy and aspirate can confirm these findings but are often available only after the peripheral blood analysis. When the white blood cell count is elevated and an evaluation of the peripheral blood and bone marrow is consistent with B-PLL, lymph node biopsy rarely adds additional information and is not necessary. Splenectomy can be diagnostic in patients with an unclear presentation and an enlarged spleen.

By definition, prolymphocytes must exceed 55 percent of lymphoid cells in the peripheral blood. By flow cytometry, these cells demonstrate a characteristic immunophenotype with light chain restriction, bright surface immunoglobulin, and the expression of B cell antigens (eg, CD20, CD22, FMC7, CD79a). CD5 and CD23 expression is usually weak or absent. CD11c, CD103, CD10, and CD25 are not expressed. (See 'Immunophenotype' above.)

It is important to exclude the leukemic variant of mantle cell lymphoma associated with the t(11;14)(q13;q32), which can be done by conventional cytogenetics, fluorescence in situ hybridization (FISH), or by immunohistochemical stains for cyclin D1. (See 'Genetic features' above.)

Disagreements among hematopathology groups have led to two new classification systems, the International Consensus Classification (ICC) [18] and the World Health Organization (WHO) classification, 5^th edition [3], which handle B-PLL differently. The ICC maintains B-PLL as a unique entity, as in the 4^th edition of the WHO classification, whereas the 5^th edition of the WHO classification lumps B-PLL and hairy cell leukemia variant together in a new provisional entity, "splenic B-cell lymphoma/leukemia with prominent nucleoli". We favor the ICC approach, particularly because B-PLL and hairy cell leukemia variant have different underlying genetic drivers and can be distinguished by morphologic and immunophenotypic criteria in most cases.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of B-PLL includes other chronic lymphoid neoplasms with a leukemic presentation (table 2). They are described in more detail below.

T cell prolymphocytic leukemia — T cell prolymphocytic leukemia (T-PLL) has a similar clinical presentation and morphologic appearance to B-PLL, but unlike B-PLL expresses one or more T cell antigens (CD2, CD3, CD7, CD52) and lacks B cell antigens. (See "Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia".)

Chronic lymphocytic leukemia — Both B-PLL and chronic lymphocytic leukemia (CLL) can present with lymphocytosis, splenomegaly, and circulating prolymphocytes in the blood, but in CLL prolymphocytes comprise less than 55 percent of the cells, whereas in most cases of B-PLL greater than 90 percent of the cells are prolymphocytes (table 2). Compared with typical CLL cells, prolymphocytes are larger cells with somewhat immature-appearing nuclear chromatin, a prominent nucleolus, and a moderate amount of slightly basophilic cytoplasm (picture 1). While prolymphocytes are seen in variable numbers in CLL, they by definition make up 55 percent or less of the circulating cells and usually comprise fewer than 10 percent. In addition, in two-thirds of cases of B-PLL the prolymphocytes are CD5 negative, whereas as a rule the prolymphocytes of CLL are CD5 positive (table 1). (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Patients with peripheral blood prolymphocyte counts between 10 and 55 percent have been designated as having chronic lymphocytic leukemia/prolymphocytic leukemia in the past, but this entity has been eliminated in the World Health Organization classification of lymphoid neoplasms [2,19,20]. Rarely, cases of CLL can undergo prolymphocytoid transformation. In such cases, the peripheral blood will contain a mixture of small mature CLL cells and prolymphocytes. The prolymphocytes in such cases usually have an immunophenotype similar to that seen with typical CLL, although sometimes with higher levels of surface Ig. In contrast, circulating cells in de novo B-PLL are monomorphic prolymphocytes with an immunophenotype characteristic of B-PLL as described above. In addition, histologic and immunophenotypic findings on bone marrow biopsy in cases of CLL with prolymphocytoid transformation are consistent with those found in CLL (eg, proliferation centers, expression of CD5 and CD23). (See 'Immunophenotype' above and "Pathobiology of chronic lymphocytic leukemia", section on 'Prolymphocytoid transformation'.)

Mantle cell lymphoma — Mantle cell lymphoma (MCL) can have a leukemic phase that mimics B-PLL and gene expression profiling suggests that B-PLL and leukemic MCL have similar patterns of gene expression [21]. As in a subset of B-PLLs, MCL cells co-express CD5 and CD20. However, the neoplastic cells of MCL express cyclin D1, which is dysregulated by a (11;14) translocation involving the cyclin D1 gene. SOX11 expression is usually present in the rare cases of MCL that do not express cyclin D1. In contrast, the malignant cells in PLL are negative for cyclin D1 and do not demonstrate t(11;14). (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Follicular lymphoma — On rare occasions, follicular lymphoma can have a leukemic phase, but this usually does not present a diagnostic dilemma, as the circulating tumor cells in typical cases are centrocytes with highly irregular or cleaved nuclear contours that by flow cytometry express CD10 and are CD5 negative (table 1). (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Lymphoplasmacytic lymphoma — Lymphoplasmacytic lymphoma (LPL), a tumor that is commonly associated with Waldenstrom macroglobulinemia, occasionally involves the peripheral blood. However, the circulating malignant cells of LPL often have a plasmacytoid appearance and are usually few in number, whereas B-PLL is usually associated with white blood cells of over 100,000 cells/microL. Moreover, B-PLL is not associated with a significant level of paraproteinemia, whereas this is typical of patients with LPL. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)

Hairy cell leukemia variant — The International Consensus Classification (ICC) classifies B-PLL and hairy cell leukemia variant (HCL-variant) as distinct mature B cell neoplasms [18], whereas the World Health Organization 5^th edition combines these into one provisional entity called "splenic B-cell lymphoma/leukemia with prominent nucleoli" [3]. We favor the ICC approach of maintaining B-PLL and HCL-variant as distinct entities.

HCL-variant exhibits morphologic features intermediate between hairy cells and prolymphocytes. Such cases may also have extreme leukocytosis, splenomegaly, and expression of the interleukin-2 receptor beta chain, but not the alpha chain (CD25). Unlike B-PLL, most cases of HCL-variant express CD103 (table 1). HCL-variant is also frequently associated with activating mutations in the MAP2K1 gene, which has not been reported in B-PLL, and unlike in B-PLL, aberrations in MYC and TP53 are infrequent in HCL-variant. (See "Clinical features and diagnosis of hairy cell leukemia", section on 'HCL variant'.)

Splenic marginal zone lymphoma — Both splenic marginal zone lymphoma (MZL) and B-PLL can present with splenomegaly and peripheral blood lymphocytosis. When compared with splenic MZL, B-PLL is more likely to present with clinically aggressive disease, B symptoms, and extreme leukocytosis (>100,000/microL). While the circulating lymphocytes in B-PLL usually have a regular, smooth cytoplasmic outline, splenic MZL cells usually have short polar villi, although this may be masked by poor slide preparation. Both B-PLL and splenic MZL express CD20 and bright surface Ig. Neither typically expresses CD5. Expression of CD22 is usually strong in B-PLL and variable in MZL. Both MZL and B-PLL involve both the splenic white pulp and red pulp, but in MZL marginal zones are usually prominent due to expansion by cells with abundant pale cytoplasm, and plasmacytic differentiation may also be observed, features that are absent in B-PLL. Bone marrow morphology in MZL may take the form of reactive-appearing follicles surrounded by marginal zone B cells, features that are not seen in B-PLL. In difficult cases, pathologic evaluation of the bone marrow, spleen, and hilar lymph nodes may be used in concert to determine the most likely diagnosis. Mutational testing may also be helpful, as the most commonly mutated genes in MZL, such as NOTCH2 and components of the NF-kB signaling pathway, have not been reported as being mutated in B-PLL. (See "Splenic marginal zone lymphoma".)

TREATMENT

Indications for and goals of therapy — The clinical course of B-PLL is variable, and therapy may be initially deferred in the rare asymptomatic patient without complications [22]. Treatment is indicated in patients with a rapidly rising white blood cell count, massive splenomegaly, anemia, thrombocytopenia, and/or systemic B symptoms (ie, fevers, night sweats, unintentional weight loss, extreme fatigue).

Patients are not cured with conventional treatment, which focuses on alleviation of symptoms, reversal of cytopenias, and improvement of quality of life. Select younger patients may be candidates for allogeneic hematopoietic cell transplantation (HCT), which offers the chance of cure. Clinical trials are evaluating the role of chimeric antigen receptor modified T cells in B-PLL and related malignancies.

Management — While there is limited data to guide therapy, B-PLL is most commonly treated with regimens used for chronic lymphocytic leukemia (CLL). While responses to these regimens have been reported, they are most frequently partial responses, and rarely durable. Individual regimens have not been directly compared, and a choice among them is made largely based on drug access, side effect profiles, and the presence of high-risk genetic features (ie, deletion 17p or TP53 mutations). The use of these regimens in CLL is discussed separately. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Treatment of relapsed or refractory chronic lymphocytic leukemia".)

The following reflects our general approach to management:

●For most patients, we offer initial treatment with a Bruton tyrosine kinase (BTK) inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib) given continuously until relapse or a time-limited therapy such as venetoclax plus obinutuzumab. None of these treatments are specifically licensed or approved for B-PLL. Data in B-PLL are largely limited to case reports or series [23-27]. Administration uses the same protocols safety measures as in CLL/SLL. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Specific therapies'.)

●If these therapies are not available, those without deletion 17p or TP53 mutation may respond to combination chemotherapy with fludarabine, cyclophosphamide, rituximab (FCR) or bendamustine rituximab (BR). Single agent rituximab may provide useful palliation for patients unfit to receive chemotherapy who do not have access to BTK inhibitors or other novel agents [28]. Alemtuzumab is available for compassionate use and is an option for patients with deletion 17p or TP53 mutations who do not have access to novel agents [29,30].

●Younger, fit patients who have responded to initial therapy, are evaluated for allogeneic HCT as prognosis in B-PLL is not as favorable as in CLL [31-33]. HCT is also considered for patients with poor or short-lived responses to initial therapy and for those who have deletion 17p or TP53 mutations. Clinical trials are evaluating the role of chimeric antigen receptor modified T cells.

●Relapsed and/or refractory disease is managed with serial therapies similar to those used for CLL. These include small molecule inhibitors of BCR signaling (eg, BTK inhibitors, idelalisib) and of BCL2 signaling (eg, venetoclax). Again, data in B-PLL are largely limited to case reports or series [23-27]. As an example, in a small series of idelalisib plus rituximab in B-PLL, responses were seen in all five patients, lasting more than six months at the time of the report [34]. Anti-CD20 monoclonal antibodies (eg, rituximab, ofatumumab, and obinutuzumab), splenectomy [35], and splenic irradiation [36] may provide effective palliation in selected cases.

Importantly, when administering BR for B-PLL, infusion reactions to rituximab are more common and can be more severe in cycle 1, especially in patients with very high white blood cell (WBC) counts. Infusion reactions can also be seen with bendamustine. Many protocols used for B-PLL follow a different administration schedule for cycle 1 to avoid giving full dose rituximab and bendamustine on the same day. One option is to administer rituximab as a single agent on the first one to two days of cycle 1 (ie, split dose over two days if WBC >25,000/microL), and to administer bendamustine on the following two days. A second option is to administer 50 mg/m² of rituximab on the first day of cycle 1, followed by the remainder of the dose (325 mg/m²) on day 3, and to give bendamustine on days 1 and 2. These adjustments during cycle 1 improve safety and do not appear to have a negative impact on disease response. By cycle 2, the WBC count will have declined dramatically in most patients and the remainder of the cycles are administered with full dose rituximab and bendamustine on day 1, followed by bendamustine alone on day 2. Similar adjustments are often made when administering other treatment regimens, such as FCR.

Given the rarity of B-PLL, there is a paucity of data evaluating these treatment options in the published literature and much of our approach is extrapolated from trials in CLL. Reports from the pre-rituximab era suggest that chlorambucil alone is not very effective in B-PLL, and combination regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) result in partial responses in up to one-third of cases [22]. Slightly higher response rates have been reported in case reports and small series of purine analogs such as fludarabine [37], cladribine [38], and pentostatin [39], used alone and in combinations. As with other CD20-positive hematologic malignancies, the incorporation of rituximab appears to increase response rates and deepen the level of response [28]. Combinations of rituximab with fludarabine or bendamustine together with an anthracycline (mitoxantrone or epirubicin) (FMR, FER, and BMR) have been reported to have significant activity in B-PLL [40-42].

PROGNOSIS — B-PLL is a heterogeneous disorder. Some cases have an aggressive course and others are more indolent. It has been difficult to determine prognostic markers for patients with B-PLL because it is such a rare tumor and because previous reports contained not only patients with B-PLL but also patients with T cell prolymphocytic leukemia and mantle cell lymphoma.

Among patients with B-PLL, prognostic features that suggest a poor outcome include anemia, thrombocytopenia, advanced age, MYC abnormalities, and the presence of TP53 mutations [5,12,43]. Unlike in patients with chronic lymphocytic leukemia, neither ZAP-70 expression, nor immunoglobulin heavy chain gene mutations, nor CD38 expression, appears to act as prognostic markers [11].

One prognostic model uses MYC abnormality (translocation or gain) and 17p deletion to risk stratify patients with B-PLL [12]. This model is based on a retrospective analysis of 34 patients with B-PLL that reported a median overall survival (OS) of 10 years for the population as a whole. Median OS was not reached for the eight patients without MYC abnormalities. Among those with MYC abnormalities, median OS was 126 months and 11 months for those without and with del17p, respectively. These results suggest that presence of both abnormalities identifies a high-risk subgroup with aggressive disease.

SUMMARY

●Clinical presentation – B cell prolymphocytic leukemia (B-PLL) is a rare B cell neoplasm comprised of prolymphocytes, typically with involvement of the peripheral blood, bone marrow, and spleen. It is most common in older adult White individuals. (See 'Epidemiology' above.)

Patients typically present with a rapidly rising white blood count >100,000/microL and massive splenomegaly with or without B symptoms (ie, fevers, night sweats, weight loss). If present, peripheral lymphadenopathy is not prominent. (See 'Clinical features' above.)

●Diagnosis – The diagnosis is usually made by bone marrow biopsy and aspirate with flow cytometry and genetic studies. By definition, prolymphocytes must exceed 55 percent of lymphoid cells in the peripheral blood. These cells express pan-B cell markers and high levels of surface immunoglobulin, and are CD5 negative in two-thirds of cases and almost always negative for CD10 (table 1). Cases of mantle cell lymphoma masquerading as B-PLL must be excluded, particularly in suspected B-PLL cases that express CD5. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of B-PLL includes other chronic lymphoid neoplasms with a leukemic presentation (table 2). (See 'Differential diagnosis' above.)

●Management – B-PLL is commonly treated with agents used for chronic lymphocytic leukemia. Individual regimens have not been directly compared, and a choice is made largely based upon the side effect profile and the clinician's experience with the regimen. (See 'Treatment' above.)

●Prognosis – B-PLL is a heterogeneous disorder. Some cases have an aggressive course and others are more indolent. Prognostic markers have been difficult to determine, but anemia, thrombocytopenia, advanced age, MYC abnormalities, and the presence of TP53 mutations appear to predict a poor outcome. (See 'Prognosis' above.)