# B-cell prolymphocytic leukemia
**B-cell prolymphocytic leukemia** (B-PLL) is a rare, aggressive mature B-cell neoplasm characterized by clonal proliferation of B-prolymphocytes, with prolymphocytes constituting more than 55% of the lymphoid cells in the peripheral blood.[1](https://www.orpha.net/en/disease/detail/86852) Patients are usually older and present with a rapidly increasing lymphocyte count, massive splenomegaly, minimal or absent lymphadenopathy, anemia, thrombocytopenia, and often [B symptoms](https://www.edgepedia.org/b-symptoms); therapy response is poor.[1](https://www.orpha.net/en/disease/detail/86852) The disease was first described in 1974 as an aggressive variant of chronic lymphocytic leukemia (CLL) and was recognized as a separate entity by the World Health Organization (WHO) classification in 2001.[2](https://haematologica.org/article/view/9795)
| Key fact | Detail |
|---|---|
| Definition | Mature B-cell neoplasm with more than 55% prolymphocytes among peripheral blood lymphoid cells; IG genes are clonally rearranged[1](https://www.orpha.net/en/disease/detail/86852) |
| Rarity | Less than 1% of all lymphoid leukemias, with around 120 cases per year in the United States[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/) |
| Typical presentation | Older patients, high leukocyte count, splenomegaly, minimal or absent lymphadenopathy, aggressive course[4](https://www.nature.com/articles/s41375-022-01764-1) |
| Cytogenetics | Complex karyotype (3 or more abnormalities) in 73% of patients; translocations involving MYC in 62%, del17p in 38%, trisomy 18 in 30%[5](https://pubmed.ncbi.nlm.nih.gov/31527074/) |
| Survival | Median overall survival 2.8 years in a 950-patient US registry cohort; median survival of 3 to 5 years reported despite treatment[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC13132662/) • [7](https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15912) |
| Classification status | Deleted as an entity in the WHO 5th edition (absorbed in part into splenic B-cell lymphoma/leukemia with prominent nucleoli); retained as a definite entity in the International Consensus Classification[4](https://www.nature.com/articles/s41375-022-01764-1) |
| Treatment | Managed with regimens used for CLL, such as ibrutinib and rituximab, tailored to the individual[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/) |
## Clinical presentation
B-PLL usually occurs in older patients and is characterized by a high leukocyte count with more than 55% prolymphocytes, splenomegaly, minimal or absent lymphadenopathy, and an aggressive course.[4](https://www.nature.com/articles/s41375-022-01764-1) The prolymphocyte count usually exceeds 90% of lymphoid cells in B-PLL, compared with less than 11% in CLL and 11 to 55% in CLL with prolymphocytoid features, and the count must be computed on peripheral blood rather than bone marrow.[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC8101659/) The neoplastic cells are large lymphocytes with somewhat immature-appearing nuclear chromatin, a prominent vesicular nucleolus, and abundant cytoplasm, and lymphocytosis is usually more than 100 × 109/L.[9](https://www.ncbi.nlm.nih.gov/books/NBK13314/)
## Diagnosis and differential diagnosis
The diagnosis is usually made from immunophenotypic and genetic analysis of peripheral blood, generally with a bone marrow biopsy and aspirate, flow cytometry, and cytogenetic studies; a splenectomy can be diagnostic when the presentation is unclear.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/) By flow cytometry the cells show a nonspecific B-cell immunophenotype with light chain restriction, bright surface immunoglobulin, and expression of B-cell antigens. CD5 and CD23 are usually absent but can be weakly expressed, while CD11c, CD103, CD10, and CD25 are not expressed.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/)
**Exclusion of mimics is central.** Because B-PLL overlaps with other splenic B-cell leukemias, the differential diagnosis includes mantle cell lymphoma with leukemic involvement, CLL with prolymphocytes, hairy cell leukemia and its variant, and splenic marginal zone lymphoma.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/) According to the International Consensus Classification (ICC), B-PLL should be diagnosed only when there is no prior history of B-CLL (ruling out CLL that has progressed to B-PLL), when cyclin D1 and SOX11 are absent (ruling out mantle cell lymphoma), and when hairy surface projections and intrasinusoidal bone marrow infiltration are not present (ruling out [hairy cell leukemia variant](https://www.edgepedia.org/hairy-cell-leukemia-variant) and splenic marginal zone lymphoma).[4](https://www.nature.com/articles/s41375-022-01764-1) [Diagnosis](https://www.edgepedia.org/diagnosis) remains challenging in the absence of a clear immunophenotypic or cytogenetic signature.[10](https://pubmed.ncbi.nlm.nih.gov/28324286/)
## Classification history
B-PLL was initially described in 1974 as an aggressive variant of CLL.[2](https://haematologica.org/article/view/9795) It was recognized as a separate entity by the WHO classification in 2001.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC11700275/) In the 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5), published in 2022, B-PLL was deleted as an entity, being regarded as a heterogeneous category that includes cases of hairy cell leukemia variant, leukemic mantle cell lymphoma, and CLL/SLL progressed to B-PLL; these cases were absorbed in part into the new entity splenic [B-cell lymphoma](https://www.edgepedia.org/b-cell-lymphoma)/leukemia with prominent nucleoli (SBLPN), which also includes hairy cell leukemia variant.[4](https://www.nature.com/articles/s41375-022-01764-1) Cases previously classified as B-PLL that show CD5 expression are classified as prolymphocytic progression of CLL/SLL in WHO-HAEM5.[12](https://onlinelibrary.wiley.com/doi/10.1111/bjh.19754) The ICC, by contrast, still regards B-PLL as a definite entity under the restrictive criteria above.[4](https://www.nature.com/articles/s41375-022-01764-1)
## Genetics
Cytogenetic and molecular assessment of 34 patients with B-PLL showed a complex karyotype (3 or more abnormalities) in 73% and a highly complex karyotype (5 or more abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC (62%), deletion of 17p (38%), trisomy 18 (30%), del13q (29%), trisomy 3 (24%), trisomy 12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) had an MYC aberration, resulting from mutually exclusive translocations or gains.[5](https://pubmed.ncbi.nlm.nih.gov/31527074/) Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1, and the majority of cases used the IGHV3 or IGHV4 subgroups (89%) with significantly mutated IGHV genes (79%).[5](https://pubmed.ncbi.nlm.nih.gov/31527074/) An earlier series of six cases found MYC aberrations in five, with high MYC protein expression in all tested cases bearing such aberrations.[13](https://pubmed.ncbi.nlm.nih.gov/25125625/)
The same 34-patient study identified three cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration without del17p), and high risk (MYC aberration with del17p), with a significant difference in outcome (P = .0006).[5](https://pubmed.ncbi.nlm.nih.gov/31527074/) A DNA methylome study of 20 cases diagnosed by ICC/WHO-HAEM4R criteria found that B-PLL has a methylation pattern distinct from CLL, mantle cell lymphoma, and splenic marginal zone lymphoma, and identified two epigenetic subgroups: epitype 1, enriched in MYC and SF3B1 mutations and with inferior overall survival, and epitype 2.[11](https://pmc.ncbi.nlm.nih.gov/articles/PMC11700275/)
## Prognosis and treatment
B-PLL has a poor prognosis, with a median survival of 3 to 5 years despite treatment; anemia, thrombocytopenia, age, and the presence of TP53 abnormalities predict a poorer outcome.[7](https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15912) In the largest reported real-world cohort, 950 patients labeled with B-PLL in the US National Cancer Database (2004 to 2019) had a median age of 72 years and a median overall survival of 2.8 years, with 1-, 5-, and 10-year survival rates of 67%, 39%, and 26%; survival did not improve over calendar time, including after the introduction of targeted agents.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC13132662/) Patients initially managed with active surveillance had a median overall survival of 7.8 years, compared with 2.1 years for those receiving upfront treatment.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC13132662/)
There is no clear consensus on optimal management of patients meeting ICC criteria for B-PLL or its reclassified WHO-HAEM5 entities, and such patients are frequently excluded from prospective clinical trials; National Comprehensive Cancer Network guidelines recommend management strategies extrapolated from high-risk CLL.[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC13132662/) In practice B-PLL is managed with regimens used for CLL, such as ibrutinib and rituximab, tailored to the individual.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/) As in CLL, treatment depends on the presence of TP53 dysfunction, and patients with TP53 mutations or deletions usually benefit from Bruton tyrosine kinase inhibitors; patients failing a BTK inhibitor may still respond to the BCL2 inhibitor venetoclax.[10](https://pubmed.ncbi.nlm.nih.gov/28324286/) • [4](https://www.nature.com/articles/s41375-022-01764-1) Drug response testing done in vitro found that B-PLL cells carrying an MYC translocation showed markedly reduced survival when treated with OTX015, an inhibitor of bromodomain and extra-terminal motif proteins that acts on MYC, together with either an agent blocking the B-cell receptor or one blocking BCL2, indicating that therapies directed at MYC could offer a promising treatment approach.[5](https://pubmed.ncbi.nlm.nih.gov/31527074/)
## References
1. [B-cell prolymphocytic leukemia, Orphanet (ORPHA:86852)](https://www.orpha.net/en/disease/detail/86852)
2. [Chronic lymphocytic leukaemia and prolymphocytic leukaemia. Two coins or two sides of the same coin? Haematologica](https://haematologica.org/article/view/9795)
3. [De-Novo B-Cell Prolymphocytic Leukemia, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10181324/)
4. [A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas, Leukemia](https://www.nature.com/articles/s41375-022-01764-1)
5. [Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53, PubMed](https://pubmed.ncbi.nlm.nih.gov/31527074/)
6. [Treatment Outcomes and Overall Survival of Patients With B-Cell Prolymphocytic Leukemia, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC13132662/)
7. [B-cell prolymphocytic leukaemia, British Journal of Haematology](https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.15912)
8. [De novo chronic lymphocytic leukemia/prolymphocytic leukemia or B-cell prolymphocytic leukemia? PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8101659/)
9. [Clinical Consequences of Defective B- and T-Cell Functions, Holland-Frei Cancer Medicine, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK13314/)
10. [Prolymphocytic Leukemia: New Insights in Diagnosis and in Treatment, PubMed](https://pubmed.ncbi.nlm.nih.gov/28324286/)
11. [Epigenetic features support the diagnosis of B-cell prolymphocytic leukemia and identify 2 clinicobiological subtypes, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC11700275/)
12. [The concept of SBLPN, British Journal of Haematology](https://onlinelibrary.wiley.com/doi/10.1111/bjh.19754)
13. [Aberrations of MYC are a common event in B-cell prolymphocytic leukemia, PubMed](https://pubmed.ncbi.nlm.nih.gov/25125625/)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Diseases and injuries › Cardiovascular and blood conditions › Blood disorders (hematologic conditions) › Leukemias › Other and rarer leukemia subtypes*
*Initially written Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license