B-cell prolymphocytic leukemia (B-PLL) is a very rare and typically aggressive malignancy (cancer) characterized by the out of control growth of B-cells (B-lymphocytes).  B-cells are a type of white blood cell that is part of the immune system. B-PLL usually affects older adults with a median age at diagnosis of 69 years, and it is slightly more common in men than women.  Most of the time, B-PLL occurs as a transformation or evolution of a more slow-growing B-cell cancer, such as chronic lymphocytic leukemia.  Rarely, this is a primary disorder. 

Signs and Symptoms

Common signs and symptoms of B-PLL include:

• High lymphocyte count
• Enlarged spleen (splenomegaly)
• B-symptoms
  • Fevers
  • Night sweats
  • Weight loss
• Low red blood count (anemia)
• Low platelet count (thrombocytopenia)

Diagnosis

B-PLL is extremely rare, and accurately diagnosing it can be difficult as B-PLL has similar clinical presentation to other mature B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma.  Therefore, it is important that an experienced hematopathologist examine and interpret a patient's lab results.  A hematopathologist is a doctor who specializes in examining tissue and diagnosing disease. B-PLL is diagnosed when more than 55 percent of the lymphocytes in the peripheral blood are prolymphocytes, or when a lymph node or bone marrow sample shows that the majority of lymphocytes are prolymphocytes.

The genetic features causing B-PLL are largely unknown. Abnormalities of the TP53 gene (deletion and/or mutation) are seen in about 50 percent of cases and abnormalities of MYC gene are seen in about 50 percent of cases.  Some patients have abnormalities in both genes.

Tests used to diagnose B-PLL include:

• CBC
• Peripheral blood smear
• Bone Marrow biopsy/aspirate
• Immunophenotyping by flow cytometry
• Cytogenetics by either karyotyping or FISH
• Molecular testing

Treatment

B-PLL is an extremely rare disease, and there is no consensus on treatment strategy. Currently B-PLL is not considered curable with standard treatments with the possible exception of a hematopoietic stem cell transplantation available only to a small number of younger and/or fitter patients.  Therefore, patients are encouraged to enroll in clinical trials whenever possible.   Clinical trials can involve new drugs, new combinations of drugs, or previously approved drugs being studied in new ways such as new drug doses or new schedules to administer the drugs. Clinical trials are conducted worldwide under rigorous guidelines to help doctors find out whether new cancer treatments are safe and effective or better than the standard treatment. 

• Watch and Wait. For the approximately 10 to 15 percent of B-PLL patients who do not have symptoms at the time of diagnosis, the treatment may be the “watch-and-wait” approach, meaning treatment is deferred or delayed until signs and symptoms of the disease appear or progress. Since B-PLL can progress rapidly, frequent monitoring including blood tests is necessary so that treatment can be started if the disease starts advancing.
• Drug Therapy. B-PLL is most commonly treated with chemo-immunotherapy combinations used to treat chronic lymphocytic leukemia.  Common regimens include:

FCR [fludarabine (Fludara®), cyclophosphamide (Cytoxan®), rituximab (Rituxan®)]

or 

BR [Bendamustine (Treanda®), Rituximab (Rituxan®)]

Patients with mutations of the TP53 gene are typically resistant to conventional therapies and may be treated with the monoclonal antibody alemtuzumab (Campath®).Researchers are studying new therapies that target B-cell signaling such as ibrutinib (Imbruvica®) and idelalisib (Zydelig®) for patients who are unable to tolerate intensive therapies and/or who have TP53 abnormalities.While ibrutinib and idelalisib have not currently been FDA approved to treat B-PLL, they have been approved to treat other B-cell malignancies.

• Hematopoietic Stem Cell Transplantation. In patients who achieve a remission following initial drug therapy, a stem cell transplantation is a treatment option that may offer a potential cure. Stem cell transplantation may be considered in younger, fitter patients who have responded to their initial therapy.  Unfortunately, a majority of patients with B-PLL are not fit enough for such an intensive treatment.  Although, in recent years, the introduction of reduced-intensity regimens have made this treatment option available to more patients. 

Reviewed by:

Jennifer Woyach, MD
Associate Professor, Division of Hematology
Section Head, Chronic Lymphocytic Leukemia
The Ohio State University Comprehensive Cancer Center
Columbus, OH

References

Dearden C. How I treat prolymphocytic leukemia. Blood 2012;120(3):538-551.

Dearden C. Management of prolymphocytic leukemia. Hematology AM Soc Hematol Educ Program. 2015;2015:361-367.

Freedman AS, Aster JC, Dearden C. B cell prolymphocytic leukemia. In UpToDate. https://www.uptodate.com/contents/b-cell-prolymphocytic-leukemia.