T-cell prolymphocytic leukemia (T-PLL) is an extremely rare and typically aggressive malignancy (cancer) that is characterized by the out of control growth of mature T-cells (T-lymphocytes). T-cells are a type of white blood cell that protects the body from infections. T-PLL affects older adults with a median age at diagnosis of 61 years, and it is more common in men than in women.

Abnormal changes (mutations) in the genes of a T-cell can cause a normal, healthy T-cell to become a cancer cell.  These genetic errors in the mutated T-cell tell the cell to keep growing and dividing when a healthy cell would typically stop dividing and eventually die. Every cell that arises from the initial leukemia cell also has the same mutated DNA.  As a result, over time the number of leukemia cells multiply and can travel in the blood to other sites including the bone marrow, spleen, liver, lymph nodes and sometimes skin.  

Chromosomal abnormalities are very common in patients with T-PLL. The most common chromosomal abnormalities are inversions or translocations involving chromosome 14 that result in mutations (changes in DNA) to the proto-oncogene TCL-1.  Proto-oncogenes are genes involved in normal cell growth.  When mutations occur to proto-oncogenes, these cells grow out of control which can lead to cancer.  Less frequently, a translocation between chromosomes X and 14 can result in mutations to proto-oncogene MTCP-1. Also frequently detected in patients with T-PLL are abnormalities in chromosome 8, primarily trisomy 8q which is an extra copy of genetic material on the long arm (q) of chromosome 8.

Deletions or mutations to the tumor suppressor gene ATM have also been observed in patients with T-PLL.  Tumor suppressor genes are a class of genes that help control cell growth.  Mutations in tumor suppressor genes can cause uncontrolled growth of cells which can lead to cancer as well. 

Recently, DNA sequencing has found a number of gene mutations, particularly in the JAK-STAT pathway that may also contribute to the development of T-PLL.  Janus kinases, or JAKs, are proteins that send signals which regulate the growth and production of certain types of white blood cells.  When JAKs send too many signals, they cause the body to make the wrong number of blood cells.  This is called overactive JAK signaling.

Signs and Symptoms

Common signs and symptoms of T-PLL include:

• Swelling of the lymph nodes (lymphadenopathy)
• Enlarged liver (hepatomegaly)
• Enlarged spleen (splenomegaly)
• Night sweats and weight loss
• Skin lesions or rash
• Elevated white blood cell counts
• Low red blood cell counts (anemia)
• Low platelet counts (thrombocytopenia)

Diagnosis

Since T-PLL is rare, it is important that an experienced hematopathologist examine and interpret the patient's lab results. A hematopathologist is a doctor who specializes in examining tissue and diagnosing disease. This is important because the treatment of T-PLL is very specific and not used for other T-cell malignancies, and an incorrect diagnosis may result in a poor outcome.

Tests used to diagnose T-PLL include:

• CBC
• Peripheral blood smear
• Bone marrow biopsy
• Immunophenotyping by flow cytometry
• Cytogenetics by either karyotyping or FISH
• Molecular testing
• Computerized Tomography (CT) scans
• Positron Emission Tomography (PET) scans

Treatment

Since current treatments for T-PLL do not typically result in long-term remissions or cures with the possible exception of a hematopoietic stem cell transplantation, patients are encouraged to consider enrolling 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. 

Current treatment approaches for T-PLL include:

• Watch and Wait. For the approximately 10 to 15 percent of T-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 T-PLL can progress rapidly, frequent monitoring including blood tests is necessary so that treatment can be started if the disease starts advancing.
• Drug Therapy. For patients with symptomatic T-PLL, drug treatment options may include:
  • Intravenous alemtuzumab (Campath®)
    • This drug is typically given 3 times a week for 4-8 weeks, depending on specific patient and disease
  • Intravenous alemtuzumab plus pentostatin (Nipent®)
  • FMC [(fludarabine (Fludara®), mitoxantrone (Novantrone®), cyclophosphamide (Cytoxan®)] followed by intravenous alemtuzumab
  • Nelarabine (Arranon®) can sometimes be used to treat T-PLL, though it is not approved by the Food and Drug Administration for T-PLL
• Hematopoietic stem cell transplantation.  In patients who achieve a remission following initial drug therapy, an allogeneic stem cell transplantation using bone marrow from a donor is the only 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.  Many patients with T-PLL are not fit enough for such an intensive treatment, although, in recent years, the introduction of reduced-intensity treatment regimens have made this treatment option available to more patients. 

Reviewed by:

Jonathan Brammer, MD 
Assistant Professor 
Division of Hematology, The Ohio State University
James Comprehensive Cancer Center
Columbus, OH

References

Catovsky D, Dearden C. Treatment of T cell prolymphocytic leukemia. In UpToDate. https://www.uptodate.com/contents/treatment-of-t-cell-prolymphocytic-leukemia.

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. Clinical manifestations, pathologic features, and diagnosis of T cell prolymphocytic leukemia. In UpToDate. https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-t-cell-prolymphocytic-leukemia.

National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): T-Cell Lymphomas. Version 3.2018. https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf.