Prolymphocytic Leukaemia

Prolymphocytic leukaemia is a rare and aggressive blood cancer that affects white blood cells. It advances rapidly and primarily affects older adults, making early diagnosis and treatment critical for managing this challenging condition.

Table of contents

• What is prolymphocytic leukaemia?
• Types of prolymphocytic leukaemia
• Who gets prolymphocytic leukaemia?
• Signs and symptoms
• What causes prolymphocytic leukaemia?
• How is prolymphocytic leukaemia diagnosed?
• Treatment options
• Outlook and survival

What is prolymphocytic leukaemia?

Prolymphocytic leukaemia (PLL) is a rare form of blood cancer that occurs when white blood cells called prolymphocytes (cells that normally help the immune system fight infections) multiply out of control in the bone marrow and later spread to the blood and other organs.^[1] The term “prolymphocytes” usually refers to immature cells, but in PLL these are actually mature cells that have become cancerous.^[11]

PLL is related to chronic lymphocytic leukaemia (CLL), but differs in important ways. In PLL, the cancer cells tend to grow and spread much faster than those in CLL.^[1] Both forms of prolymphocytic leukaemia have been recognized by the World Health Organization as distinct from CLL.^[1]

• Bone marrow
• Blood
• Lymph nodes
• Spleen
• Liver
• Skin

Types of prolymphocytic leukaemia

Prolymphocytic leukaemia occurs in two main forms, depending on which type of white blood cells are affected.^[11]

B-cell prolymphocytic leukaemia (B-PLL)

B-cell prolymphocytic leukaemia affects white blood cells called B lymphocytes (B cells), which normally produce antibodies to fight infections. B-PLL is the more common form, accounting for 80% of all PLL cases.^[1] However, it makes up fewer than 1 percent of all types of leukaemia involving B cells.^[15]

The defining characteristic of B-PLL is when more than 55% of the lymphocytes in the circulating blood are prolymphocytes, or when a majority of the lymphocytes in a lymph node or bone marrow sample are prolymphocytes.^[1] It is also characterized by an enlarged spleen, elevated white blood cell counts, and limited or no lymph node involvement.^[1]

Some researchers think B-PLL develops when a slow-growing B cell cancer, such as CLL or mantle cell lymphoma, transforms into B-PLL, rather than appearing initially on its own.^[1]

T-cell prolymphocytic leukaemia (T-PLL)

T-cell prolymphocytic leukaemia affects white blood cells called T lymphocytes (T cells), which help destroy infected cells and regulate immune responses. T-PLL accounts for 20% of PLL cases.^[1] It is a very rare and aggressive cancer that comprises approximately 2% of mature lymphocyte leukaemias in adults.^[2]

T-PLL differs from B-PLL in that it may involve the lymph nodes and the skin, while B-PLL generally does not.^[1] The disease is often widespread at diagnosis and involves the peripheral blood, bone marrow, lymph nodes, liver, spleen, and skin.^[2]

Who gets prolymphocytic leukaemia?

Prolymphocytic leukaemia is extremely rare. Around 70 people are diagnosed with T-cell PLL each year in the UK.^[3] Both forms of PLL primarily affect older adults, with most people diagnosed in their 60s. The average age of patients with T-PLL is 65, with an age range from 30 to 94 years.^[2] For B-PLL, the median age of diagnosis is 69 years.^[11]

Unlike more common forms of leukaemia, PLL mainly affects older adults and not children.^[1] T-cell PLL affects men and women equally.^[3] For B-PLL, males are slightly more likely to develop the condition than females.^[15]

Risk factors for developing PLL include older age, being assigned male at birth, and a family history of blood and bone marrow cancers.^[11] People with a genetic condition called ataxia telangiectasia (an inherited disorder affecting coordination and other body systems) have an increased risk of developing T-cell PLL and may develop it at a younger age.^[3] Patients with this condition have mutations of the ATM gene, which occur in 80 to 90% of the T-PLL population.^[2]

Signs and symptoms

Although B-PLL and T-PLL share some symptoms, they have distinct features. Some people don’t have symptoms when they are first diagnosed and may only be found to have the condition after a blood test for something else.^[3] However, symptoms usually develop over time.

Symptoms of B-cell prolymphocytic leukaemia

Symptoms of B-PLL may include:^[1]

• Fevers
• Night sweats
• Unexplained weight loss
• Low red blood count
• Low platelet count
• An enlarged spleen
• Elevated white blood cell counts

Symptoms of T-cell prolymphocytic leukaemia

Symptoms of T-PLL may include:^[1][3]

• Swelling of lymph nodes
• Enlarged liver
• Enlarged spleen
• Rash or skin lesions (this may look different on black or brown skin)
• High white blood cell counts
• Low red blood cell counts, or anaemia (a condition where you don’t have enough healthy red blood cells)
• Low platelet counts
• Night sweats
• Weight loss
• Fever
• Feeling tired, breathless or dizzy due to anaemia
• Tummy pain, bloating or discomfort due to a swollen spleen or liver
• Bruising or bleeding easily (for example, nose bleeds or bleeding gums when brushing teeth)
• Swelling around the eyes or in the legs, due to a build up of fluid

What causes prolymphocytic leukaemia?

The exact cause of PLL is not yet fully understood. The disease is thought to develop when genetic changes or mutations in the genes of bone marrow cells cause the body to produce abnormal white blood cells that grow uncontrollably and crowd out healthy cells.^[11]

T-PLL has no known environmental risk factors.^[2] It is not because of anything the person has or has not done.^[3] People with T-cell PLL have genetic changes in their leukaemia cells that make the cells grow out of control, though researchers do not know exactly why these genetic changes happen.^[3]

Research using advanced genetic testing has identified mutations in several genes associated with T-PLL, including IL2RG, JAK1, JAK3, STAT5B, EZH2, FBXW10, and CHEK2.^[2] The most common DNA changes are in a gene called proto-oncogene TCL-1, which controls cell growth and division. The genetic mutations turn it into an oncogene, which can trigger the growth of cancer cells.^[13]

For B-PLL, researchers believe the disease develops when a slow-growing B cell cancer, such as CLL or mantle cell lymphoma, transforms into B-PLL rather than appearing initially on its own.^[1]

How is prolymphocytic leukaemia diagnosed?

Diagnosing prolymphocytic leukaemia involves several tests to examine blood and sometimes bone marrow samples. These samples go to a laboratory for specialist testing.^[3]

Blood tests

Blood tests are the primary diagnostic tool. They are used to:^[3]

• Measure numbers of red blood cells, white blood cells and platelets. If a person has PLL, they will have high levels of abnormal cells and may have low levels of healthy blood cells.
• Look at blood cells under a microscope to check for abnormal blood cells.
• Perform specialist tests to identify the specific type of leukaemia cells.

For T-PLL diagnosis, a high lymphocyte count (greater than 100 x 10⁹/L) along with low amounts of red blood cells and platelets in the blood are common findings.^[4]

Bone marrow tests

Sometimes doctors need to take samples from the bone marrow to confirm the diagnosis. This involves taking a small amount of bone marrow, usually from the hip bone, to examine the cells more closely.^[3]

Specialist testing

The samples undergo additional specialist testing to identify the specific characteristics of the leukaemia cells. For T-PLL, tests show that the cells have features of mature T-cells and are typically positive for certain markers (CD2, CD3, and CD7) and negative for others (TdT and CD1a).^[4][7]

Genetic testing looks for specific chromosomal abnormalities. In T-PLL, the most frequent chromosomal abnormality is an inversion of chromosome 14, found in 80% of cases, while 10% of cases show a different type of chromosomal rearrangement.^[4] Abnormalities of chromosome 8 are seen in approximately 75% of patients.^[4]

For B-PLL, about 50% of people have changes in the TP53 gene, 50% have changes in the MYC gene, and about 1 out of 4 people have a deletion in part of chromosome 13.^[15]

Treatment options

Treatment for prolymphocytic leukaemia varies depending on the type and whether symptoms are present. After confirming the diagnosis, doctors determine whether the disease is active, as only active disease requires immediate treatment.^[2]

Monitoring without immediate treatment

If a person doesn’t have symptoms, they may not need treatment straight away.^[3] Between 20 and 30% of T-PLL patients initially present with inactive disease, but they almost always progress to an active format within 2 years.^[2] During this time, the healthcare team will monitor the person closely.

Antibody therapy

For T-PLL, alemtuzumab (also known by the brand name Campath) is an anti-CD52 monoclonal antibody (a laboratory-made protein that attacks cancer cells) and remains the first line of therapy for treatment-naive and relapsed/refractory patients.^[7] This medication attacks white blood cells and has been used in treatment with some success.^[4]

For B-PLL with certain genetic features, treatment with bendamustine and rituximab has shown effectiveness. This combination brought complete response in patients that lasted for 25, 33, and 34 months in reported cases.^[10]

Chemotherapy

T-cell prolymphocytic leukaemia is difficult to treat, and it does not respond well to most available chemotherapeutic drugs.^[4] Chemotherapy’s efficacy is generally poor, and agents that can offer a response cannot provide long-term control.^[2] Various treatments have been attempted with limited success, including purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy regimens.^[4]

Stem cell transplant

Bone marrow transplantation (also called stem cell transplant) can provide a long-term response, but typically only in patients with a good complete response to initial chemotherapy, those in good health, and young enough to allow a transplantation protocol.^[2]

Clinical trials

Because PLL is so rare, prospective clinical trials are difficult to conduct as patients have a short life expectancy after initial diagnosis.^[7] However, people with PLL might have the option to participate in clinical trials testing new treatments.^[3] Researchers are developing newer approaches based on recognizing the genetic characteristics of each patient and targeting the identified defective genes.^[7] As researchers understand more about the disease, new treatments are emerging that may offer improved options in the future.^[1]

Outlook and survival

Prolymphocytic leukaemia is an aggressive disease, and people with PLL generally have a poor outlook. Unlike more common forms of leukaemia, PLL tends to advance rapidly.^[1] People usually improve with treatment, but over time the cancer often comes back.^[1]

T-cell PLL has a particularly rapid doubling time and a difficult course. The median survival historically has been about 1 year.^[2] The survival time for individuals with T-PLL is typically less than 2 years from diagnosis, although this can vary depending on several factors, including the individual’s age, general health status, and the extent of genetic abnormalities.^[13]

Most people with prolymphocytic leukaemia need treatment within 1 to 2 years of diagnosis.^[3] The outlook depends on multiple factors unique to each person, and healthcare teams will discuss individual circumstances and prognosis with patients and their families.