What is T-Cell Prolymphocytic Leukemia?
T-PLL, or T Prolymphocytic Leukemia, is a pretty uncommon but severe type of leukemia affecting T-cells. The T-cells become overactive and multiply rapidly, leading to this disease. Usually, people diagnosed with this condition are around 65 years old, but it can affect people anywhere between 30 to 94 years old. In fact, T-PLL makes up only 2% of all cases of leukemia that affect mature lymphocytes – a type of white blood cell.
The disease grows fast and unfortunately, most people only survive for about a year after being diagnosed. If you were to look at a group of 100 patients, on average, you’d find that 20 to 30 of them don’t show signs of the disease being active when they are first diagnosed. However, this form of leukemia never just goes away, and within two years, the disease becomes active in all of these patients.
T-PLL usually shows up in a lot of places in the body, including the blood, bone marrow, lymph nodes, liver, spleen, and the skin. It’s worth noting that the name “Prolymphocyte” isn’t quite accurate because the cancer cells in this condition come from T-cells that have matured past the thymus stage, an important part of their development.
Once confirmed, the next step is to figure out how active the disease is, because only then can treatment begin. Traditional chemotherapy hasn’t been very effective against T-PLL. While there are treatments that can counteract the effects of the disease, none can offer a long term solution.
Bone marrow transplantation might offer some hope, but typically only for patients who have responded well to initial chemotherapy, are in good health overall, and are young enough to undergo this intense medical procedure.
What Causes T-Cell Prolymphocytic Leukemia?
T-PLL, a type of leukemia, doesn’t have any exact causes we know of, and we don’t know of any environmental risks that could lead to this disease either. However, through very detailed genetic testing methods like whole genome sequencing and whole exome sequencing, it has been found that certain genes (IL2RG, JAK1, JAK3, STAT5B, EZH2, FBXW10, and CHEK2) can undergo changes that may contribute to T-PLL.
People with a rare genetic disorder called ataxia-telangiectasia, or ATM for short, have been observed to have a higher chance of developing T-PLL. ATM is a disorder passed down from parents to their children, where people affected tend to experience a progressive loss of some functions of the nervous system (like ataxia, which can cause difficulties with movement and balance), have weakened immune systems, experience problems with developing various organs, and develop small spider-like vessels in the skin and eyes. Mutations affecting the ATM gene on a specific area of a particular chromosome (11q23 to be exact) are found in a majority – 80 to 90% – of people with T-PLL.
Also, while it’s not very common, T-PLL has been linked to breast cancer and people who have had a kidney transplant.
Risk Factors and Frequency for T-Cell Prolymphocytic Leukemia
T-PLL, a kind of rare T cell leukemia, makes up about 2% of mature lymphocytic leukemia cases in adults. It commonly affects older people, usually those over 65 years of age, but can occur in individuals between 30 and 94 years old. Men are slightly more likely to get this disease, with a ratio of 1.33 males diagnosed for every female.
Signs and Symptoms of T-Cell Prolymphocytic Leukemia
T-cell prolymphocytic leukemia (T-PLL) is usually diagnosed by combining various factors including a person’s symptoms, imaging results, genetic and blood tests. Patients often experience symptoms like night sweats, weight loss, fatigue, and weakness. Common blood test findings can include a high white blood cell count, unusual white blood cells, anemia, and low platelet count. Nearly all patients with low red or white blood cells or platelets will show changes in their bone marrow, although a biopsy is not always necessary for diagnosis. Other important clinical signs can include an enlarged liver or spleen, widespread swollen lymph nodes, skin or mucosal lesions, and accumulations of fluid (mainly in the space around the lungs or, less commonly, in the abdomen).
- Night sweats
- Weight loss
- Fatigue
- Weakness
- High white blood cell count
- Unusual white blood cells
- Anemia
- Low platelet count
- Enlarged liver or spleen
- Widespread swollen lymph nodes
- Skin or mucosal lesions
- Accumulations of fluid, primarily around the lungs
Testing for T-Cell Prolymphocytic Leukemia
To evaluate a patient with T-cell Prolymphocytic Leukemia (T-PLL), a form of cancer that affects a specific type of white blood cell, doctors often run a list of specific tests. These tests generally include the following:
1. A Complete Blood Count (CBC) test is done to check for the number of different types of cells in the blood.
2. Other routine chemistries that monitor liver and kidney functions, and electrolytes that control the body’s balance of fluids.
3. Alkaline phosphatase and lactate dehydrogenase (LDH), two types of enzymes in the body, which may be indicative of disease progression.
Along with these laboratory tests, imaging studies, such as chest X-ray or a CT scan of the chest, abdomen, and pelvis, are performed to see the extent of the disease. Positron Emission Tomography (PET) scans, another type of imaging studies, aren’t generally recommended.
An assessment of blood via a smear test is also crucial as it gives a clue about the shape and size of the blood cells, known as morphology. Three main variants have been identified in T-PLL. However, cell morphology alone can’t diagnose T-PLL because there’s no clinical difference between these variants.
Bone marrow aspiration or biopsy sometimes helps in understanding the cellular structure of the bone marrow. A biopsy of the spleen or skin might be suggested if a patient’s symptoms warrant such procedures.
Flow cytometry, a laboratory technique used to measure the physical and molecular characteristics of cells, is often necessary for a T-PLL diagnosis. This test checks for the presence of certain proteins on the surface of cells that are typical in this condition.
For the initial evaluation, a test to determine if the T-cell receptor gene is normal or abnormal (clonal) is often conducted. Other genetic abnormalities, identified usually by complex lab procedures, can also suggest T-PLL.
The official diagnostic criteria for T-PLL require either all three major criteria or the first two major criteria and one minor criterion. The major criteria include an increase in certain types of cells, evidence of T-cell clonality, which means the T-cells have an abnormal gene structure, and specific genetic abnormalities. The minor criteria include other genetic abnormalities or a symptom specific to T-PLL like enlargement of the spleen.
Treatment Options for T-Cell Prolymphocytic Leukemia
Patients who are not showing symptoms are typically monitored, similar to a “wait-and-see” approach. They should come in for monthly check-ups, which include physical examinations and blood tests. If they start to show symptoms, they should then start treatment. Remember that not having symptoms is usually a temporary phase, and patients will eventually progress. This is why it’s important to stay alert and prepared.
The treatment of a type of cancer called T-PLL has become quite specific, and where possible, patients should be considered for clinical studies. Previous treatment methods such as spleen removal, spleen radiation, cleansing of the blood, or using a combination of drugs (CHOP) are not effective for treating T-PLL. Certain medications like fludarabine, cladribine, and pentostatin have a very limited effect.
Alemtuzumab is the primary treatment for patients who have never received treatment before, as well as those with disease that doesn’t respond to treatment or has come back. It brings about a positive response in 90% of cases and completely eliminates symptoms in about 80% of cases in newly diagnosed patients. This medication is delivered via an IV for 10 to 12 weeks, which is preferred over subcutaneous (under the skin) injection as the drug’s effectiveness is reportedly less in the latter method. Alemtuzumab is a lab-made protein that targets CD52, a marker on T-cells (a type of white blood cell that fights infections). It binds to CD52, causing the cell to die. However, even with the best responses to treatment, the disease often comes back within two years.
For this reason, a procedure known as a hematopoietic stem cell transplant (HSCT) is used after treatment to reinforce the benefits. An HSCT using cells from a donor (allogeneic HSCT) is preferred, especially when started within a year of diagnosis, for patients who are fit and whose disease is in complete response (meaning all signs of disease have disappeared). Both autologous (using your cells) and allogeneic HSCT are considered equally good, though data on the former are limited. Medical opinion varies, but with ideal conditions, allogeneic HSCT has proven to control the disease for up to seven years.
When possible, patients should consider participating in studies for newer treatments. Recent clinical trials have shown some promise for a drug called Venetoclax in treating T-PLL. Venetoclax works by blocking a protein (B-cell Lymphoma 2 or BCL-2) that helps cancer cells survive. Combining this with another drug, Ruxolitinib, thought to enhance the action of Venetoclax. Further studies on this combination are expected in the future.
What else can T-Cell Prolymphocytic Leukemia be?
When diagnosing T-cell prolymphocytic leukemia (T-PLL), doctors have to rule out several other medical conditions that might be causing the symptoms. Here are some of the conditions that need to be looked into:
- B-cell prolymphocytic leukemia (B-PLL); Unlike T-PLL, B-PLL patients don’t usually have large lymph nodes and rarely show skin changes. The cells exhibit strong B-cell indicators (CD19, CD20, CD22) with additional positive markers of CD79a and CD5.
- Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL); The cells are usually positive for CD5 and CD23; weakly positive for CD22 and CD79b. CD10 is usually negative.
- Mycosis fungoides (MF) / Sezary syndrome (SS); Cells in Sezary syndrome are positive for CD2 and CD3, predominantly positive for CD4, positive for CD25 and negative for TCL1. They usually do not have CD7 and CD26. Up to 20% of patients may develop skin lesions.
- Adult T cell lymphoma/leukemia (ATLL); This condition is typically caused by a chronic HTLV-1 infection. The cells are positive for CD3, CD4, and CD25, but negative for TCL1. High calcium levels are common in ATLL patients.
- T cell large granular lymphocyte leukemia (LGL); The cells are typically negative for TCL1, but positive for CD2, CD3, CD8, CD16, and CD57. They sometimes express CD7 and rarely CD4. Patients might have slightly enlarged spleens, but seldom show swollen lymph nodes.
- Hairy cell leukemia (HCL); This rare, low-grade mature B-cell cancer features cells that show B-cell markers of CD19, CD20, and CD22. Other markers include CD11c, CD25, CD103, CD125, and CD200. The condition is often identified by a physical exam that shows a significantly enlarged spleen.
It’s very important for doctors to take all these possibilities into account when diagnosing T-PLL so they can make the most accurate diagnosis possible.
What to expect with T-Cell Prolymphocytic Leukemia
T-cell prolymphocytic leukemia (T-PLL), is a severe type of cancer that typically results in a life expectancy of one to two years. The average survival duration is 21 months. There are some patients who might have a slower-progressing variant of T-PLL, which can lead to a better chance of survival. Factors that may worsen the prognosis, or expected course of the disease, include being older than 65 years, having fluid build-up in the body (effusion), liver or nervous system involvement, large lymph nodes, high lymphocyte (a type of white blood cell) count, high expression of proteins called TCL1 and AKT1, and a genetic alteration in a gene called JAK3.
Having at least five genetic irregularities is also seen as a negative factor affecting survival. Moreover, having a high level of two specific proteins in the blood, lactate dehydrogenase (LDH) or beta-2-microglobulin, may indicate a poor response to treatment.
Possible Complications When Diagnosed with T-Cell Prolymphocytic Leukemia
Before starting treatment with alemtuzumab, some preliminary steps are needed to avoid complications. These include preventative measures against ‘tumor lysis syndrome’, which is a rapid release of cell contents into the blood, and ‘antimicrobial prophylaxis’, which provides protection against certain infections (like Pneumocystis jiroveci and varieties of Herpesviridae such as HSV and CMV). Also, one needs to watch out for CMV reactivation, which is the recurrence of an old infection in the body. There is no current advice for CNS prophylaxis, which would provide protection for the brain and spinal cord.
Bone marrow transplantation could be an impactful follow-up treatment for patients with a type of rare lymphoma called T-PLL, so steps should be taken to type-match the patient’s human leukocyte antigen (HLA). HLA is a protein that helps the immune system distinguish body’s own proteins from proteins made by foreign invaders; it’s found on the surface of nearly every cell in the human body. The lengthy process of matching a patient’s HLA type with that of their siblings should begin as soon as possible.
Treatment Preparation:
- Preventive measures against tumor lysis syndrome
- Protection against Pneumocystis jiroveci and Herpesviridae infections
- Monitoring for the reactivation of CMV infection
- Initiation of human leukocyte antigen (HLA) typing for potential bone marrow transplantation
Preventing T-Cell Prolymphocytic Leukemia
Before starting treatment, it’s essential for patients to understand what to expect in terms of their recovery (prognosis), and any potential side effects from chemotherapy and bone marrow transplant procedures. Chemotherapy is a type of treatment that targets cancer cells, while a bone marrow transplant involves replacing damaged or destroyed bone marrow with healthy bone marrow stem cells.
