Adult T-cell lymphoma/leukaemia

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ATLL, Adult T-cell leukemia, Adult T-cell lymphoma, Adult T-cell leukemia/lymphoma (HTLV-1 positive)

Adult T-cell leukemia/lymphoma is a rare cancer linked to a virus that can remain silent for decades before causing serious disease in a small number of infected individuals.

Table of contents

• What is Adult T-cell leukemia/lymphoma?
• The virus behind the disease
• Where the disease occurs
• Four different forms of the disease
• Parts of the body commonly affected
• Signs and symptoms
• Treatment approaches
• Outlook and survival

What is Adult T-cell leukemia/lymphoma?

Adult T-cell leukemia/lymphoma (ATLL) is a rare type of cancer that affects certain white blood cells called T-cells, which are cells that help the body fight infections^[1]. This cancer can appear in different parts of the body, including the blood (which doctors call leukemia), the lymph nodes (which they call lymphoma), the skin, or in multiple other areas^[1].

ATLL is classified as a form of non-Hodgkin lymphoma, a broad category of cancers that affect the lymphatic system^[1]. More specifically, it falls under a group called peripheral T-cell lymphomas, meaning the cancer develops from mature T-cells that are found outside the bone marrow^[2].

• Blood
• Lymph nodes
• Skin
• Lung
• Liver
• Gastrointestinal tract
• Central nervous system
• Bone marrow
• Bone

The virus behind the disease

ATLL is caused by infection with the human T-cell lymphotropic virus type 1 (HTLV-1), which is a type of virus known as a retrovirus^[1]. HTLV-1 was the first human retrovirus ever discovered^[2]. However, while approximately 10 million people worldwide are infected with this virus, only about 1 to 5 percent of infected individuals will eventually develop ATLL^[1][2]. Currently, doctors have no way of predicting which infected patients will develop the cancer^[1].

When someone gets infected with HTLV-1, the virus enters T-cells and inserts its genetic material into the cell’s DNA as a single copy^[12]. Most people who are infected remain without symptoms throughout their entire lives^[1]. For those who do develop ATLL, there is typically a very long period—often many decades—between the initial infection and the development of cancer^[12].

The HTLV-1 virus can be transmitted in several ways. The most common route is from mother to child, which can happen through the placenta during pregnancy, at childbirth, or during breastfeeding^[1][2]. The virus can also spread through sexual contact or through contact with infected blood, including blood transfusions^[1][2].

Where the disease occurs

HTLV-1 and ATLL are not evenly distributed around the world. The virus is most commonly found in specific geographic regions, including southwestern Japan, the Caribbean islands, parts of West Africa, northeast Iran, and areas of South and Central America^[1][2]. In these areas where the virus is common (called endemic regions), the disease occurs much more frequently than elsewhere.

In Japan, which has some of the highest rates in the world, the annual incidence is around 60 cases per 100,000 carriers of the virus, with about 1,000 deaths each year^[2]. By contrast, ATLL is very rare in North America. A recent report showed an incidence rate of only 0.06 per 100,000 population in North America between 2001 and 2015^[2].

The disease typically affects adults, with most patients diagnosed around the age of 62 years^[17]. Studies show a slight male predominance, though both men and women can be affected^[2].

Four different forms of the disease

ATLL is classified into four distinct clinical subtypes, each with different characteristics, symptoms, and outlook. Understanding which type a patient has is important because it determines how doctors will approach treatment^[1][2].

The acute subtype is the most common form and is aggressive, meaning it grows and spreads quickly^[1]. Patients with acute ATLL may develop symptoms rapidly, including fatigue, skin rash, and swollen lymph nodes in the neck, underarm, or groin^[1]. The cancer is primarily present in the blood, often with very high white blood cell counts^[2].

The lymphomatous subtype is also aggressive^[1]. Unlike the acute form, this type is found primarily in the lymph nodes rather than the blood, though it may still cause elevated white blood cell counts^[1].

The chronic subtype is a slower-growing form of the disease^[1]. It can result in elevated lymphocytes (a type of white blood cell) in the blood, along with enlarged lymph nodes, skin rash, or fatigue^[1]. The chronic subtype can be further divided into favorable and unfavorable types based on certain characteristics, which affects how it is treated^[2].

The smoldering subtype is the least aggressive form^[1]. Patients with smoldering ATLL often have very mild symptoms or no symptoms at all, aside from perhaps a few skin lesions^[1]. This type can persist for a long time without causing serious problems, though it can progress to a more aggressive form^[2].

Parts of the body commonly affected

ATLL typically presents with widespread involvement throughout the body. Most patients have cancer cells in both the lymph nodes and the blood when they are first diagnosed^[4]. It is very rare for a patient to have only bone marrow involvement^[4].

The most common sites where ATLL can be found include the skin, lungs, liver, gastrointestinal tract, central nervous system, and bone marrow^[4]. Patients often present with swollen lymph nodes throughout the body, an enlarged liver or spleen (called hepatosplenomegaly), and skin involvement^[2].

One striking feature of ATLL is its tendency to affect bones. Patients may develop bone invasion and osteolysis, which means the breakdown of bone tissue, similar to what happens in some other cancers that spread to bone^[6]. The bone lesions in ATLL are predominantly destructive, with little new bone formation^[6].

Signs and symptoms

The symptoms of ATLL vary depending on which subtype a person has and where in the body the cancer is located. Some symptoms are common across different types, while others are more specific to the aggressive or indolent forms^[15].

Common symptoms that can occur in any subtype include swollen lymph nodes, an itchy skin rash, and bloating or abdominal pain due to an enlarged liver or spleen^[15]. Many patients also develop an increased rate of infections because ATLL causes severe weakening of the immune system^[2].

The aggressive subtypes—acute and lymphomatous ATLL—often cause what doctors call B symptoms, which include fever, drenching night sweats, and unexplained weight loss^[15]. Patients may experience persistent fatigue, meaning they feel much more tired than usual for several days with no clear reason^[1].

A distinctive feature of ATLL is high calcium levels in the blood, called hypercalcemia, which affects many patients^[6]. This can cause symptoms such as watery diarrhea, constipation, and fatigue^[15]. The high calcium levels result from substances produced by the cancer cells that cause bone breakdown^[6].

In the blood, doctors may observe leukemic cells with a characteristic appearance—the nucleus (center) of the cell has multiple lobes, giving it a distinctive shape that doctors describe as “flower cells”^[4].

The less aggressive forms—chronic and smoldering ATLL—typically cause fewer and milder symptoms^[15]. Smoldering ATLL may produce no symptoms at all other than occasional skin lesions^[1][15].

Treatment approaches

Treatment for ATLL depends heavily on which subtype a patient has, as well as their overall health and whether certain advanced treatments are available. The approach differs significantly between the slow-growing and aggressive forms of the disease^[9].

For patients with the slower-growing subtypes—smoldering and favorable chronic ATLL—doctors may initially recommend active surveillance, also known as “watchful waiting”^[9]. This means not starting treatment right away but instead monitoring the patient closely through regular physical exams and periodic imaging tests^[9]. Treatment begins only if the patient develops symptoms or if the disease shows signs of getting worse^[9].

For these less aggressive forms, a combination of antiviral drugs—specifically zidovudine (also called AZT) plus interferon-alpha—has shown good results^[9][10]. This combination targets the virus and can lead to significant improvement in survival^[10].

The aggressive subtypes—acute, lymphomatous, and unfavorable chronic ATLL—require more intensive treatment. For skin-involved ATLL, doctors may use skin-directed therapies such as topical steroids (medicines applied directly to the skin) or radiation therapy applied only to affected areas^[9].

The main treatment for aggressive ATLL involves chemotherapy, which uses drugs to stop the growth of or kill cancer cells^[9]. Common chemotherapy combinations include CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOEP, dose-adjusted EPOCH, or hyper-CVAD alternating with high-dose methotrexate and cytarabine^[9].

Some newer treatments include chemoimmunotherapy, which combines chemotherapy with drugs that help the immune system fight cancer^[9]. One example is BV-CHP, which includes the drug brentuximab vedotin combined with chemotherapy, used for lymphomas that have a specific protein called CD30 on their surface^[9].

For many patients with aggressive ATLL, doctors consider allogeneic hematopoietic stem cell transplantation (also called alloHSCT) as a potentially curative approach^[12]. This is a procedure where a patient receives healthy stem cells from a donor to replace their diseased bone marrow. The evidence suggests that combination chemotherapy followed by allogeneic transplantation offers the best chance for long-term survival in aggressive ATLL^[12].

Recently, a drug called mogamulizumab has shown promise in treating ATLL^[17]. Another medication, lenalidomide, has also demonstrated encouraging results^[17].

Outlook and survival

The prognosis for ATLL varies significantly depending on the subtype. Unfortunately, the aggressive forms of this disease carry one of the poorest outlooks of any type of non-Hodgkin lymphoma^[17].

For patients with acute or lymphomatous ATLL, or chronic ATLL with unfavorable features, the outlook is poor, with overall survival typically less than one year without stem cell transplantation^[2][12]. In a large study looking at many patients with ATLL, the 5-year overall survival was only about 14 percent, with failure-free survival of 12 percent^[17].

The poor outcomes in aggressive ATLL result from several factors. The cancer cells are often resistant to chemotherapy, making treatment difficult^[2]. Additionally, patients with ATLL have severe weakening of their immune system, making them vulnerable to serious infections that can be life-threatening^[2]. Most patients with aggressive disease die within one year of diagnosis^[6].

In contrast, the favorable chronic and smoldering subtypes carry a relatively better prognosis^[2]. These slower-growing forms respond well to antiviral therapy, and patients can experience significant prolongation of survival^[10]. However, even these less aggressive forms can eventually progress to become more aggressive over time^[2].

For patients who are able to undergo allogeneic stem cell transplantation, the outlook may be better, as this represents a potentially curative approach^[12]. With improving understanding of how ATLL develops and progresses at the molecular level, researchers hope that new treatment options will continue to emerge that can improve outcomes for patients with this challenging disease^[17].