Aggressive NK-cell leukemia (ANKL)

Natural killer (NK) cells are white blood cells that help the body fight viruses and cancer. In aggressive NK-cell leukemia, mature NK cells turn cancerous and grow out of control. The leukemia cells are found mainly in the blood, the bone marrow, the liver and the spleen. The nose and skin are affected much less often.

Doctors first described ANKL in the 1980s. The World Health Organization (WHO) lists it as its own disease, separate from extranodal NK/T-cell lymphoma, a related NK-cell cancer that usually starts in the nose. It is also different from NK-cell large granular lymphocytic leukemia, which usually grows slowly. ANKL is very rare. About 400 cases had been reported in medical journals worldwide by 2018.

The Epstein-Barr virus (EBV) is found in the leukemia cells in most cases. A 2018 review put the share of cases without EBV at about 1 in 10. EBV itself is very common. The U.S. Centers for Disease Control and Prevention says most people are infected at some point in their lives, usually without symptoms, so having had EBV does not mean a person will get this leukemia.

Gene studies of the leukemia cells find acquired changes, most often in a cell-signaling pathway called JAK/STAT, in genes that help switch other genes on and off, and in TP53, a gene that normally stops damaged cells from growing. In some younger people, ANKL develops from chronic active EBV infection, a long-lasting form of the virus infection.

Most people become very ill quickly, over weeks or sometimes months. Common signs are high fever, feeling very unwell, a large liver and spleen, abnormal liver tests and low blood counts. Many people also develop a clotting and bleeding problem called disseminated intravascular coagulation (DIC).

ANKL often triggers hemophagocytic lymphohistiocytosis (HLH), a dangerous overreaction of the immune system that causes high fevers and damages organs. In a study of 113 people in China, about 1 in 6 had a slower start. They had symptoms like infectious mononucleosis (mono) for 3 months or longer before the leukemia became severe. Because early signs are not specific, the diagnosis can be delayed.

ANKL mostly affects adults between about 20 and 50, though teenagers and people in their 70s have also had it. One review gives a median age of 40, with men and women affected about equally. It is more common in East Asia. It has also been reported in Latin America and among people of European ancestry.

Doctors usually suspect ANKL when a person becomes very ill over a short time with high fever, a large liver and spleen, abnormal liver tests, low blood counts and a clotting problem. Many also have signs of HLH, an immune overreaction. These signs are not specific, so the diagnosis can be hard. Doctors weigh three things: how the cells look and which markers they carry, where the disease is found, and the pattern of the illness.

The diagnosis is made from blood and bone marrow samples. Under the microscope the cells often look like large granular lymphocytes, though their look varies. A marker test (flow cytometry) finds NK cells that usually carry CD2 and CD56, and often CD16, but lack CD3 on their surface. Their T-cell receptor genes are not rearranged, which helps tell them apart from T cells. A test called EBER in situ hybridization looks for EBV inside the cells, and a blood test measures EBV DNA.

Sometimes only a few leukemia cells are in the marrow at first. In one study, fewer than 5% of marrow cells were abnormal NK cells in half of the patients. So doctors may test more samples of blood, marrow or other tissue. Gene tests on the cells can add detail, and pathologists compare the results with related NK-cell diseases, such as NK/T-cell lymphoma that has spread to the marrow.

Treatment usually starts right away. There is no single agreed first treatment, and a 2018 review noted that no prospective trial had been done only for ANKL. The leukemia cells are sensitive to a medicine called L-asparaginase, so care teams usually choose a combination that includes it. One example is SMILE (dexamethasone, methotrexate, ifosfamide, etoposide and asparaginase). In a Japanese study of 108 people, 66% of the 38 people who got SMILE first had a response, more than with other first treatments.

When HLH is present, teams also treat the inflammation, often with etoposide. Medicines that block PD-1, an immune checkpoint, are being studied. In one Chinese hospital, people who were not transplanted and who got a PD-1 medicine with chemotherapy lived longer than those who did not. Only 7 people got the PD-1 medicine, and the study looked back at past records.

Chemotherapy alone rarely keeps ANKL away for long. For people whose leukemia responds and who are well enough, a donor (allogeneic) stem cell transplant is the only treatment reported to offer a chance of cure. Results are much better when the leukemia is in complete remission at the time of transplant. Some studies suggest that a transplant done as early as possible gives better results. The role of a transplant using a person’s own cells is uncertain.

ANKL often starts as a medical emergency. Many people are too sick at first for full treatment. In a Korean study of 51 people, more than a third were very limited in daily activity at diagnosis. About 1 in 7 died before chemotherapy could start. Treatment often happens in the hospital, alongside care for HLH and clotting problems.

For those who reach a donor transplant, the leukemia coming back is the main danger. In a Japanese registry study, the leukemia came back or grew within a year of transplant in 55.5% of people. But people who were alive and free of relapse 12 months after transplant did much better: 85.2% of them were alive 5 years after transplant.

Because the disease moves so fast, families face big decisions in a short time. These include intensive chemotherapy, a donor search and a transplant. In one Chinese study, the 7 people who had a transplant got it a median of 73 days after diagnosis.

A transplant for ANKL uses blood-forming stem cells from another person. The donor can be a matched brother or sister, an unrelated volunteer from a registry, donated umbilical cord blood or a half-matched (haploidentical) relative. In the Japanese registry study, about half of the 59 transplants used cord blood.

Timing matters. Remissions in ANKL can be short, and outcomes are poor without a transplant. So researchers recommend early referral to a transplant center and starting the donor search early. For people with no matched relative, unrelated volunteers and public cord blood units can make a transplant possible while the leukemia is still in remission.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

ANKL is one of the hardest leukemias to treat. Reviews describe a median survival of less than 2 months in past groups of patients, even with intensive chemotherapy. Many people are very sick when it is found.

Results have been better for people treated with asparaginase-based chemotherapy such as SMILE and for those who went on to a donor transplant. In a Japanese study of 108 people, 30.1% of those treated with SMILE were alive 2 years later, compared with 7.0% of people given other treatments. After a transplant, being in complete remission at the time of transplant is an important sign of a better result.

These numbers come from small groups of people treated in the past, mostly in studies that looked back at records. They describe groups, not what will happen to any one person.