Aggressive NK-cell leukemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[3] Maria Fernanda Villarreal, M.D. [4]
Synonyms and keywords: ANKL

Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of natural killer cells (NK cells) and a rapidly declining clinical course. There is no classification system for aggressive NK-cell leukemia. The pathogenesis of aggressive NK-cell leukemia is characterized by the proliferation of natural killer cells. Aggressive NK-cell leukemia is very uncommon, and is most commonly seen among middle aged adults. The most common risk factors in the development of aggressive NK-cell leukemia is the Epstein-Barr virus (EBV) infection. The majority of patients with aggressive NK-cell leukemia are symptomatic at diagnosis. Early clinical features include fatigue, night sweats, and fever. Physical examination among patients with aggressive NK-cell leukemia may be remarkable for hepatosplenomegaly. Aggressive NK-cell leukemia may also be diagnosed using bone marrow biopsy, findings of which can include extensive marrow replacement by leukemic cells and reactive histiocytes displaying hemophagocytosis. The mainstay of therapy for aggressive NK-cell leukemia is anthracycline-containing chemotherapy.

• In 1986, Dr. Fernandez and his colleagues reported the first case of aggressive NK-cell leukemia.^[1]
• In 1989, Dr. Kawa and his colleagues first reported the association between EBV virus and aggressive NK-cell leukemia.^[2]

• There is no classification system for aggressive NK-cell leukemia.
• This disorder is classified as a large granular lymphocyte (LGL) leukemia according to third WHO classification.^[3]

• The pathogenesis of aggressive NK-cell leukemia is characterized by the aggressive, systemic proliferation of natural killer cells.
• Although the exact association of EBV and aggressive NK-cell leukemia remain to be cleared, EBV has been suggested to play a role in its pathogenesis.^[4]
• On microscopic histopathological analysis, characteristic findings of aggressive NK-cell leukemia include large cells with abundant blue cytoplasm, azurophilic granules, irregular nuclei, open chromatin, and distinct nucleoli.^[5]
• CD11b and CD16 show variable expression in aggressive NK-cell leukemia.
• The table below demonstrates the immunophenotype for patients with aggressive NK-cell leukemia.^[5]

Status	Antigens
Positive	CD2, CD3ε, CD56, perforin, granzyme B, TIA-1, CCR5
Negative	CD57

• There are no established causes for aggressive NK-cell leukemia.

• Aggressive NK-cell leukemia must be differentiated from other diseases that cause fever, fatigue, and lymphadenopathy such as Human immunodeficiency virus, chronic neutrophilic leukemia, and juvenile myelomonocytic leukemia.
• Aggressive NK-cell leukemia should also be differentiated from other lymphoprolierative disorders originating from natural killer cells including extranodal NK/T cell lymphoma, nasal type (NKTCL) and chronic lymphoproliferative disorder of NK cells (CLPD-NK).^[6]

• Aggressive NK-cell leukemia is a rare disorder.^[7][8]
• Aggressive NK-cell leukemia is more commonly observed among young adults with median age of 42 years old.
• Aggressive NK-cell leukemia affects men more frequently than women.
• Aggressive NK-cell leukemia usually affects individuals of the Asian race.^[9]

• Common risk factors in the development of aggressive NK-cell leukemia include Epstein-Barr virus (EBV) infection^[7][2]

• There is insufficient evidence to recommend routine screening for aggressive NK-cell leukemia.

• The majority of patients with aggressive NK-cell leukemia are symptomatic at the time of diagnosis.^[9]
• Early clinical features include fatigue, night sweats, and fever.
• If left untreated, patients with aggressive NK-cell leukemia may progress to develop recurrent infections.
• Common complications of aggressive NK-cell leukemia, include Coagulopathies, hemophagocytic syndrome, multiple organ failure, and myelofibrosis.^[10]
• Prognosis is generally poor, and the median survival rate of patients with aggressive NK-cell leukemia is few months.

• The table below shows the staging system for aggressive NK-cell leukemia according to the Ann Arbor staging system.^[11]

Stage	Staging Criteria
Stage I	Confined to one lymph node
Stage II	Confined to more than one lymph node On one side of the diaphragm
Stage III	Confined to lymphatic tissue or spleen On both sides of the diaphragm
Stage IV	Bone marrow or liver/ extranodal involvement with widespread involvement

• Symptoms of aggressive NK-cell leukemia may include fever, swelling in the lymph nodes in the neck, night sweats, persistent fatigue, Loss of appetite, weight loss, nausea, vomiting, Yellow discoloration of the sclera, and Enlarged liver or spleen.^[12][13]

• Patients with aggressive NK-cell leukemia usually appear icteric and malnourished.^[10][9]
• Physical examination may be remarkable for fever, icterus, hepatosplenomegaly, and lymphadenopathy.

• Laboratory findings consistent with the diagnosis of aggressive NK-cell leukemia include:^[14]

Peripheral Blood Smear may show large granular lymphocyte (LGL), fine or coarse azurophilic granules and nucleoli of varying prominence, and nuclei may be irregular and hyperchromatic.

• There are no cytogenetic abnormalities specific to ANKL.
• However, following cytogenetic abnormalites have been reported more frequently among patients with aggressive NK-cell leukemia.
  • chromosomes 6q and 11q ^[15]
• Complete blood count (CBC) may show cytopenias.^[16]

• There are no ECG findings associated with aggressive NK-cell leukemia.

There are no x-ray findings associated with aggressive NK-cell leukemia.

• There are no echocardiography/ultrasound findings associated with aggressive NK-cell leukemia.

• There are no CT scan findings associated with aggressive NK-cell leukemia.

• There are no MRI findings associated with aggressive NK-cell leukemia.

• There are no other imaging findings associated with aggressive NK-cell leukemia.

• Aggressive NK-cell leukemia may also be diagnosed using bone marrow biopsy.^[17]
• Findings on bone marrow biopsy, include extensive marrow replacement by leukemic cells and reactive histiocytes displaying hemophagocytosis.

• The mainstay of therapy for aggressive NK-cell leukemia is anthracycline-containing chemotherapy.^[18]
• L-asparaginase containing chemotherapy regimen followed by allogeneic stem cell transplantation shows to slightly prolong life, but relapse is almost assured.^[19]
• Other novel treatments may include pralatrexate.
• None of the aforementioned treatment regimens have been curative.
• Allogeneic bone marrow transplantation has been reported successful in some cases.^[20]

• Surgery is not recommended among patients with aggressive NK-cell leukemia.

• There are no primary preventive measures available for aggressive NK-cell leukemia.

• There are no secondary preventive measures available for aggressive NK-cell leukemia.