Aggressive natural killer cell leukemia: diagnosis, treatment recommendations, and emerging therapies

ABSTRACT

Introduction

Aggressive natural killer cell leukemia (ANKL) is a rare hematologic malignancy characterized by the EBV-driven proliferation of mature natural killer cells. It mostly frequently affects younger adults and has a fulminant course with a median overall survival of 2 months. Challenges in managing this disease include an aggressive clinical course, hematologic complications, limited clinical evidence, and a lack of consensus on therapeutic strategies.

Areas covered

Here, authors reviewed the key aspects of the epidemiology and current understandings of the molecular pathogenesis of ANKL. The available clinical evidence and proposed diagnostic and therapeutic algorithms in treating ANKL are discussed. Currently, the only potential cure is induction therapy with L-asparaginase–based combined chemotherapy regimens, followed by allogeneic hematologic stem transplant. However, options are extremely limited in the relapsed/refractory setting. Recently, international efforts have been made to understand the aberrant molecular pathways of ANKL and identify potential drug targets for this disease; PD-1 inhibitors, EBV-specific cytotoxic lymphocyte therapy, BCL-2 inhibitors, and JAK2 inhibitors in combination with other agents have been shown to have promising potential in treating this aggressive disease.

Expert Opinion

When clinical trials are not available, a personalized approach using next-generation sequencing results should be encouraged in the relapse/refractory setting.

KEYWORDS:

• Aggressive natural killer cell leukemia
• natural killer cells
• biomarkers
• diagnosis
• management
• therapeutics

Article highlights

• Aggressive natural killer cell leukemia (ANKL) is an aggressive hematologic malignancy of mature EBV-infected natural killer cells. It mostly affects younger adults and carries poor survival.

• ANKL is associated with hematologic complications, such as disseminated intravascular coagulopathy and hemophagocytic lymphohistocytosis, which require early recognition and prompt management.

• Recent advances in understanding the molecular pathogenesis of ANKL have led to the identification of several promising drug targets: PD-1 blockade, JAK/STAT pathway inhibition, BCL-2 inhibition, and EBV-specific cytotoxic lymphocytes.

• For young and fit adults, L-asparaginase–based therapy, such as modified SMILE, is recommended as induction therapy. Allogeneic hematopoietic stem cell transplant should be performed when response is achieved, as it is the only potential cure for ANKL.

• For patients with relapsed or refractory disease, a personalized approach based on a tumor somatic mutational panel, PD-L1 expression, and BCL-2 expression is recommended.

Acknowledgments

Editorial assistance was provided by the Moffitt Cancer Center’s Office of Scientific Writing by Dr. Paul Fletcher & Daley Drucker. No compensation was given beyond their regular salaries.

Declaration of interest

L Sokol has disclosed serving as a consultant for Dren Bio; receiving support for clinical trial for Bioniz Therapeutics; and advisory board participation for Kyowa Kirin. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Data Availability Statement

Data will be made available upon reasonable request

Additional information

Funding

This paper was not funded.