Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease

Abstract

Large Granular Lymphocyte Leukemia (LGLL) is a rare, chronic lymphoproliferative disorder of effector cytotoxic T-cells, and less frequently, natural killer (NK) cells. The disease is characterized by an indolent and often asymptomatic course. However, in roughly 50% of cases, treatment is required due to severe transfusion-dependent anemia, severe neutropenia, or moderate neutropenia with associated recurrent infections. LGLL represents an interesting disease process at the intersection of a physiological immune response, autoimmune disorder, and malignant (clonal) proliferation, resulting from the aberrant activation of cellular pathways promoting survival, proliferation, and evasion of apoptotic signaling. LGLL treatment primarily consists of immunosuppressive agents (methotrexate, cyclosporine, and cyclophosphamide), with a cumulative response rate of about 60% based on longitudinal expertise and retrospective studies. However, refractory cases can result in clinical scenarios characterized by transfusion-dependent anemia and severe neutropenia, which warrant further exploration of other potential targeted treatment modalities. Here, we summarize the current understanding of the immune-genomic profiles of LGLL, its pathogenesis, and current treatment options, and discuss potential novel therapeutic agents, particularly for refractory disease.

Keywords: immunogenomics; large granular lymphocytic leukemia; refractory disease.

Figure 1

Diseases commonly associated with LGLL and schematic representation of underlying pathogenesis. MGUS: Monoclonal gammopathy of undetermined significance; PRCA: pure red cell aplasia; AIHA: autoimmune hemolytic anemia; MDS: Myelodysplastic syndrome; HSC: hematopoietic stem cell. AICD: activation-induced cell death; STAT: Signal Transducer and Activator of Transcription 3; TCR: T-cell receptor; CTL: cytotoxic T-cells; ITP: Immune thrombocytopenic purpura; MM: multiple myeloma; RCC: Renal cell carcinoma; RF: rheumatoid factor; ANA: antinuclear antibodies. Figures were generated with BioRender.com (accessed on 20 August 2021).

Figure 2

Pathways and agents described as having potential interest for the treatment of refractory LGLL. The humanized IgG1 Risankizumab is a mAB targeting the p19 subunit of IL-23 receptor and selectively inhibiting IL-23 and the STAT pathway, blocking IL-17 and IL-22 production. The ROCK2 inhibitor Belumosudil inhibits the STAT3 phosphorylation process. Anti-IL-6 mAB Tocilizumab and Siltuximab inhibit the JAK pathway by binding to the gp130 subunit. Secukinumab and Ixekizumab are anti-IL-17 mAB blocking the interaction with the IL-17 receptor with subsequent STAT3 and NF-kB pathway inhibition. Bortezomib is a proteasome inhibitor that downregulates the NF-kB pathway activity, ultimately blocking the degradation of different pro-apoptotic factors. Abatacept, by binding to CD80/CD86 on APC, blocks the CD28-mediated APC and T-cell interaction. Sirolimus is an inhibitor of the mammalian-Target of rapamycin (mTOR) kinase pathway, leading to cytokine-mediated T-cell activation and STAT3 inhibition. Alemtuzumab is anti-CD52, causing lymphocyte depletion through complement-medicated cell lysis and antibody-mediated cytotoxicity. Epigenetic modifiers such as Belinostat can restore SOCS3 expression, which results in STAT3 pathway inhibition. Figures were generated with BioRender.com (accessed on 20 August 2021).