Large granular lymphocytic leukemia – A retrospective study of 319 cases

Abstract

Large granular lymphocytic leukemia (LGLL) is a rare hematological malignancy that arises from cytotoxic T lymphocytes (T‐LGLL) in 85% of cases and natural killer (NK) cells in the rest. A significant knowledge gap exists regarding the pathogenesis, treatment choices, and prognostic factors of LGLL. We report a cohort of 319 consecutive LGLL patients who presented to our cancer center between 2001 and 2020. A total of 295 patients with T‐LGLL and 24 with chronic NK‐cell lymphoproliferative disorder (CLPD‐NK) were identified. The median age was 65 years (range, 17–90 years). Eighty‐three patients (26.0%) had autoimmune diseases. A total of 119 patients (37.3%) had coexisting malignancies, 66 (20.7%) had solid tumors, and 59 (18.5%) had hematological malignancies. Most coexisting malignancies were diagnosed before the diagnosis of LGLL. Treatment was needed for 57% of patients. Methotrexate (MTX), cyclophosphamide (Cy), and cyclosporine A (CSA) were most used and had similar response rates between 61.5%–74.4%. Cy produced more complete responses (32.3%) compared to MTX and CSA (15.7% and 23.1%, respectively). Thrombocytopenia, splenomegaly, and female gender (after controlling for autoimmune diseases) were associated with decreased response rates to MTX, CSA, or Cy. Autoimmune diseases were associated with increased response rates. Thrombocytopenia was an independent risk factor for worse survival.

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

“…In addition to its effects on DNA replication, MTX suppresses the activation of JAK/STAT signaling [39]. Indeed, STAT3 Y640F mutant cases appear to be more likely to respond to MTX treatment [40], which is also the preferred choice when treating LGLL patients with associated rheumatoid arthritis (RA), neutropenia, or other autoimmune conditions [17]. CsA, as a calcineurin inhibitor, blocks NF-AT, IL-2, and IFN-γ expression [26].…”

“…Moreover, it has been shown that HLA-DR4 carriers may have a higher likelihood of CSA responsiveness, suggesting the presence of underlying antigen-driven mechanisms in different contexts characterized by specific immunogenetic predisposition [41]. Cy appears to be a good option, especially for cases with concurrent PRCA or profound anemia [17]. Chronic daily oral administration seems to be the preferred approach rather than periodic intravenous (IV) boluses.…”

“…Clinically, LGLL patients may remain asymptomatic for many years due to the aforementioned indolent course of the disease [1,17]. However, severe neutropenia, moderate symptomatic neutropenia, transfusion-dependent anemia, or autoimmune hemolytic anemia may necessitate therapy.…”

A non‐cytotoxic regimen of decitabine to treat refractory T‐cell large granular lymphocytic leukemia

“…Overall response rates (ORR) have been reported at 38%‐60% for MTX, 45%‐92% for CsA, and 47%‐72% for Cy, 2 , 3 and a recent retrospective analysis reported comparable ORR of 61.5%‐74.4% for all three agents. 4 Even less data exist as to the management of refractory cases. Several drugs inhibiting epigenetic repressing enzymes of the histone deacetylase (HDAC) class are approved for treating other peripheral T‐cell malignancies, and a case report described the successful use of the HDAC‐inhibitor belinostat (1000 mg/m 2 intravenously, days 1–5 in 21‐day cycles) to produce red cell transfusion independence in a patient with T‐LGL and anemia refractory to MTX, CsA, and Cy.…”

“…Guided by single‐arm studies, three drugs—methotrexate (MTX), cyclosporine (CsA), and cyclophosphamide (Cy)—are routinely used as first‐line therapies. Overall response rates (ORR) have been reported at 38%‐60% for MTX, 45%‐92% for CsA, and 47%‐72% for Cy, 2,3 and a recent retrospective analysis reported comparable ORR of 61.5%‐74.4% for all three agents 4 . Even less data exist as to the management of refractory cases.…”