A Single-Centre Series of 40 Patients with Bone-Marrow Biopsy-Defined Large Granular Lymphocyte Leukemia; High Rates of Sustained Response to Oral Methotrexate

Abstract 3937

Large granular lymphocyte (LGL) leukaemia is a rare lymphoproliferation originating in activated cytotoxic CD8+ T cells or occasionally NK cells. Published series incorporating 40 or more patients are few in number with some differences in diagnostic definitions, making comparisons between studies challenging. Investigators have chiefly relied on peripheral blood for diagnosis; typically defined as a persistent excess (>0.5×10⁹/l) of LGLs, associated with monoclonal T-cell receptor (TCR) gene rearrangements by PCR. However, benign monoclonal CD8⁺T-cell expansions, phenotypically indistinguishable from T-LGL, are well recognised in both healthy elderly individuals and those with autoimmune disease. To-date, reported response rates to oral Methotrexate (MTX) have been in the order of 40–60%, with MTX-failure reportedly occurring in two-thirds of patients after 1 year of follow-up.

We studied 40 patients diagnosed with LGL leukemia at Nottingham University Hospitals NHS Trust, UK, between 1990 and 2011. All patients had a persistent (>6 months) large granular lymphocytosis and, importantly, 97.5% (39/40) patients had undergone a bone marrow (BM) biopsy. In all cases an interstitial infiltrate of cytotoxic T cells and/or NK cells, typically demonstrating characteristic linear arrays, established the diagnosis. A majority of patients had correlative peripheral blood PCR studies confirming clonal TCR gene rearrangements in 80%. Although 5 patients had a polyclonal TCR gene, for all such patients the BM findings (>20% LGLs in some cases) together with clinical context (neutropenia, lymphocytosis and 2 cases of pure red cell aplasia (PRCA)) established the diagnosis of LGL leukemia.

The median age at diagnosis was 66 years (21–90 years), with an equal sex distribution. The median total lymphocyte count at clinical presentation was 2.7×10⁹/l (0.7–9.4 x10⁹/l) and a lymphocyte count of ≥2×10⁹/l was seen in 27 patients (68%). Thirty patients (75%) were neutropenic at diagnosis (median neutrophil count 0.9 x10⁹/l (range 0.0–6.5 x10⁹/l). In 13 cases neutropenia was accompanied by anemia, thrombocytopenia or both. Rheumatoid factor was positive in 11 of 27 assessable cases (41%), whilst 11 of 40 (28%) had associated autoimmune clinical disorders, including Rheumatoid arthritis (n=6).

With a median follow-up for living patients of 3.2 years (range 1.0–15.1 years), 15 patients (38%) have never required treatment. One further patient was already established on MTX at LGL diagnosis. Treatment was not required in any patients who presented with an isolated, asymptomatic lymphocytosis (n=8, 20%).

The median time from diagnosis to treatment was 2.1 months; all treatment-requiring patients needed therapy within 6 months of presentation. Treatment was indicated in 24 patients: neutropenia and recurrent infections (n=8); severe neutropenia (n=6); cytopenias associated with other symptoms (mouth ulcers, skin lesions, organomegaly) (n=8); and PRCA (n=2).

MTX (10mg/m², weekly) was employed as first-line therapy (n=9) and after failure of Prednisolone (0.5–1mg/kg) monotherapy (n=7). Amongst 16 MTX-treated patients, 14 (87.5%) achieved a haematological PR (n=6) or CR (n=8) after a median of 2.5 months (1–9 months). (Improvements in quality of response) Continuing responses (haem-PR to CR) were seen up to 2yrs after starting MTX (of MTX). Notably, for the 14 MTX-responders the median duration of response was 6.5 years (0.3–16), censoring for death and drug-cessation due to patient choice. Neither of the 2 patients with PRCA responded to MTX, but Ciclosporin and Fludarabine were effective salvage therapies for MTX-failures.

This is one of the largest single-centre series of LGL leukemia reported to-date. The strengths of our study include robust diagnostic evidence of LGL leukemia including BM biopsy and a long follow-up duration. By contrast to the published data, we describe high rates of response to MTX in both steroid-exposed and naive patients. Time to response exceeded 4 months in some cases and responses were sustained for >5 years in a majority of patients. The role of MTX in LGL leukemia warrants further study.