Evaluation of Therapy in Symptomatic Patients with Lymphoproliferative Disorders of Large Granular Lymphocytes in Italy

Chronic proliferations of large granular lymphocyte (LGL) are characterized by the expansion of cytotoxic T or NK cells. Relevant clinical features include neutropenia and anemia, either symptomatic or asymptomatic. The immunological and biological features of patients’LGL and the frequent association with autoimmune conditions represent the rationale for the immunosuppressive therapy frequently used in these conditions. However, no common criteria for starting therapy have been defined nor standard therapy has been established. We herein present data on 30 symptomatic patients treated in different Italian Centers, in the context of a collaborative study sponsored by the GIMEMA group.

Diagnosis of lymphoproliferative disorder of LGL was made according to published criteria (Blood 1997, 1:89) and WHO classification 2008. Twentyseven patients were diagnosed as LGL leukemia and 3 as NK chronic lymphoproliferative disorder (NK-CLPD). Patients required treatment for symptomatic neutropenia, more frequently represented by recurrent bacterial infections (23/30), transfusion dependent anemia (4/30), other reasons (5/30; n: 2 pulmonary hypertension, n:2 aggressive disease and n:1 neurologic involvement).

First line therapy consisted of methotrexate (MTX) at 7,5 mg/m²/week in 13/30 patients; cyclosporin A (CyA, (2-3 mg/Kg/die) in 10/30 patients; cyclophosphamide (CY, 50–100mg/die) in 5/30 patients; (immuno)-chemotherapy (Campath-fludarabine, CVP, CHOP-like regimens) in 2 patients characterized by aggressive clinical presentation of disease with B symptoms. Steroid was generally given for short period (1 mg/kg p.o. prednisone) and then tapered off in all but 2 patients. Growth factors (G-CSF and EPO) were also used for short period of times. Before considering failure, each treatment was continued for at least 4 months. Response criteria were defined according to Lamy and Loughran (Blood 2011, 10:117).

Second line therapy with MTX, CyA and CY was used in 2, 4 and 3 patients, respectively.

Time to response to MTX therapy ranged from 1 to 12 months. The overall response rate were 60% (9/15), with 3 CR and 6 PR. The duration of response ranged from 5 to 48 months. The 5 patients failing MTX as first line therapy were treated with CY (n:2, 1 CR, 1 PD), with CyA (n:2, 2 PR) and 1 rapidly progressed and died.

Time to response to CyA ranged from 2 to 12 months. The overall response rate were 50% (7/14) with 2 CR and 5 PR. The duration of response ranged from 1 year to 10 year. The 5 patients failing first line CyA therapy were treated with MTX (n:1, with PR), with CY (n:2, with failure, but one case was rescued using the combination of CyA/CY), 1 patient with chemotherapy with failure; for 1 patient the follow up is too short.

Time to response to CY ranged from 3 to 9 months. The overall response rate were 37.5% (3/8):2 CR, 1 PR. The duration of response ranged from 5 months to 5 years. The 3 patients failing CY at first line were treated with bendamustine (n:1), with alemtuzumab (n:1), with MTX (n:1) with failure in each cases

Two patients with very aggressive presentation were treated with chemotherapy: 1 case rapidly progressed and died; 1 case, who failed CT, was treated first with CyA and then with MTX with failure. This patient underwent allotransplant.

Immunosuppressive therapy with MTX or CyA or CY represents the common initial approach to patients with symptomatic LGL proliferation. Patient failing one therapy can be efficiently rescued by one of the other immunosuppressive drugs. Although any conclusive evaluation is difficult due to the low number of patients, our data are likely to indicate that the duration of response after treatment with CY and CyA is longer than the response obtained with MTX. The aggressive initial presentation of disease correlates with a very dismal prognosis. A prospective randomized clinical trial comparing these three different clinical approaches is going to start in Italy.

No relevant conflicts of interest to declare.