Lymphoproliferative Disorder and Acquired C1-INH Deficiency. A Case Series of 48 Patients

Abstract 1596

Angioedema with acquired deficiency of C1 inhibitor (C1-INH) is a rare syndrome associated with B lymphocyte disorders, usually identified as acquired angioedema (AAE). The clinical features of C1-INH deficiency, more often of genetic origin (hereditary angioedema HAE), include subcutaneous swelling, edema of the gastrointestinal wall causing temporary bowel obstruction with severe pain and edema of the upper respiratory tract that can lead to asphyxia. AAE associated B cell disorders result in autoantibodies to C1-INH, monoclonal gammopathies of uncertain significance (MGUS) and non Hodgkin Lymphomas (NHL). The 3 conditions may be concomitantly present suggesting that expansion of an anti C1-INH B lymphocyte clone is the primum movens of the disease. The burden of AAE derives from either the associated limphoproliferative disorder or the frequency and severity of angioedema symptoms: both conditions may lead to death. Here we report on the long term follow up of 48 patients (median age at onset of angioedema symptoms 57, range 39/79) with AAE with specific focus on the fate of lymphoproliferative disease and on the therapeutic problems. Patients were followed for a median of 6 years ( 1–25); diagnosis was based on C1-INH activity <50% of normal. Autoantibodies to C1-INH were positive in 35 of 48 patients (13 IgG, 13 IgM, 5 IgA, 2 IgG-IgM, 2 IgA-IgM). Nineteen (40%) fulfilled diagnostic criteria for MGUS. MGUS and auto antibodies to C1-INH coexisted in 13 patients all, but one, sharing the same heavy chain isotype. In 7, binding of the M component to purified C1-INH could be demonstrated. Twelve patients presented NHL. Based on WHO classification 10 had indolent lymphoma (2 lymphoplasmocytic/Waldestrom disease; 4 small lymphocytic lymphoma, 4 splenic marginal zone lymphoma, 1 follicular lymphoma). Median time between onset of angioedema symptom and diagnosis of NHL was 1 year (ranging from 15 years before to 12 years after). One lymphocytic and 1 marginal splenic lymphoma did not need treatment at 5 and 8 years follow up respectively. Two marginal splenic lymphoma are in remission after splenectomy at 2 and 7 years follow up. One marginal splenic lymphoma remitted upon splenectomy, chemotherapy and rituximab (3 years follow up). One lymphoplasmocytic lymphoma is in remission 2 years after rituximab. Two lymphocytic lymphoma remain on control with chemotherapy at 16 and 3 years respectively. One lymphoplasmocytic lymphoma progessed to death despite chemotherapy and rituximab. One follicular lymphoma is in remission 6 years after chemotherapy. Two high grade malignant lymphoma, a large B cell and a mantle cell, both progressed to death within 12 months despite chemotherapy and splenectomy the first and chemotherapy the second. Reversal of complement abnormalities was achieved upon therapy induced remission of NHL. Because of the frequency of angioedema recurrences 28 patients required prophylactic treatment successfully achieved with tranexamic acid in 23 patients and with danazol in 5. Breakthrough angioedema attacks were treated with plasma derived C1-INH, which was effective in 16 patients and non effective in 8. In these 8 patients, angioedema attacks were successfully treated with icatibant, a specific antagonist of the B2 receptors of bradykinin, the mediator of symptoms (median time to resolution 6.75 hours, range 0.5–39.75 hours). Ecallantide, a recombinant small protein that blocks plasma kallikrein, the bradykinin releasing enzyme, has also been successfully used to treat two angioedema attacks in two patients. During the follow up period 5 patients died for causes other than NHL or angioedema and one patient is in irreversible cerebral coma for severe hypoxia following a laryngeal edema, which did not respond to plasma derived C1-INH (icatibant was not available at that time). Our data suggest that in AAE different forms of B cells disorders coexist and/or evolve into each other probably starting from the pathologic prolypheration of clone(s) autoreactive against C1-INH. Hence, angioedema symptoms and B cell disorders are two aspect of a single disease. Blocking bradykinin or its release are valid alternatives to treat angioedema symptoms and may be lifesaving therapies for those patients who do not respond to plasma derived C1-INH.