Immunoglobulin G (IgG) Subclasses in Chronic Lymphocytic Leukaemia
Authors: Freeman Jane A. , Forsyth Cecily J. , Mackinlay Naomi J. , Han Ping , Mulligan Stephen P. 
Published: April 2020

Abstract
Hypogammaglobulinaemia is a common complication of Chronic Lymphocytic Leukaemia (CLL) with an incidence that varies considerably in the reported literature. Immunoglobulin replacement therapy has documented benefit for patients with hypogammaglobulinaemia, CLL and recurrent episodes of infection. Very little data exists on IgG subclasses in CLL. We measured IgG subclasses together with immunoglobulins G, A and M, protein EPG and immunofixation in a cohort of patients with CLL representing a variety of disease stages, treatment status and history of infection to analyse the implications of IgG subclass deficiency in the disease. There were 155 patients analysed with 89 males and 66 females with mean age 67.4 (range 21–95) years. Distribution by Binet Stage was A-107, B-38, C-10. There were 111 patients untreated and 44 who had received chemotherapy, 21 with fludarabine based therapy and 11 containing rituximab (all FCR, 2 with lumiliximab). Five patients had received prior intravenous gammaglobulin (IVIg) and were excluded from further analysis. In the remaining 150 patients with no exposure to IVIg, low immunoglobulin levels were as follows: IgG &lt;6.0g/L–46 (30.6%); IgA &lt;0.69g/L–46 (30.6%); IgM &lt;0.5g/L-87 (58%). IgG subclass deficiency were as follows: IgG1 &lt;4.0g/L-39; IgG2&lt;1.3g/L-28; IgG3 &lt;0.4g/L-79; IgG4 &lt;0.05g/L–35, with a total of 97/150 patients (64.6%) having a deficiency of at least one IgG subclass defined at these levels. IgG subclass deficiency was seen in 52 patients with a normal total IgG level ≥6.0g/L. Entirely normal immunoglobulin levels (IgG, A, M and IgG subclass) were seen in only 26 patients, none of these patients had recurrent infection. Recurrent episodes of infection were seen in 24 patients of whom 13 had total IgG &lt;6.0g/L. Recurrent infection with total IgG≥6.0g/L was seen in 11 patients. The incidence by clinical stage of infection and IgG subclass deficiency are shown in the table.
Stage No patients Infection % infection No IgG subclass deficiency. A 106 10 yes 4% All (100%) 96 no 50 (52%) B 37 11 yes 29.7% All (100%) 26 no 19 (73%) C 7 3 yes 43% All (100%) 4 no All (100%)
Chemotherapy exposure correlated strongly with clinical stage and disease progression and a separate treatment effect could not be discriminated in this series. Paraproteins were seen in 24 patients, 14 IgG, (3 IgG1, 2 IgG4, others indeterminate), 6 IgA and 4 IgM. Polyclonal hypergammaglobulinaemia was present in 5 patients, 3 of whom had predominantly an increased IgG2. There were 19/129 (14.7%) patients with a positive Coombs’ test (direct antiglobulin test-DAT), all of whom had at least one immunoglobulin abnormality; 12 a total IgG &lt;6.0g/L, 16 at least one IgG subclass deficiency and 6 paraproteins. Analysis of immunoglobulin levels and IgG subclasses in a cohort of patients with variety of clinical stage shows IgG subclass deficiency is common, especially in advanced Stage B and C disease. All combinations of IgG subclass deficiency may be seen in CLL. IgG subclass deficiency (64.6%) is more common than low total IgG (30.6%) and the rate of infection (16%). Abnormal immunoglobulin levels appear associated with a positive DAT (100%). Paraproteins were seen in 16% of patients.