IgA Levels Can Predict Survival in CLL Patients: A Retrospective Analysis of 183 Cases in a Brazilian Cohort

Background: Immunosuppression and frequent infections has impact on morbidity and mortality in CLL patients. It is basic related with chronic immune dysregulation or treatment toxicities. Hypogammaglobulin is a frequent event in CLL and can explain some of the infection susceptibility related to the disease. Low IgG levels were associated with a higher frequency of bacterial infections, commonly Streptococcus pneumoniae and Haemophilus influenza. Although hypogammaglobulin can contribute with repeated infections in CLL patients, the prognostic value of this occurrence is controversial. At our center we routinely test Ig levels at time of CLL diagnosis.

Methods: A retrospectively analysed was done with 183 patients diagnosed with typical CLL between 2007 to 2013 for clinical and laboratorial features (sex, age, CBC, CD38, Beta-2-microglobulin, albumin, Binet staging, direct coombs test and Ig levels) and survival (overall and time to first treatment). The statistical analysis was done on IBM SPSS v.20. This study received approval on the ethical committee from our institution.

Results: Median follow up of this cohort was 52 months. Median age was 65y (34-90) and 98 were male (52.1%). Most of them, 61.1% (n=110) were Binet A, 17.8% (n=32) Binet B and 21.1% (n=38) Binet C. Direct coombs test was positive in 9.9% of cases (n=16). CD38 was positive in 23.3% (n=40). The IgG, IgM and IgA levels were above normal laboratory value in 15.3% (n=29), 6.9% (n=13) and 6.3% (n=12), respectively, and it was below in 26.5% (n=50), 35.6% (n=67) and 36% (n=68), respectively. Twenty-three patients (12.2%) had both low levels of IgG, IgM and IgA and 57.7% had at least one Ig subtype at low level. When we consider only the IgA, 42.3% (n=80) had above or below levels. Albumin level was below 4.5 g/dl, 4.0 g/dl and 3.5 g/dl in 63.2% (n=115), 20.3% (n=37) and 9.3% (n=17), respectively. Beta-2 microglobulin level was higher than 2.5 mg/dl in 55% (n=93). The median overall survival was not reached and 76.8% +- 3.8% were alive at 52 months. On the univariate analysis (Kaplan-meier) of overall survival, high Binet staging (p=0.001), altered (high or low) IgG level (p=0.017), altered IgA level (p<0.001), any low Ig level (p<0.001), positive coombs test (p=0.006), beta-2-microglobulin higher than 2.5 mg/dl (p<0.001) and CD38 membrane expression showed worse prognosis. The multivariate model (cox regression) showed that just IgA at high or low level (p=0.002), coombs (p=0.022) and high Beta-2-microglobulin (p=0.001) had impact on survival. Hundred and eight patients with Binet A were included at time of first treatment survival analysis with median follow up of 58 months. The median TTFT again was not reached, but at 58 months was 58% (+- 5.6%). On the univariate analysis low albumin (p=0.039), IgA high or low levels (p=0.003), any low Ig level (p=0.037) and high Beta-2-microglobulin (p<0.001) were significant, remaining only IgA level (p=0.04) and high beta-2-microglobulin (p=0.006) at multivariate analysis.

Conclusion: This analysis suggests that low or high IgA level are associated with a worse prognosis. This could be explained by immune suppression (mucous immune system depression) and higher susceptibility for bacterial infection (mortality cause not evaluated). The fact that this group had a shorter time to first treatment can not be explained by the same reason. Maybe not normal IgA levels itself can be associated with a more aggressive and progressive disease. Despite of all the bias of a retrospective study (loss of follow up, missing values) and lack of FISH and IgVH mutational status at the diagnosis, this data points the importance of Ig level evaluation at the time of diagnosis