A new risk model to predict time to first treatment in chronic lymphocytic leukemia based on heavy chain immunoparesis and summated free light chain

Abstract

Background Chronic lymphocytic leukemia (CLL) is frequently accompanied by immune dysregulation. Aims In this multicenter prospective study, we investigated whether heavy + light chains (HLC: IgGκ, IgGλ, IgAκ, IgAκ, IgMκ, IgMλ) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) could be used as novel prognostic markers of immunoparesis in 105 treatment‐naïve patients with CLL. Results Heavy + light chains immunoparesis of ≥1, ≥2, and ≥3 isotypes was evident in 74 (70%), 58 (55%), and 36 (34%) patients, respectively. Severe HLC immunoparesis was identified in 40 (38%) patients. Of the IgG subclasses, IgG1 and IgG2 were most frequently suppressed, affecting 46 (44%) and 36 (34%) patients, respectively; 63 (60%) patients had low levels of at least one IgG subclass. In multivariate analysis, severe HLC immunoparesis (hazard ratio [HR]: 36.5; P = .010) and ΣFLC ≥ 70 mg/L (HR: 13.2; P = .004) were the only factors independently associated with time to first treatment (TTFT). A risk model including these variables identified patients with 0, 1, and 2 risk factors and significantly different TTFT (P < .001). Patients with two factors represented an ultra‐high‐risk group with a median TTFT of only 1.3 months. Conclusion The above findings demonstrate the potential for the use of HLC immunoparesis, together with sFLC measurements, as future prognostic biomarkers in CLL.

Secondary Immune Deficiency and Primary Immune Deficiency Crossovers: Hematological Malignancies and Autoimmune Diseases

“…Patients were classified as high confidence/high risk, low confidence, and high confidence/low risk for infection. The model did not provide information regarding immunoglobulins, which is in contrast to other studies which have found that significant hypogammaglobulinemia (IgG <4g/L) or low IgG and IgA are associated with the risk of serious infection ( 58 , 59 ). Using the CLL-TIM algorithms, the occurrence of infections several years prior to the diagnosis of CLL was highly specific for the risk of infection after diagnosis but prior to CLL treatment.…”

“…found that significant hypogammaglobulinemia (IgG <4g/L) or low IgG and IgA are associated with the risk of serious infection (58,59). Using the CLL-TIM algorithms, the occurrence of infections several years prior to the diagnosis of CLL was highly specific for the risk of infection after diagnosis but prior to CLL treatment.…”

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…Thus, the model may simplify the risk stratification in clinical management. Tamar Tadmor et al proposed a new risk model based on heavy+light chains (HLC) and IgG subclasses to predict TTFT [ 104 ]. The model separated patients into 3 subgroups according to the numbers of risk factors and patients with 2 risk factors are of ultra-high-risk with a median TTFT of only 1.3 months.…”

Prevalence and the impact of hypogammaglobulinemia in newly diagnosed chronic lymphocytic lymphoma patients

“…Although the association of pretreatment hypogammaglobulinemia with overall survival is uncertain, most studies including ours show clear association with stage, a marker of disease burden, and possibly duration of having CLL [8,9,23] that explained the shorter time to the first treatment in these studies. Hypogammaglobulinemia is likely a consequence of the oncogenic process of CLL since it is rarely found prior to a few years before the diagnosis [24]; however, the exact process is unknown.…”