Serum Immunoglobulins Are an Independent Prognostic Marker of Time to First Therapy in Newly Diagnosed Chronic Lymphocytic Leukemia (CLL) and Monoclonal B-Cell Lymphocytosis (MBL)

Background: Immune dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and several studies suggest that hypogammaglobulinemia at the time of CLL diagnosis may predict shorter time to first therapy (TTFT; Parikh et al, 2015). However, it is unclear if hypogammaglobulinemia can predict TTFT independent of the CLL-International Prognostic Index (CLL-IPI) and the tumor mutational load (TML). We sought to determine if serum immunoglobulin (Ig) levels at diagnosis can independently predict outcomes in patients with CLL and its precursor, high-count monoclonal B-cell lymphocytosis (MBL).

Methods: We used the Mayo Clinic CLL Database to identify newly diagnosed CLL/MBL consented within 2 years of diagnosis. Next generation sequencing (NGS) was performed using a 59 gene panel (SureSelect) to detect mutated CLL genes. Serum Ig levels were quantitated by radial immunodiffusion (Immunoplates). Serum Ig levels below the lower limit of normal were defined as hypogammaglobulinemia. We used Chi-squared or Fisher’s exact tests to compare discrete variables and the Kruskal Wallis test for continuous variables. TTFT was calculated from date of diagnosis to date of first treatment or date last known to be untreated. We used Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for TTFT and overall survival (OS) associations.

Results: We identified 895 newly diagnosed patients (588 CLL and 307 MBL) who had undergone NGS for recurrent somatic mutations and had serum Ig levels available at the time of diagnosis. The median absolute B-cell count was 6.7 x10⁹/L; 613 (69%) were male, 375 (42%) had unmutated IGHV genes, and 81 (9%) had TP53 disruption. Based on CLL-IPI, 412 (46%) patients had low risk, 285 (32%) had intermediate risk, and 198 (22%) had high/very high risk. The most commonly mutated genes were NOTCH1 (14%), SF3B1 (11%), TP53 (10%), NFKBIE (8%), ATM (6%), and BIRC3 (6%). Based on the number of genes with high impact or hotspot mutations, we classified 40%, 29%, and 31% patients with TML scores of 0, 1, or 2+, respectively.

At CLL/MBL diagnosis, the median serum IgG, IgA, and IgM was 891 mg/dL (111-2620), 121 mg/dL (1-1150), and 44 mg/dL (5-1320), respectively; 284 (32%) patients had low serum IgG, 128 (17%) had low serum IgA, and 322 (42%) had low serum IgM. Low serum IgA was associated with mutations in NOTCH1, SF3B1, ATM, BIRC3 and NFKBIE, low IgM was associated with SF3B1 and BIRC3 mutations (all comparisons, P < .05), and low IgG was associated with BIRC3 mutation (P = .05).

The median follow-up for the cohort was 8.4 years. A total of 359 patients progressed requiring therapy (299 CLL and 60 MBL), and 265 patients died (177 CLL and 88 MBL). The TTFT was significantly shorter for patients with low serum IgG compared to normal serum IgG at diagnosis (median 4.4 vs 10.8 years) and similar findings were observed in individuals with low serum IgA (1.7 vs 10.8 years) and those with low serum IgM (4.6 vs 11.1 years). On univariable analysis, the following were associated with a shorter TTFT: low serum IgG (HR: 1.8, 95% CI 1.4-2.2), low serum IgA (HR: 3.5, 95% CI 2.7-4.4), low serum IgM (HR: 1.9, 95% CI 1.5-2.3), TML score of 1 (HR: 1.7, 95% CI 1.3-2.2), TML of 2+ (HR: 4.4, 95% CI 3.4-5.7), CLL-IPI intermediate risk (HR: 3.7, 95% CI 2.8-4.8), and CLL-IPI high/very high risk (HR: 7.6, 95% CI 5.8-10.1) (all comparisons, P < .0001). In multivariable analyses after adjusting for CLL-IPI and TML, low serum levels of IgG (HR: 1.8, 95% CI: 1.5-2.3), IgA (HR: 2.4, 95% CI: 1.8-3.0), and IgM (HR: 1.8, 95% CI: 1.5-2.3) were independently associated with a shorter TTFT (all comparisons, P < .0001). No significant differences in OS were detected between patients with low and normal serum IgG, IgM, and IgA on univariate analysis. Similar results for TTFT and OS were observed after adding clonal B-cell count to the Cox model.

Conclusions: Our study shows that low serum Ig levels at the time of initial diagnosis is predictive of TTFT independently of the CLL-IPI and TML, which can further risk stratify individuals with newly diagnosed CLL/MBL. Additionally, low serum IgA, IgM, and IgG levels at diagnosis are significantly associated with specific somatic mutations in individuals with newly diagnosed CLL/MBL.