Hypogammaglobulinemia is a strong predictor of time to first treatment in chronic lymphocytic leukemia

Background: Management of chronic lymphocytic leukemia (CLL) dramatically improved since the introduction of novel therapies. Rarely patients requires treatment at diagnosis and approximately a third of patients will never require therapy. Predictive and prognostic factors are well known (IGHV, del11q, del17p, TP53); CLL-IPI score including age, clinical stage, beta2microglobulin, IGHV and deletion 17p and/or TP53 mutation has been recently validated. It identifies 4 risk groups with significantly different time to first treatment (TTFT) and overall survival (OS). Hypogammaglobulinemia (HYPO) is a typical feature of CLL, with an incidence of 20-60% at diagnosis and a relationship with infections occurrence. Prognostic significance of HYPO at diagnosis has not been extensively evaluated in terms of OS and TTFT. Only IgG serum levels have been reported to be associated with TTFT but no data are available on other immunoglobulin classes (Ig). Aims: To evaluate the impact of HYPO and single Ig classes on TTFT in a retrospective cohort of CLL patients and to assess the relationship between HYPO and CLL-IPI. Methods: We retrospectively evaluated 698 consecutive CLL patients diagnosed at our Institution from 1983 till 2016. Data from laboratory, biological analysis and clinical stage were collected. We also evaluated immunoglobulin (Ig) status (i.e. IgG, IgM and IgA) at diagnosis and calculated CLL-IPI. HYPO was defined basing on our laboratory cut-offs (IgA 70mg/dl, IgG 700mg/dl, IgM 40mg/dl). However, as no recognized prognostic/predictive Ig cut off has been reported to date, we aimed to identify a prognostic threshold for each Ig class. Results: From 698 patients assessed, 410 cases were evaluable for Ig values at diagnosis. IgA levels were lower than 70mg/dl in 17,4%, IgG lower than 700mg/dl in 22,2%, and IgM lower 40mg/dl in 33.7%. Forty-six percent of patients presented deficit of at least one Ig class, while 7.8% of patients had all Ig low. Each Ig deficit was related with a shorter TTFT with the following hazard ratios (HRs): 2.09 (1.45-3.03) for IgA (P<0.0001), 1.58 (1.10-2.27) for IgG (P=0.008) and 1.52 (1.09-2.13) for IgM (P=0.01) (Figure 1, A-B-C). However, only IgA deficit maintains statistical significance in multivariate analysis [HR 1.59 (1.08-2.35)]. A prognostic threshold for each Ig class was identified maximizing the differences in TTFT and the following values were obtained: 80mg/dl for IgA, 410mg/dl for IgG and 18mg/dl for IgM (Figure 1, D-E-F). Considering CLL-IPI, 186 patients presented IPI 0-1, 99 had IPI 2-3, 32 patients IPI 4-6, and 12 patients had IPI 7-10. Even in our series, CLL-IPI separated four risk groups with different TTFT and OS, suggesting that our cohort may be suitable to evaluate new prognostic factors. As regards the relationship between HYPO and CLL-IPI, we observed a correlation with IgA levels, using our laboratory cut-off. Moreover, we found a relationship among CLL-IPI and both IgA and IgM values, when using the newly validated Ig cut-off. Finally, CLL-IPI was a stronger prognostic factor for TTFT than HYPO in our analysis. However, the addition of IgA deficit to CLL-IPI appears to further improve CLL prognostication.Summary/Conclusions: In conclusion, HYPO significantly impacts on CLL prognosis. Moreover, even if CLL-IPI has a stronger prognostic value for TTFT compared to HYPO, the addition of IgA deficit appears to further improve CLL prognostication.