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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. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate disease characteristics and long‐term outcomes in patients requiring second‐line treatment following fludarabine, cyclophosphamide, and rituximab (FCR), for relapsed/refractory disease (R/R), or following discontinuation due to toxicities. Method: A retrospective analysis of 126 chronic lymphocytic leukemia patients treated with frontline FCR: 63 received second‐line treatment (41 relapsed, nine refractory [SD/PD], 13 prior toxicity). Time to next treatment (TTNT) was calculated from beginning FCR to initiation of second‐line therapy. Overall and event‐free survival was calculated from initiation of salvage treatment (OS2/EFS2). Results: Median follow‐up for the entire cohort was 67 and 37 months from second‐line therapy. TTNT < 24 months was associated with shorter OS2 and EFS2 similar to those observed with primary refractory disease (OS2 19 and 23 months; EFS2 12 and 9 months for TTNT < 24 months and SD/PD, respectively). TTNT ≥ 24 months (71% chemotherapy‐based second‐line), had longer OS2 and EFS2 (48 and 20 months). Among the 13 patients receiving second‐line therapy after discontinuing FCR due to toxicity EFS2 was 41 months (59 months from initiation of FCR). Conclusion: With limitations of sample size and treatment heterogeneity, patients progressing <24 months following FCR have poor outcomes, similar to refractory patients, while longer remissions are indicative of a chemoimmunotherapy sensitive disease. Patients who discontinue FCR for toxicities may achieve excellent outcomes with subsequent treatment. [ABSTRACT FROM AUTHOR]