Long-term event-free survival in patients with IGHV-mutated high-count monoclonal B-cell lymphocytosis and atypical, non-CLL-like phenotypes

Abstract

Abstract Monoclonal B-cell lymphocytosis (MBL) is a frequent precursor of chronic lymphocytic leukemia (CLL) and among the most common premalignant hematologic conditions. It can be either classified by clone size (low-count, LC-MBL versus high-count, HC-MBL) or by immunophenotype (CLL-like, atypical, and non-CLL-like MBL). LC-MBL is most frequent, whereas HC-MBL and, in particular, atypical/non-CLL-like MBL are far less abundant. Although the overall annual risk of CLL progression is low (around 1%), the progression risk varies highly between individuals and more detailed evidence according to the various MBL subtypes, specifically in HC-MBL and atypical/non-CLL-like subtypes, is limited. Reviewing 25 years of clinical courses, we here present the long-term follow-up of a MBL population (n=378) consecutively surveyed at tertiary care centers in Innsbruck/Austria, and Munich/Germany. This MBL population included 235 (62.2%) and 143 (37.8%) patients with HC-MBL and LC-MBL, respectively. 44 (11.8%) patients were diagnosed with atypical MBL, and 38 (10.2%) with non-CLL-like MBL. With a median follow-up of 110 months (range, 4 - 273) a very low CLL progression rate was detected in LC-MBL patients (3/143, 2.1%), which was paralleled by rather stable median MBL clone sizes [27 cells/ul (range, 1-443) at diagnosis, 58 cells/ul (range, 3-7249) at 5 years, and 166 cells/ul (range, 20-14877) at 10 years]. Patients with atypical and non-CLL-like MBL experienced a numerically higher but still low progression rate [5/44 (11.4%) and 2/38 (5.2%) events, respectively]. Here, MBL clone sizes over time were: 430 cells/ul (range, 3 – 4943) at diagnosis, 927 cells/ul (range, 5-26268) at 5 years, and 5958 cells/ul (range, 174-11742) at 10 years in atypical MBL patients, and 60 cells/ul (range, 1-4199) at diagnosis, 179 cells/ul (range, 17-2928) at 5 years, and 1410 cells/ul (range, 20-13099) at 10 years in non-CLL-like MBL patients. FISH analysis with a CLL Panel at MBL diagnosis was performed in 149/378 (39.4%) patients. 81/149 (54.7%) subjects showed at least one chromosomal aberration. 13q deletion (47/149, 31.5%) and trisomy 12 (16/149, 10.7%) were most common, while 17p deletion (7/149, 4.7%) and 11q deletion (2/149, 1.3%) were detectable in only very few subjects. Targeted NGS analysis (TP53, NOTCH1, BIRC3, SF3B1) at MBL diagnosis was done in 136/378 (36.1%) individuals. Interestingly, TP53 mutations were most abundant (12/136, 7.5%), followed by SF3B1 (9/136, 6.6%), NOTCH1 (6/136, 4.5%), and BIRC3 (4/136, 3%). None of these genetic abnormalities was independently associated with CLL progression in multivariate analysis. The IGHV mutational status was assessed in 152/378 (40%) patients and did not significantly impact on the risk of CLL progression in HC-MBL patients within the first 5 years after diagnosis with 26/49 (53.1%) events and 52/103 events (50.5%) in those with unmutated IGHV (IGHV-UM) and mutated IGHV (IGHV-M), respectively (p=0.24). However, a long-term event-free survival (EFS) plateau was seen in IGHV-M MBL beyond 5 years after diagnosis. This was in contrast to uncensored IGHV-UM patients who continuously developed progression events during long-term follow-up. Accordingly, similar median MBL clone size dynamics were detected during the first years upon MBL diagnosis [2498 cells/ul (range, 524-4943) at diagnosis and 4166 cells/ul (range, 504-41922) at 3 years in IGHV-M HC-MBL patients versus 2916 cells/ul (range, 616-4579) at diagnosis, and 5489 cells/ul (range, 1397-75829) at 3 years in IGHV-UM HC-MBL patients]. After longer follow-up, however, there was a significant rise of the median MBL clone sizes in IGHV-UM MBL patients, reflecting clonal expansion [12356 cells/ul (range, 1033-91377) at 5 years and 21369 cells/ul (range, 11267-167326) at 10 years in IGHV-UM HC-MBL patients versus 7135 cells/ul (range, 1129-44917) at 5 years and 13475 cells/ul (range, 2423-68848) at 10 years in IGHV-M HC-MBL patients, p=0.03]. In summary, long-term event-free survival in IGHV-M CLL-like HC-MBL patients after 5 years without progression is excellent. A slightly increased, but still low progression risk for the rare, atypical and non-CLL MBL subtypes similar to that of CLL-like LC-MBL is seen. Given that 75% of CLL-like MBL patients are considered IGHV-M, our results may provide a rationale for deescalated monitoring strategies in this population. Our findings warrant prospective validation in larger, independent patient cohorts.