REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)

Background
Chronic lymphocytic leukemia (CLL) patients with somatically hypermutated IGHV genes (M-CLL) within their B-cell receptor immunoglobulin (BcR IG) generally display favorable biological profiles with an indolent disease course. However, neither the biological background nor the clinical presentation and outcome of M-CLL is uniform, thus justifying the quest for parameters that would assist in refining prognosis. 

Aims

Development of a novel prognostic index tailored to M-CLL.

Methods
Cox-regression models were used to assess the impact of demographic, clinical, genomic and immunogenetic features on time-to-first-treatment (TTFT) in 1359 M-CLL cases. 

Results
Main features of the studied cohort were as follows: median age: 64 years (22-92); males: 810/1359 (60%), Binet A/B/C: 1169/79/53 (90%/6%/4%); CD38 expression (CD38+): 161/1225 (13%). Except for del(13q) (494/836, 59%) and trisomy 12 (+12, 142/1072, 13%), other genomic aberrations were relatively rare [del(11q): 49/1076 (4.5%), TP53 abnormality (TP53abn) i.e. del(17p) and/or TP53 mutations: 52/1144 (4.5%), NOTCH1 mutations (NOTCH1m): 23/1333 (2%), SF3B1m: 33/897 (4%), MYD88m: 23/556 (4%)]. Borderline mutated IGHV genes (germline identity, GI: 97-97.99%) were expressed by 101 cases (7%). Thirty-three (2.5%) and 26 (2%) patients were assigned to stereotyped subsets #4 (IGHV4-34/IGKV2-30) and #2 (IGHV3-21/IGLV3-21), respectively. All the aforementioned parameters were evaluated for their impact on TTFT, using  univariate regression analysis. As expected, Binet stage C at diagnosis emerged as the most powerful marker (HR: 9.44, 95% CI, 7.45-11.97, p<0.0001). Among the remaining cases (Binet A/B), representing 96% of the cohort, the following parameters were significantly associated with shorter TTFT: Binet B (HR: 7.35, 5.51-9.81, p<0.0001), subset #2 membership (HR: 4.24, 2.32-7.76, p=0.0001), CD38+ (HR: 2.62, 1.98-3.50, p<0.0001), TP53abn (HR: 2.56, 1.64-4, p=0.0003), +12 (HR: 1.75, 1.27-2.41, p=0.002), male gender (HR: 1.52, 1.2-1.9, p=0.004). In contrast, a trend for favorable outcome was observed for subset #4 membership (HR: 0.43, 0.16-1.18, p=0.06). Taking into consideration the above HRs as well as median TTFT, we defined 4 groups among Binet A/B patients (n=934) with different TTFT (Figure 1): (i) high risk (n=88, 9%): Binet B or subset #2 membership (median TTFT: 2.1 years, 65% and 85% probability of treatment initiation (TI) at 5 and 10 years from diagnosis, respectively); (ii) intermediate risk (n=199, 22%): Binet A and occurence of one or more of: CD38 expression/TP53abn/+12 (median TTFT: 12 years, 33% and 45% TI at 5 and 10 years, respectively); (iii) low risk (n=619, 66%): Binet A with no CD38+/TP53abn/+12 (median TTFT: not yet reached, 15% and 25% TI at 5 and 10 years, respectively); and (iv) very low risk (n=28, 3%): subset #4 membership (median TTFT not yet reached,  0% and 10% TI at 5 and 10 years, respectively). 

Summary

We report a simple prognostic index for M-CLL capable of identifying patients who will experience short TTFT as well as those who will probably never require treatment, applicable even within early clinical stage CLL. At the ends of the clinical spectrum described by this novel index lie stereotyped subsets #2 (aggressive) and #4 (indolent). This further highlights the importance of distinct BcR IG configuration, likely linked to distinct immune signaling, for CLL ontogeny and evolution and indicates that subclassifying M-CLL based on stereotypy is relevant in the context of everyday routine practice. 

Keyword(s): Chronic lymphocytic leukemia, Prognosis

www.eha.org