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S. Jaramillo et al.
and clinical behavior than IGHV mutational status alone, at least in certain cases.
Subset #4 is known to have an indolent clinical course and is most frequent among younger patients.15,19 According to our findings, subset #4 had the most favor- able prognosis regarding PFS and TTFT compared to the remaining subsets in the early stage CLL population. Furthermore, in the advanced stage CLL analysis, subset #4 showed a longer TTNT compared to mutated CLL and a longer PFS compared to all other subsets. It is striking that for all time-dependent endpoints in the early stage as well as the advanced stage cohort, the outcome of subset #4 patients appeared to be even better than M-CLL. This again points to the hypothesis that subset and therefore BcR IG structure may be more relevant in pathogenesis and prognosis than IGHV mutational status.
Subset #8 has been associated with increased risk of Richter transformation and trisomy 12.35,36 In the advanced stage CLL, we observed a higher rate of trisomy 12 and a higher incidence of Richter transformation compared to the other subsets. Subset #8 showed a shorter PFS com- pared to subsets #1 and 2 in advanced stage CLL cases. However, due to the small size of this subgroup popula- tion, this could not be tested in a multivariable analysis.
The strength of the current study is also one of its weaknesses, as due to the long follow-up time there was no inclusion of novel agents such as ibrutinib, idelalisib and venetoclax in the treatment schedules. Data of patients treated within clinical studies of novel agents including long follow-up with relevant event numbers and categorized according to the subset classification are not yet available. First analyses indicate that the prognos- tic power of IGHV mutational status is lost with these agents,37 and it would be interesting to see if the subset assignment remains a prognostic factor with these treat- ments. Furthermore, chemo-immunotherapy remains a possible standard of care for patients without high-risk markers and mutated IGHV.38 According to our data, sub- set assignment by BCR stereotype is relevant for therapy assessment. Therefore, the patients mentioned above
should be treated taking into consideration the subset assignment. Future studies will evaluate the relevance of the subset classification regarding the response to novel therapies.
Taken together, we confirmed for the first time in prospective clinical trials that subset #2 is an independent prognostic marker for shorter TTFT, TTNT and PFS in CLL, regardless of the IGHV mutational status. Therefore, patients with CLL subset #2 should be closely monitored. Given this, CLL clinical guidelines should include subset #2 also when mutated as an independent marker for high risk in patients receiving chemo-immunotherapy. Furthermore, our study showed that assignment to stereo- typed subsets may have a different impact depending on clinical stage in chemo-immunotherapy settings. Subsets #1, 2 and 8 had similar prognosis in most clinical out- comes to U-CLL. However, advanced stage CLL subsets #1, 2 and 8 had a longer PFS than U-CLL. Subset #4 was found to have a better clinical course compared to other subsets in both early and advanced stage CLL and was similar to M-CLL.
For the first time in prospective multicenter clinical tri- als, subset # 2 appeared as an independent prognostic fac- tor and subsets #1, 8 and 4 were found to have a distinc- tive clinical course and should be proposed for risk strati- fication of patients.
Funding
SJ, SS, CS, ET, JB received research support by DFG SFB1074 subproject B1 and B2, BMBF PRECISE and EU grant Fire CLL. AA, KS: were supported in part by the frame- work of action “Postdoctoral Researchers Support” of the opera- tional programme “Research Projects for Postdoctoral Researchers” implemented by the Hellenic Foundation for Research & Innovation; the project “CRIPIS II ODYSSEUS” funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) and co- financed by Greece and the European Union (European Regional Development Fund)". PG received research support by ERA- NET TRANSCAN-2 JTC 2016 #179 NOVEL.
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