Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: analysis within prospective clinical trials of the German CLL Study Group (GCLLSG)

Haematologica. 2020 Nov 1;105(11):2598-2607. doi: 10.3324/haematol.2019.231027.


Almost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinicobiological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: i) early-stage patients (watch-and-wait arm of the CLL1 trial) (n=592); ii) patients in need of treatment, enrolled in 3 phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1861). Subset #1 was associated with del(11q), higher CLL international prognostic index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (HR: 4.2, CI: 2-8.6, p<0.001), and shorter time-to-next-treatment (TTNT) in the advanced-stage cohort (HR: 2, CI: 1.2-3.3, p=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other M-CLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset # 2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients.

Trial registration: NCT00262782 NCT00281918 NCT01010061.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell* / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell* / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell* / epidemiology
  • Mutation
  • Prognosis
  • Prospective Studies
  • Retrospective Studies


  • Immunoglobulin Heavy Chains

Associated data


Grants and funding

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 framework of action “Postdoctoral Researchers Support” of the operational 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 cofinanced by Greece and the European Union (European Regional Development Fund)". PG received research support by ERANET TRANSCAN-2 JTC 2016 #179 NOVEL.