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

Sonia Jaramillo, Andreas Agathangelidis, Christof Schneider, Jasmin Bahlo, Sandra Robrecht, Eugen Tausch, Johannes Bloehdorn, Manuela Hoechstetter, Kirsten Fischer, Barbara Eichhorst, Valentin Goede, Michael Hallek, Hartmut Döhner, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos, Stephan Stilgenbauer, Sonia Jaramillo, Andreas Agathangelidis, Christof Schneider, Jasmin Bahlo, Sandra Robrecht, Eugen Tausch, Johannes Bloehdorn, Manuela Hoechstetter, Kirsten Fischer, Barbara Eichhorst, Valentin Goede, Michael Hallek, Hartmut Döhner, Richard Rosenquist, Paolo Ghia, Kostas Stamatopoulos, Stephan Stilgenbauer

Abstract

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: ClinicalTrials.gov NCT00262782 NCT00281918 NCT01010061.

Figures

Figure 1.
Figure 1.
Outcomes of early stage chronic lymphocytic leukemia (CLL) cases according to subset classification. (A) Median time-to-first-treatment (TTFT) subset #1: 33.7 months, subset #2: 65.0 months, subset #4: not reached, subset #8: 26.3 months, U-CLL: 52.2 months, M-CLL: not reached. (B) Median progression-free survival (PFS) from diagnosis subset #1: 15.9 months, subset #2: 22.8 months, subset #4: not reached, subset #8: 25.7 months, U-CLL: 28.8 months, M-CLL: 92.6 months. (C) Median overall survival (OS) from diagnosis subset #1: 112.5 months, subset #2: not reached, subset #4: not reached, subset #8: 49.0 months, U-CLL: not reached, M-CLL: not reached; Cum: cumulative.
Figure 2.
Figure 2.
Outcomes of advanced stage chronic lymphocytic leukemia (CLL) cases according to subset classification. (A) Median time-to-first-treatment (TTFT) for the subset #1: 20.6 months, subset #2: 28.5 months, subset #4: 42.8 months, subset #8: 5.5 months, U-CLL: 17.8 months, M-CLL: 36.1 months. (B) Median timeto- next-treatment (TTNT) for the subset #1: 60.2 months, subset #2: 57.3 months, subset #4: not reached, subset #8: 43.7 months, U-CLL: 47.4 months, M-CLL: not reached. (C) Median progression-free survival (PFS) for subset #1: 41.7 months, subset #2: 33.3 months, subset #4: not reached, subset #8: 26.3 months, U-CLL: 26.5 months, M-CLL: 54.7 months. (D) Median overall survival (OS) for subset #1: 67.5 months, subset #2: not reached, subset #4: not reached, subset #8: 43.3 months, U-CLL: 78.9 months, M-CLL: not reached; Cum: cumulative.
Figure 3.
Figure 3.
Outcomes of early stage chronic lymphocytic leukemia (CLL) cases according to subset #2 classification and IGHV mutation. (A) Median time-to-first-treatment (TTFT) for u-subset #2: 26.8 months, msubset #2: 65.0 months, u-HV3-21: 45.7 months, m-HV3-21: not reached, u-IGHV: 51.4 months, m-IGHV: not reached. (B) Median progression- free survival (PFS) from diagnosis for u-subset #2: 11.2 months, m-subset #2: 35.7 months, u-HV3-21: 29.8 months, m-HV3-21: not reached, u-IGHV: 28.1 months, m-IGHV: 92.6 months. (C) Median overall survival (OS) from diagnosis for u-subset #2: not reached, m-subset #2: not reached, u-HV3-21: not reached, m-HV3-21: not reached, u-IGHV: not reached, m-IGHV: not reached; Cum: cumulative.
Figure 4.
Figure 4.
Outcomes of advanced stage chronic lymphocytic leukemia (CLL) cases according to subset #2 classification and IGHV mutation. (A) Median time-to-firsttreatment (TTFT) u-subset #2: 32.9 months, m-subset #2: 16.5 months, u-HV3-21: 14.2 months, m-HV3-21: 26.8 months, u-IGHV: 18.1 months, m-IGHV: 36.3 months. (B) Median time-to-next-treatment (TTNT) u-subset #2: 49.2 months, m-subset # 2: 58.7 months, u-HV3-21: 50.6 months, m-HV3-21: not reached, u-IGHV: 47.8 months, m-IGHV: not reached. (C) Median progression-free (PFS) survival u-subset #2: 21.4 months, m-subset #2: 35.5 months, u-HV3-21: 31.4 months, m- HV3-21: 57.6 months, u-IGHV: 26.7 months, m-IGHV: 54.7 months. (D) Median overall survival (OS) from diagnosis u-subset #2: not reached, m-subset #2: not reached, u-HV3-21: not reached, m-HV3-21: not reached, u-IGHV: 77.4 months, m-IGHV: not reached; Cum: cumulative.

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