Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG)

For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ≥ 24 months. 15% of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis.

In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10⁻⁴. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors.

This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-β2m. A combination of MRD levels of >10⁻² or of MRD levels of >10⁻⁴ to <10⁻²plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970–10.347; p<0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799–11.844, p<0.0001).

The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation.

Figure 1:

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PFS high risk vs low risk

Total n=143, HR n=40, LR n=103

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PFS high risk vs low risk

Total n=143, HR n=40, LR n=103

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Figure 2:

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OS High risk vs low risk

Total n=143, HR n=40, LR n=103

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OS High risk vs low risk

Total n=143, HR n=40, LR n=103

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